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Annexin A protein family: Focusing on the occurrence, progression and treatment of cancer

Annexin A protein family: Focusing on the occurrence, progression and treatment of cancer TYPE Review PUBLISHED 03 March 2023 DOI 10.3389/fcell.2023.1141331 Annexin A protein family: Focusing on the occurrence, progression OPEN ACCESS EDITED BY Masahide Takahashi, and treatment of cancer Fujita Health University, Japan REVIEWED BY 1† 1† 3† 1 Huhu Zhang , Zhe Zhang , Tingting Guo , Guang Chen , Liang Weng, Xiangya Hospital, Central South 1 3 2 1 Guoxiang Liu , Qinghang Song , Guichun Li , Fenghua Xu , University, China 1 1 1 1 1 Motoshi Suzuki, Xiaolei Dong , Fanghao Yang , Can Cao , Di Zhong , Shuang Li , Fujita Health University, Japan 1 1 1,4 1 Ya Li , Mengjun Wang , Bing Li * and Lina Yang * *CORRESPONDENCE Lina Yang, Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China, [email protected] Department of Traditional Chinese Medicine, The People’s Hospital of Zhaoyuan City, Yantai, China, 3 4 Bing Li, Health Science Center, Qingdao University, Qingdao, China, Department of Hematology, The Affiliated [email protected] Hospital of Qingdao University, Qingdao, China These authors have contributed equally to this work SPECIALTY SECTION The annexin A (ANXA) protein family is a well-known tissue-specific multigene This article was submitted to Cancer Cell Biology, 2+ family that encodes Ca phospholipid-binding proteins. A considerable amount a section of the journal of literature is available on the abnormal expression of ANXA proteins in various Frontiers in Cell and Developmental Biology malignant diseases, including cancer, atherosclerosis and diabetes. As critical regulatory molecules in cancer, ANXA proteins play an essential role in cancer RECEIVED 10 January 2023 ACCEPTED 23 February 2023 progression, proliferation, invasion and metastasis. Recent studies about their PUBLISHED 03 March 2023 structure, biological properties and functions in different types of cancers are CITATION briefly summarised in this review. We further discuss the use of ANXA as new class Zhang H, Zhang Z, Guo T, Chen G, Liu G, of targets in the clinical diagnosis and treatment of cancer. Song Q, Li G, Xu F, Dong X, Yang F, Cao C, Zhong D, Li S, Li Y, Wang M, Li B and Yang L (2023), Annexin A protein family: KEYWORDS Focusing on the occurrence, progression annexin a protein family, structure, cancer progression, biomarker, treatment, inhibitor and treatment of cancer. Front. Cell Dev. Biol. 11:1141331. doi: 10.3389/fcell.2023.1141331 1 Introduction COPYRIGHT © 2023 Zhang, Zhang, Guo, Chen, Liu, Song, Li, Xu, Dong, Yang, Cao, Zhong, Li, ANXs are proteins that are encoded by a highly conserved multigene family and are Li, Wang, Li and Yang. This is an open- widely found in animals, plants and protists (Geisow et al., 1987). In 1978, ANXs were given access article distributed under the terms of the Creative Commons Attribution different names based on their different biochemical properties and were divided into five License (CC BY). The use, distribution or categories: A, B, C, D and E . The ANXA protein family in humans contains 12 species, reproduction in other forums is ANXA1– ANXA11 and ANXA13 (Croissant et al., 2021), all of which are small soluble permitted, provided the original author(s) and the copyright owner(s) are credited proteins. They are uniquely expressed in specific tissues; for example, ANXA3 induces and that the original publication in this human umbilical vein endothelial cell migration and tubulogenesis (Park et al., 2005), journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Abbreviations: ALL, Acute lymphoblastic leukemia; ANXA, Annexin A; ANXs, Annexins; ATP, Adenosine triphosphate; Bcl-2, B-cell lymphoma-2; EGFR, Epidermal growth factor receptor; EMT, Epithelial- mesenchymal transition; ERK, Extracellular signal-regulated kinase; FHIT, Fragile histidine triad; GBM, Glioblastoma multiforme; HIF, Hypoxia Inducible Factor; HepG2, Human hepatocellular carcinomas; HPV, Human papillomavirus; IL-6, Interleukin-6; JAK2, Janus-family tyrosine kinase 2; MAPK, Mitogen- activated protein kinase; MEK, MAPK/ERK kinase; MMPs, Matrix metalloproteinases; MYC, Myelocytomatosis oncogene cellular homolog; PI3K, Phosphoinositide 3 kinase; AKT, AKT8 virus oncogene cellular homolog; RRM2, Ribonucleotide reductase M2 subunit; STAT3, Signal transducer and activator of transcription 3; TAGLN, Transgelin; NF-κB, Nuclear factor κ B; TFP, Trifluoperazine; NBC, Triple negative breast cancer; TSG, Tumor necrosis factor-stimulated gene; VEGF, Vascular endothelial growth factor. Frontiers in Cell and Developmental Biology 01 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 2+12 ANXA4 is specifically expressed in cochlear and vestibular hair cells in the presence of Ca . This binding is, however, reversible. The 2+ (Li et al., 2021a), while, while ANXA5 participates in the activation removal of Ca reveals the N-terminus hidden in the centre of the of immune T cells (Hu et al., 2020). C-terminus (Rintala-Dempsey et al., 2008). The coordination of Tissue-specific ANXA proteins exist in different cancers, ANXA to calcium ions requires the involvement of water molecules including hepatocellular carcinoma (Dong et al., 2014), gastric to ensure the two ligands remain stable (Rintala-Dempsey et al., 2+ cancer (Wang et al., 2013), breast cancer (Sharma et al., 2012), 2008). Besides Ca , the N-terminal of ANXA has multiple binding ovarian cancer (Manai et al., 2020) and lung cancer (Zhou et al., sites, including interacting partners. For instance, the S100 family, 2+ 2021a). In addition, numerous studies have indicated that ANXA is which comprises electron chiral Ca binding proteins (Bharadwaj expressed irregularly in disparate cancers. For instance, ANXA2 is et al., 2013), functions to regulate cell proliferation, membrane elevated in breast cancer and stimulates fibrinolytic enzyme transport and calcium homeostasis (Donato et al., 2013). The production, which results in angiogenesis and metastasis. In S100–ANXA interaction has been shown to play a role in contrast, ANXA6 expression is downregulated in primary gastric membrane fusion by linking an S100 protein to two ANXA cancer tissues and directly inactivates the Ras/MAPK signalling proteins on a phospholipid membrane (Rintala-Dempsey et al., pathway (Wang et al., 2013) to inhibit gastric cancer growth. 2008). Because of these different sequences in the N-terminal, Aside from ANXA2 and ANXA6, other ANXA family proteins ANXA members display distinctive properties and diverse can be used as markers of tumour occurrence and development as functions. ANXA3 has a strong binding ability to phospholipids they affect a variety of signal pathways, such as cancer cell invasion, via the substitution of classical Trp-5 with alanine (Hofmann et al., migration, apoptosis and autophagy. Furthermore, some ANXA 2000), while ANXA1 phosphorylates diverse protein residues via its proteins cause drug resistance and are thus potential therapeutic N-terminal kinases characteristic (Rosengarth et al., 2001). targets for tumours. A discussion of ANXA and their inhibitors may Generally, these subtle changes do not affect their basic structure provide better strategies for the early diagnosis, clinical treatment of ANXA proteins. and prognosis of cancer. 3 The role of ANXA protein family in 2 The molecular structure of ANXA cancer progression protein family 3.1 The role of ANXA protein family in cell The ANXA protein family contains structural and biological proliferation features. Structurally, the C-terminal region is conserved, with most membrane-bound proteins consisting of four fragments of around The ANXA protein family can inhibit tumour proliferation by 70 amino acids each, which are internally and intrinsically affecting cell membrane and cytoskeleton formation. In homologous to the membrane-bound proteins. An exception is nasopharyngeal carcinoma, decreased ANXA1 leads to the the ANXA6 protein, which has eight core fragments that form a upregulation of S100A9/vimentin, which increases tumour high alpha helix and a closely spaced disc-like structure (Figure 1) invasion by regulating the function of the cytoskeletal proteins (Li et al., 2022). (Xiao et al., 2017). When ANXA2 expression is effectively The biological functions of the superfamily members differ inhibited, the growth and motility of both the human colorectal depending on the N-terminal domain, which is where most of cancer cell line CACO2 and human hepatocellular carcinoma cell their post-translational modifications occur (Wang et al., 2019). line SMMC7721 are significantly reduced, and the motility- In biology, the ANXA protein family is a group of calcium- associated microstructures, such as pseudopods and filamentous dependent phospholipid-binding proteins, so called because they pseudopods, as well as the polymerisation of microfilaments and only bind to phospholipid membranes with conformational changes microtubules, are significantly inhibited (He et al., 2019). FIGURE 1 Schematic diagram of ANXA protein structure. ANXA consists of two regions, one of which is the C-terminus, the characteristic highly conserved core structural domain that usually consists of four repetitive sequences (A), while ANXA6 has eight repetitive sequences (B), each of which contains a calcium-binding motif. Another region is the N-terminal, where the amino acid arrangement order and length of each ANXA varies. Frontiers in Cell and Developmental Biology 02 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 FIGURE 2 Signaling pathways of ANXA protein family regulating tumor cell proliferation. Except for ANXA6, the rest of the ANXA protein family was overexpressed and promoted the proliferation of tumor cells. The members of the ANXA protein family play the opposing roles of promoting and inhibiting tumour proliferation through their participation in or activation of signalling pathways. The exceptions are ANXA5, ANXA6, ANXA10 and ANXA11, which play roles in several tumour types, while other ANXA members promote tumour cell proliferation (Grewal et al., 2010; Li et al., 2018a; Liu et al., 2019; Liu et al., 2020; Liu et al., 2021a; Zhou et al., 2021a; Zhou et al., 2021b; Gu et al., 2021; Huang et al., 2021; Ju et al., 2021; Wei and Zhu, 2021). In hepatocellular carcinoma, the overexpression of ANXA2 (Zhang et al., 2013), ANXA3 (Guo et al., 2021a), ANXA4 (Liu et al., 2017), ANXA5 (Sun et al., 2018) and ANXA11 (Liu et al., 2019) promotes proliferation because ANXA2–ANXA5 affect Wnt/β-catenin, MEK-ERK, PI3K/AKT-HIF-α and other pathways. It is worth mentioning that ANXA4 may be a key factor in hepatocellular carcinoma FIGURE 3 tumorigenesis (Liu et al., 2017), as downregulating Regulation of the ANXA protein family in the cell cycle. Members ANXA4 expression can inhibit hepatocellular carcinoma of the ANXA protein family promotes tumor cell cycle progression. proliferation and tumorigenesis in vitro and in vivo. Similarly, in lung cancer, the overexpression of ANXA8 activates the EGFR/ AKT/mTOR signalling pathway to promote proliferation (Zhou et al., 2021a), while in thyroid cancer, increased ANXA1 promotes studies have demonstrated that ANXA proteins are involved in the thyroid cancer proliferation by mediating IL-6/JAK2/STAT3 (Zhao regulation of tumour proliferation, and these studies may provide new ideas and directions for research on tumour prevention and et al., 2021). In contrast, the overexpression of the ANXA10 gene targeted therapies depending on the understanding of their role in significantly inhibits HepG2 cell proliferation in vitro, and its the pathogenesis of malignant tumours (Figure 2). downregulation inhibits papillary thyroid cancer proliferation; it acts directly on TSG101 by inactivating the MAPK/ERK signalling pathway (Wei and Zhu, 2021). In gastric cancer, different ANXA 3.2 The role of the ANXA protein family in the proteins show either proliferation promoting or inhibiting effects. cell cycle For instance, ANXA2 directs the interaction of the protein YES1 and involves the EphA2-YES1-ANXA2 pathway (Mao et al., 2021), The cell cycle is a complex process involving many regulatory which promotes gastric cancer progression and metastasis, while ANXA6 (Wang et al., 2013) suppresses gastric cancer progression by proteins that guide cells through specific sequences of events that inhibiting Ras/MAPK signalling. Moreover, increased culminate in the production of two daughter cells (Schafer, 1998). ANXA5 inhibits cervical cancer proliferation by regulating the The ANXA protein family plays critical roles in cell cycle regulation expression of Bcl-2 and Bax (Li et al., 2018a). A large number of in a complex manner (Figure 3). ANXA1 promotes G /G phase 0 1 Frontiers in Cell and Developmental Biology 03 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 cyclic arrest in leukaemic K562 and U937 cells and promotes apoptosis in leukaemia (Tsai et al., 2013; Sabran et al., 2019). In one study, silencing ANXA1 in hypopharyngeal carcinoma not only significantly decreased the proportion of G /G phase cells, but 0 1 significantly increased the proportion of S phase cells, which enhanced cell activity and promoted cell cycle progression (Li et al., 2021b). ANXA2 regulates c-Myc expression by binding to the 5′UTR of 2+ its mRNA in a Ca -dependent manner at the two pseudoknots of the internal ribosome entry site. Thus, downstream cyclinD1, a cell cycle regulator protein, is affected, which leads to cell proliferation and a high proportion of S-phase cells (Strand et al., 2021; Sun and Zhang, 2021). The downregulation of ANXA2 stalls cells in the G phase or S-G /M phase in gastric cancer (Sun et al., 2013) and glioblastoma multiforme (Maule et al., 2016), respectively. A study FIGURE 4 showed that the ANXA3 silencing group had a lower proliferation Regulation of ANXA protein family in apoptosis and autophagy. rate in breast cancer and a higher cell ratio in the G /G compared to 0 1 ANXA1 promoted cellular autophagy and ANXA6 inhibited cellular the control group (Li et al., 2018b). In oncogenic human autophagy. In terms of apoptosis, except for ANXA10, which had a dual role, the rest of the ANXA protein family inhibited tumor cell papillomavirus-positive non-small cell lung cancer, ANXA4 is apoptosis. mediated by HPV16E7 and HPV16E6/E7, promotes cell proliferation and regulates the cell cycle and mitosis (Ciotti et al., 2009). Meanwhile, the combination of epigallocatechin gallate and quercetin enhance ANXA5 to effectively inhibit colorectal cancer arrest at the G stage (Xue et al., 2009; Al-Ghamdi et al., 2021). tumour cell line 168FARN, the knockdown of ANXA1 inhibited the Furthermore, the overexpression of ANXA9 has been found to invasion and metastasis of breast cancer (Tu et al., 2017), with less increase the migration of gastric cancer and form larger and expression of epithelial–mesenchymal transition (EMT) markers, more cell clones, which decrease in the G phase and increase in wave proteins and myosin light-chain kinase. the S and G phases (Zhou et al., 2021b). ANXA10 is frequently In addition to ANXA1, the ANXA proteins ANXA2, found to be highly expressed in human oral cancer, and this high ANXA9 and ANXA10 are associated with tumour cell adhesion, expression may promote G phase cell cycle progression by invasion and metastasis (Xu et al., 2015; Yu et al., 2018; Sun et al., activating the ERK/MAPK signalling pathway, which in turn 2019). Once ANXA2 binds to fibrinogen and tissue-type fibrinogen results in the reduced expression of member-dependent kinases activators, it can activate metalloproteinase (MMPs), which will in of cell cycle proteins (Shimizu et al., 2012). To date, most studies turn disrupt the integrity of the extracellular matrix, resulting in have described ANXA protein family members as promoting the cell tumour invasion and metastasis (Xu et al., 2015). Accordingly, in cycle in cancer, although little is known about the associated gastric cancer HGC-27 cells, the inhibition of ANXA2 was found to mechanisms. Future investigations regarding the impact of significantly reduce the migration and secretion of MMPs and ANXA proteins on the regulation of the cell cycle would inhibit cancer invasion and metastasis (Han et al., 2017). certainly inspire more exploration of their biological effects. Similarly, Shi et al. (2020) Found that TAGLN2–ANXA2 interaction induces invasion and metastasis in hepatocellular carcinoma. In oesophageal cancer, the overexpression 3.3 The role of ANXA protein family in of ANXA2 promotes ESCC cell invasion in vitro and metastasis in invasion and metastasis vivo through the activation of the MYC-HIF-1α-VEGF cascade (Ma et al., 2018). More meaningfully, some clinical studies have shown Invasion describes the occupation of adjacent normal tissues by the relationship between the expression levels of ANXA2 and the cancer cells after leaving the tumour parent body, and metastasis is invasion and metastasis of prostate cancer. ANXA2 can therefore be the spread of tumour cells from the primary site to distant organs used as a prognostic biomarker for aggressive prostate cancer (Tan (Hart and Fidler, 1980). Increasing evidence has elucidated the et al., 2021). ANXA9 expression levels have been correlated with the critical role of the ANXA protein family in cancer invasion and depth of invasion and lymphatic metastasis of colorectal cancer (Yu metastasis (Xu et al., 2015). Proteomics technology has revealed that et al., 2018). Patients with colorectal cancer and positive ANXA1 mainly regulates the processes related to tumour cell ANXA9 expression were found to have a poorer prognosis, skeletal remodelling and immune responses, thus affecting the which indicates that ANXA9 could be an independent risk factor invasive migration of cancer cells (Tu et al., 2017). Of particular for survival. In extrahepatic cholangiocarcinoma, ANXA10 can interest, ANXA1 plays dual roles with regard to invasion and induce tumour proliferation, EMT facilitation and tumour metastasis among different tumour cells (Liu et al., 2014; Swa metastasis (Sun et al., 2019). A large number of preclinical and et al., 2015). A study showed that the inhibition of ANXA1 in clinical studies have demonstrated that most ANXAs exhibit nasopharyngeal carcinoma increased the trauma-healing ability of obviously invasive and metastatic properties. This may provide the cells, and the activation of the ANXA1 gene decreased the an explanation for cancer survival via the broken host immune trauma-healing rate by 70%. Conversely, in the mouse mammary defence and distant cancer growth. Accordingly, inhibiting Frontiers in Cell and Developmental Biology 04 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 ANXA-associated targets may offer new approaches to mitigate 3.6 Summary cancer metastasis and improve patient survival. There is a growing consensus that ANXA proteins play a role in cancer and that the ANXA protein family is involved in tumour cell 3.4 The role of ANXA protein family in cell proliferation, cell cycle regulation, invasive metastasis, apoptosis and apoptosis autophagy in numerous cancers (Table 1). The consensus thus far is that ANXA proteins in tumour cells may be mediators of Apoptosisisanordered andcoordinated cellular process that tumorigenesis, proliferation and metastasis, that is, ‘angels of life’ occurs under physiological and pathological conditions (Wong, for some tumours and ‘demons of death’ for others. This summary 2011). Evidence suggests that the ANXA protein family has a dual therefore provides an exciting opportunity for the treatment of role in tumour cell apoptosis, namely, anti-apoptotic and pro- various cancers. apoptotic activity (Figure 4)(Huang et al., 2008; Liu et al., 2012; Wei and Zhu, 2021). ANXA2 silencing significantly decreases the mRNA and protein expression of Bcl-1 and promotes apoptosis 4 The role of ANXA protein family as a in osteosarcoma through the AKT signalling pathway and, in biomarker in cancer diagnosis lung cancer, by the activity of p53 (Huang et al., 2008; Pan et al., 2018). The upregulation of ANXA4 enhances its interaction with Previous studies have confirmed that the ANXA protein family NF-κB p50, activates the NF-κB signalling pathway, promotes is significantly associated with tumour development and can be used cell cycle progression and inhibits apoptosis (Liu et al., 2020). as a biomarker for cancer diagnoses. Through an in vitro study of ANXA7 knockdown reduces mRNA, the protein levels of LEPR 268 lung cancer patients, Rong et al. (2014) found that the and the intracellular signalling pathways of the ERK1/2, JAk2/ expression of ANXA1 in the cancer tissues and serum of lung STAT3 and PI3K-related proteins, thereby promoting apoptosis cancer patients was significantly higher than normal. Elevated in hepatocellular carcinoma (Huang et al., 2021). While serum ANXA1 was noted to closely correlate with the clinical ANXA10 plays a diverse role in different tumours, in manifestations in these patients. A large number of studies have hepatocellular carcinoma, the overexpression of also demonstrated that, in addition to lung cancer, ANXA10 significantly promotes apoptosis. Conversely, in ANXA1 expression is upregulated in a variety of cancers, papillary thyroid cancer, the knockdown of including hepatocellular carcinoma (Zhuang et al., 2019), ANXA10 promotes apoptosis by inhibiting the MAPK/ERK colorectal cancer (Liang and Li, 2021), pancreatic cancer (Novizio signalling pathway through the downregulation of TSG101 et al., 2021), melanoma (Delorme et al., 2021), and endometrial (Liu et al., 2012; Wei and Zhu, 2021). Although studies have cancers (Aboulouard et al., 2021). By constructing a risk model, shown the functional diversity of ANXA proteins in apoptosis, a Liang and Li (2021) found that ANXA1 expression levels were deeper understanding of ANXA would make an important associated with the level of immune infiltration in colorectal contribution to the field of cancer treatment by enhancing cancer. ANXA1 could therefore be used as a biomarker for apoptosis. colorectal cancer diagnoses and as an independent prognostic indicator for patients. Further, other ANXA protein family members have shown abnormal expression in many cancers. 3.5 The role of ANXA protein family in For example, the high expression of ANXA3 has been closely autophagy associated with upper tract urothelial carcinoma (Lu et al., 2014; Liu et al., 2021a), and patients with higher ANXA3 have been Autophagy is a catabolic process involving the lysosomal found to have a higher rate of postoperative recurrence (Liu renewal of proteins and organelles to maintain cellular et al., 2021a). Additionally, ANXA5 is significantly expressed in homeostasis and reduce metabolic stress (Lozy and Karantza, non-papillary bladder cancer (Wu et al., 2021), and lung cancer 2012). Autophagy is one of the most important programmed cell patients with high Cir–ANXA seven expression tend to have a death mechanisms, and the ANXA protein family has a poorer prognosis (Wang, 2021). Meanwhile, considerable impact on autophagy (Figure 4). ANXA ANXA8 expression has been noted as significantly more regulates the formation of vesicular lipid membranes and enhanced in ovarian malignant tissues than benign tumours promotes cellular cytokinesis (Xi et al., 2020). Respective and normal ovarian tissues and is associated with a poor members of the ANXA protein family have different effects prognosis (Gou et al., 2019), and ANXA10 has recently been on autophagy in various cancers. ANXA1 inhibits cellular shown to be a prognostic biomarker for papillary thyroid cancer autophagy and promotes tumour invasion and metastasis as well as a potential therapeutic target (Liu et al., 2021b). through PI3K/AKT signalling activation in nasopharyngeal Similarly, ANXA13 expression is upregulated in colorectal carcinoma (Zhu et al., 2018). In contrast, autophagy induced cancer and promotes the invasion of cancer (Jiang et al., by ANXA6 in cervical cancer may be related to the inhibition of 2017). This suggests that ANXA has already been used as a the PI3K-AKT and ERK signalling pathways of mTOR diagnostic biomarker in a variety of cancers. More specifically, activation (Sun et al., 2020). Elucidating the molecular due to its unique structure, ANXA6 may act as either a tumour mechanism of ANXA in autophagy may assist in identifying suppressor or a tumour promoter depending on the type and new therapeutic targets and developing novel treatment stage of cancer. ANXA6 expression has been reported to strategies. be upregulated in cancers such as pancreatic cancer Frontiers in Cell and Developmental Biology 05 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 TABLE 1 The role of ANXA family proteins in cancer progression. Member Cancer type Type cell Expression Effect Reference patterns ANXA1 Thyroid carcinoma TPC-1 mRNA and protein High ANXA1 expression promotes Zhao et al., (2021) the proliferation of thyroid cancer cells Nasopharyngeal 5–8F 6–10B Protein ANXA1 promotes migration, Xiao et al., (2017), Liu et al., carcinoma invasion, and metastasis of (2014) Zhu et al., (2018) nasopharyngeal carcinoma cells, and autophagy activation inhibits metastasis of nasopharyngeal carcinoma with high ANXA1 expression Hypopharyngeal FaDu mRNA and protein Silencing ANXA1 inhibited apoptosis Li et al., (2021b) carcinoma and increased the proportion of S- phase cells Leukemic K562 U937 mRNA and protein ANXA1 induces apoptosis and G /G Sabran et al., (2019) 0 1 phase cycle arrest in K562 and U937 cells Breast cancer 168FARN Protein The expression of vimentin and Tsai et al., (2013) myosin light chain kinase decreased after inhibiting ANXA1 ANXA2 Colorectal Cancer ATCC mRNA and protein Significant reduction in growth and He et al., (2019) motility of colorectal cancer when ANXA2 expression was inhibited Inhibition of ANXA2 Gastric carcinoma HGC-27; MKN45 Protein significantly reduces cell Han et al., (2017); Mao et al., proliferation, migration and matrix (2021) metalloproteinase secretion Glioblastoma Primary GBM cells Protein ANXA2 knockdown stalled the cell Maule et al., (2016) cycle in S-G2/M phase Esophageal cancer KYSE Protein Overexpression of ANXA2 activates Ma et al. (2018) the MYC-HIF1A-VEGF cascade through Prostate cancer Tissue Protein High expression of ANXA2 promotes Tan et al. (2021) invasion and metastasis Hepatocellular carcinoma Huh-7 QGY-7703; mRNA and protein TAGLN2-Annexin A2 interactions He et al., (2019), Zhang et al., HepG2; SMMC-7721 induce invasion and metastasis, (2013), Shi et al., (2020) shRNA-mediated ANXA2 silences inhibit proliferation, invasion, migration, and tumorigenic potential of hepatoma Lung cancer BE1 Protein Knockdown of ANXA2 promotes Huang et al., (2008) apoptosis and inhibits cell proliferation in lung cancer cells Osteosarcoma U-2 OS mRNA and protein ANXA2 promotes OS cell Pan et al., (2018) proliferation, migration, and invasion, and inhibits apoptosis ANXA3 Hepatocellular carcinoma HepG2 Protein ANXA3 promotes proliferation and Guo et al., (2021a) angiogenesis of hepatocellular carcinoma Breast carcinoma MDA-MB-231 Protein After ANXA3 silencing, the Li et al., (2018b) proportion of G0 / G1 phase cells increased and cell proliferation rate decreased ANXA4 ovarian clear cell ES-2 RMG-1 Protein ANXA4 promotes cell proliferation Liu et al., (2020) carcinoma and inhibits cell apoptosis (Continued on following page) Frontiers in Cell and Developmental Biology 06 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 TABLE 1 (Continued) The role of ANXA family proteins in cancer progression. Member Cancer type Type cell Expression Effect Reference patterns Hepatocellular carcinoma SMMC-7721 mRNA and protein Down-regulation of ANXA4 Liu et al., (2017) expression inhibits hepatocellular carcinoma cell proliferation and tumorigenesis Lung cancer A549 Protein ANXA4 is mediated by HPV16E7 Ciotti et al., (2009) and HPV16E6/E7, promotes cell proliferation, and regulates cell cycle and mitosis ANXA5 Cervical carcinoma HeLa Protein Increased ANXA5 expression Li et al., (2018a) inhibits the proliferation and metastasis of cervical cancer cells ANXA5 Hepatocarcinoma Tissue Protein overexpression promotes clinical Sun et al., (2018) progression and lymphatic metastasis in hepatocellular carcinoma Colorectal cancer ATCC mRNA and protein In colorectal cancer, ANXA5 is Xue et al., (2009) inhibited, resulting in G phase arrest ANXA6 Gastric cancer MKN28 mRNA and protein ANXA6 plays an oncogenic role in Wang et al., (2013) gastric cancer cells Cervical cancer HeLa Protein In cervical cancer, ANXA6 induces Sun et al., (2020) autophagy ANXA7 Hepatocellular carcinoma Hca-F Hca-P mRNA and protein ANXA7 promotes the proliferation, Huang et al. (2021) migration and invasion of lymphatic metastatic cells from hepatocellular carcinoma and inhibits their apoptosis. ANXA8 Lung cancer A549 Protein Overexpressed ANXA8 promotes the Zhou et al. (2021a) proliferation of lung cancer cells ANXA9 Gastric cancer HGC-27 mRNA and protein Overexpression of ANXA9 increased Zhou et al., (2021b) the number of gastric cancer cells migrating Colorectal cancer Caco-2; HCT116; SW620 mRNA and protein The expression level is correlated Yu et al., (2018) with the invasion depth and lymphatic metastasis of colorectal cancer ANXA10 Thyroid carcinoma BCPAP; TPC-1; KTC-1 mRNA and protein ANXA10 inhibits PTC cell Wei and Zhu, (2021) proliferation and promotes PTC cell apoptosis by binding with TSG101 Hepatocellular carcinoma HepG2 mRNA and protein Overexpression of ANXA10 gene Liu et al., (2012) inhibits proliferation and promotes apoptosis of HepG2 cells in vitro Oral cancer HSC-2; HSC-3; KON mRNA and protein ANXA10 promotes G phase cell Shimizu et al., (2012) cycle progression in oral cancer Extrahepatic QBC-939; FRH-0201 mRNA and protein Induction of proliferation, EMT Sun et al., (2019) cholangiocarcinoma facilitation and tumor metastasis ANXA11 Hepatocellular carcinoma Huh7; HCCLM3 mRNA and protein ANXA11 promotes metastasis and Liu et al. (2019) the EMT pathway in hepatocellular carcinoma (Leca et al., 2016), ovarian cancer (Noreen et al., 2020), female (TNBC) (Korolkova et al., 2020). Such studies offer some thyroid cancer (Lee et al., 2018), and esophageal important insights for the use of ANXA6 as a biomarker for adenocarcinoma (Zaidi et al., 2014), but downregulated in the progression of these cancers (Table 2). In addition, hepatocellular carcinoma (Meier et al., 2016), gastric cancer ANXA1 expression is significantly increased in small cell lung (Wang et al., 2013), breast cancer (Sakwe et al., 2011), cervical cancer patients with bone metastases than without bone cancer (Lomnytska et al., 2010) and triple negative breast cancer metastases (Chen et al., 2021). The elevation of ANXA1 has Frontiers in Cell and Developmental Biology 07 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 TABLE 2 The role of ANXA as a biomarker in cancer diagnosis. Member Cancer type ANXA protein expression Ref ANXA1 Hepatocellular carcinoma High expression Zhuang et al. (2019) Colorectal cancer High expression Liang and Li (2021) Pancreatic cancer High expression Novizio et al. (2021) Melanoma High expression Delorme et al. (2021) Endometrial cancer High expression Aboulouard et al. (2021) ANXA2 Lung cancer High expression Leca et al. (2016) ANXA3 Upper tract urothelial carcinoma High expression Lu et al. (2014), Liu et al. (2021a) ANXA5 Non-papillary bladder cancer High expression Wu et al. (2021) ANXA6 Pancreatic cancer High expression Leca et al. (2016) Ovarian cancer High expression Noreen et al. (2020) Female thyroid cancer High expression Lee et al. (2018) Esophageal adenocarcinoma High expression Zaidi et al. (2014) Hepatocellular carcinoma Low expression Meier et al. (2016) Gastric cancer Low expression Wang et al. (2013) Breast cancer Low expression Sakwe et al. (2011) Cervical cancer Low expression Lomnytska et al. (2010) Triple-negative breast cancer Low expression Korolkova et al. (2020) ANXA7 Lung cancer High expression Wang (2021) ANXA8 Ovarian cancer High expression Gou et al. (2019) ANXA10 Papillary thyroid cancer High expression Liu et al. (2021b) ANXA13 Colorectal cancer High expression Jiang et al. (2017) been detected in colorectal cancer patients with micro-metastases cancer (Gaudio et al., 2013; Wei et al., 2015; Gaudio et al., 2016). in the anterior lymph nodes than in matched individuals with However, ANXA4 can bind to the N-terminal part of the Fhit protein, a normal lymph nodes (He et al., 2010). ANXA3 expression was tumour suppressor gene, to form an ANXA4–Fhit complex, which also found to be higher in lung cancer patients with lymph node specifically prevents cytoplasmic translocation and generates drug metastases than those without metastases. Accumulating resistance (Huebner and Croce, 2001; Gaudio et al., 2013; Wei et al., evidence thus suggests that AXNA may be used as a potential 2015). Not only is the Fhit protein closely associated with ANXA4 and biomarker for cancer metastasis (Liu et al., 2021a). drug resistance, but also ATP7A. Toosendanin targets ANXA4/ATP7A to reduce the binding of ANXA4 to ATP7A and to mediate the sensitisation of non-small cell lung cancer to cisplatin (Zheng et al., 5 The role of ANXA protein family in 2018). Additionally, a vitro drug sensitivity assay demonstrated that the cancer treatment overexpression of ANXA3 significantly enhanced the resistance of hepatocellular carcinoma cells to cisplatin (Tong et al., 2015; Liu 5.1 Role of ANXA protein family in therapy et al., 2021a), 5-fluorouracil (Pan et al., 2015; Tong et al., 2015; Liu resistance et al., 2021a) and adriamycin (Liu et al., 2021a). A previous study found that the secretion of ANXA6-containing exosomes promoted paclitaxel Therapy resistance is one of the fundamental reasons for cancer resistance in breast cancer cells as well as cancer progression in a YAP1- progression. It is primarily driven by tumour cells’ intrinsic dependent manner (Guo et al., 2021b). At thesametime, reduced mechanisms. Previous studies have shown that ANXA promotes ANXA6 expression has been shown to sensitise TNBC cells to therapy resistance to a large number of drugs, which suggests that tyrosinase inhibitors (Korolkova et al., 2020), and Hsa-miR-105- ANXA plays an important role in treatment resistance. For example, 1 expression can be downregulated in cisplatin-resistant ovarian ANXA4 was found to be overexpressed in paclitaxel-resistant lung cancer cells by targeting ANXA9 (Kou et al., 2021). The cancer (Wei et al., 2012; Matsuzaki et al., 2014; Wei et al., 2015; Yao aforementioned information reveals a possible mechanism by which et al., 2016). In normal conditions, paclitaxel induces the translocation tumour cells become resistant to some anticancer drugs by affecting of ANXA4 to the cytoplasmic membrane and promotes apoptosis in ANXA proteins. Frontiers in Cell and Developmental Biology 08 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 TABLE 3 Inhibitors of ANXA family protein. Member Inhibitors Inhibitor Effect Ref type ANXA1 N-t-Boc-Met-Leu-Phe(BOC-1) Compound Binds competitively to FRP2 receptors Liu et al. (2015), Vago et al. (2016), Bai et al. (2020) ANXA2 RatRib120 Nucleases Target ANXA2 mRNA Aareskjold et al. (2019) 2-[5-(4,6-dimethyl-pyrimidin-2-ylsulfanylmethyl)-4-furan-2- Compound Acts on the N-terminal of ANXA2 to inhibit Reddy et al. (2014) ylmethyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-substituted (R)- the inhibitor compound of ANXA2 bound to acetamide analogues and 3,4,5-trisubstituted-1,2,4-triazole S100A10 and inhibits ANXA2 itself analogues 2+ ANXA5 Benzothiazolecipine K201 Compound Binds to ANXA5 and inhibits its Ca channel Kaneko et al. (1997), activity Gerke and Moss (2002) 2+ La Cation block the synexin channel of ANXA5 Rojas et al. (1990) 2+ ANXA7 La Cation block the synexin channel of ANXA7 Burns et al. (1989) 2+ Cd (>10 nM) Cation block the synexin channel of ANXA7 Pollard and Rojas (1988) Nifedipine (>300 nM) Compound block the synexin channel of ANXA7 Pollard and Rojas (1988) ANXA8 all-trans-retonoic acid Compound Down-regulation of highly expressed Chang et al. (1992) ANXA8 in acute promyelocytic leukemia patients Pan-inhibitors Derivatives of phenothiazine, especially trifluoperazine (TFP) Compound Inhibits the repair function of cell membrane or Heitmann et al. (2021) of ANXA plasma membrane by impairing the function of ANXA Besides the traditional drugs mentioned above, some novel ANXA sheds light on the utilisation of ANXA against drug targeted drugs have been found to produce resistance by affecting resistance and potential improvements in treatment efficacy. ANXA proteins. Xiong et al. noted that upregulation of the ribonucleotide reductase M2 subunit (RRM2) causes resistance to sunitinib in renal cancer cells because it 5.2 Role of ANXA protein family in stabilises ANXA1 and activates the AKT pathway modulation of therapy efficiency independently of its nucleotide reductase activity (Xiong et al., 2021). Spijkers-Hagelstein et al. found that As previously discussed, the ANXA protein family plays critical role ANXA2 was associated with glucocorticoid resistance in in the development of cancer, so ANXA proteins have become viable children with acute lymphoblastic leukaemia (ALL). The new targets for cancer treatment. Natural compounds are one of the downregulation of ANXA2 expression significantly increased directions that may be used to effect the use of ANXA2 in treatment. the sensitivity of ALL cells to glucocorticoids and prednisolone, For instance, the ginsenosides Rg5 and Rk1 can specifically bind to and when ANXA2 was overexpressed in ALL cells, Src kinase ANXA2. This interaction can inhibit NF-κB activity, downregulate activity was enhanced, which resulted in glucocorticoid apoptosis inhibitory proteins, activate caspases and promote apoptosis resistance. Meanwhile, the downregulation of (Wang et al., 2018). Picrasidine, a plant alkaloid purified from the ANXA2 blocked this process, leading to increased sensitivity traditional Chinese medicine bitter ginseng, has been shown to achieve to prednisolone and thus improved therapeutic efficacy. anti-tumour activity by targeting ANXA2 (Wang et al., 2017), and cicer Recently, ANXA2 has also been reported as a drug arietinum lectin inhibits the EGFR -mediated signalling pathway by resistance-associated protein in ovarian cancer (Cruz et al., blocking the binding of ANXA2 and galactose lectin-3, with apoptosis 2017). Furthermore, the knockdown of ANXA3 has been as a consequence, and inhibiting cancer proliferation and migration found to inhibit the resistance of hepatocellular carcinoma (Shetty et al., 2016). A researcher designed a cationic lipid-directed cells to sorafenib (Tong et al., 2018). The mechanism nanoparticle, which is essentially an ANXA2 shRNA carrier, and found involved the overexpression of ANXA3 in sorafenib-resistant that it can suppress tumour growth by silencing ANXA2 (Andey et al., hepatocellular carcinoma cells, which inhibited PKCd/p38- 2014). It has also been proposed that CBP12, a colorectal cancer binding associated apoptosis to promote cell survival. ANXA3 may peptide, can target ANXA2 with specificaffinity and thus has the therefore be important in the development of multidrug potential to become a novel targeted drug (Li et al., 2021c). In the resistance in hepatocellular carcinoma patients. Although the meantime, Du et al. found that ANXA3 and HIF-1α act together to mechanisms remain unclear, the anti-resistance function of promote colon carcinogenesis, while HIF-1α siRNA can inhibit the Frontiers in Cell and Developmental Biology 09 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 expression of HIF-1α and ANXA3 in transplantation tumour tissues affects the membrane-forming ability of ANXA and, to some (Du et al., 2020), Liu et al. demonstrated that miR-1253 upregulates the extent, impairs ANXA proteins from binding to membrane expression of the pro-apoptosis-related proteins Bax and caspase-3 and patches (Table 3)(Heitmann et al., 2021). Not only inhibitors, downregulates the expression of the anti-apoptosis-related protein but also their functions need deeper investigation. It remains an Bcl2 via the degradation of ANXA3 as its target, thereby promoting open question whether inhibitors are a potential target for cancer the apoptosis of cancer cells (Liu et al., 2021c). treatment and further, how to transferthisknowledge to clinical To date, a negligible number of studies addressing this area of application. research have been published. Future research involving drugs that target ANXA will undoubtedly inspire the development of new strategies that enhance therapy efficiency. 6 Conclusion and future directions Most of the numerous members of the ANXA protein family have 5.3 The inhibitors of the ANXA protein family been found to be associated with cancer, which is characterised by abnormal changes in the normal cellular pathway through the up- or Only a few studies are available on ANXA protein family inhibitors. downregulation of expression. Due to the individual characteristics of The downregulation of ANXA expression mainly uses gene knockout tumour cells and the various post-translational patterns of the ANXA and gene silencing. However, the identification of ANXA inhibitors protein family, members of the ANXA protein family trigger different would be beneficial as this would enable the targeting of ANXA proteins tumorigenesis and metastasis, thus leading to variable outcomes. A more forcancertreatment.Asdescribed previously with respecttotheir in-depth study of the ANXA protein family in the tumour 2+ structure, the functioning of ANXA proteins depends strictly on Ca , microenvironment, with careful consideration of the timing and and some ion channel blockers exert an inhibitory effect on ANXA approach to target selection, may suggest more biologically proteins (Kourie and Wood, 2000). In earlier studies, Pollard et al. meaningful clinical treatment strategies. In the early stages of cancer, 2+ found that concentrations of Ca greaterthan10 nMwereabletoblock high expression of ANXA proteins may promote metastasis. It is 2+ the synexin channel of ANXA7. While the non-activating Cd channel therefore important to consider the timing of the use of ANXA inhibitor nifedipine required concentrations greater than 300 mM proteins as clinical prognostic biomarkers. The expression of ANXA (Pollard and Rojas, 1988). Burns et al. pointed that the synexin proteins is significantly altered during cancer progression, so they can be 2+115,116 channel of ANXA5 was sensitive to 0.2 nM La .These ions used as diagnostic and prognostic biomarkers for certain cancers. and compounds inhibit ANXA function by blocking ion channels. Furthermore, targeting ANXA proteins has emerged as a promising Similarly, it was determined that benzothiazolecipine K201 could bind new strategy for cancer therapy. ANXA proteins are also closely 2+ to ANXA5 and inhibit its Ca channel activity because K201 was able associated with multidrug resistance in many cancers, including to inhibit the hinge movement of the ANXA5 module in a metastable cisplatin, paclitaxel and sorafenib resistance. If this could be a 2+ manner, thereby blocking Ca movement in ANXA5 (Kaneko et al., research direction and the sensitivity of cancer cells to drugs could be 1997; Gerke and Moss, 2002). In a recent study, Aareskjold et al. improved, it would undoubtedly be of significant help in cancer synthesised RatRib120, a nuclease, with the ability to stably integrate treatment. Currently, most of thedrugstudies involvingANXA with host DNA and enabled it to downregulate ANXA2 expression by proteins are still in the laboratory stage with only a few clinical targeting the ANXA2 mRNA (Aareskjold et al., 2019). In addition, applications. How to apply these findings to clinical treatment is thus ANXA8, which is highly expressed in patients with acute promyelocytic one of the future challenges in cancer research. Basic research on the leukaemia, was found to be inhibited by all-trans-retinoic acid, an ANXA protein family is currently relatively shallow, and many members inhibitor that can help patients with symptom relief (Chang et al., 1992). of this protein family have not been studied in an integrated manner with ANXA proteins characteristically bind to their receptors and relieve the aim of enhancing tumour prevention and treatment. Future research specific biological effects, so the inhibitors of ANXA receptors are key should focus on the role of the ANXA protein family in the tumour regulators of ANXA protein functions. n-t-Boc-Met-Leu-Phe is a classic microenvironment and consider tumour-related macrophages, tumour- ANXA1 receptor blocker (Liu et al., 2015; Vago et al., 2016; Bai et al., related fibroblasts and lymphatic metastasis to achieve the combination 2020) that competitively binds to the FRP2 receptor (Bai et al., 2020). In of cancer prevention and treatment. Moreover, such research should addition, due to the function of the interaction between ANXA and focus on drug screening, as well as drug resistance and its role in immune S100A10 in cancer, Reddy et al. screened 29 potential inhibitor suppression mechanisms, and aim to achieve precise treatments. compounds and determined that 2-[5-(4,6-dimethyl-pyrimidin-2- ylsulfanylmethyl)-4-furan-2-ylmethy l-4H-[1,2,4]triazol-3-ylsulfanyl]- N-substituted (R)-acetamide analogues and 3,4,5-trisubstituted-1,2,4- Author contributions triazole analogues were the two inhibitors that attached to the N-terminal of ANXA2 (Reddy et al., 2014). This attachment not HZ and TG contributed to the collection of data, preparation of only disrupted the interaction between ANXA and S100A10, but the figures and tables, and writing of the manuscript. GC and GL also inhibited ANXA2 activity. contributed to data collection and preparation of Figure 1. QS and A recent study found that phenothiazine derivatives, GL contributed to data collection and preparation of Figures 2, 3. especially trifluoperazine (TFP), are able to inhibit the repair FX, XD, and FY contributed to data collection and preparation of function of ANXA proteins at the cell membrane. TFP delays the Figure 4 and Table 1. CC and DZ contributed to data collection and accumulation of ANXA2-GFP at the damaged plasma preparation of Tables 2, 3. SL, YL, and MW reviewed the membrane, inhibits ANXA-mediated membrane curvature, manuscript. ZZ has revised the language and grammar of the Frontiers in Cell and Developmental Biology 10 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 article. LY and BL contributed to the establishment of the structure Conflict of interest of this manuscript and acted as the supervisor. All authors read and approved the final manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding This work was supported by National Natural Science Publisher’s note Foundation of China (No.81803895) and Shandong Province Natural Science Foundation (ZR2021YQ57). All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the Acknowledgments reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or Figures 2, 3 and 4 were drawn by Figdraw (www.figdraw.com) endorsed by the publisher. References Aareskjold, E., Grindheim, A. K., Hollås, H., Goris, M., Lillehaug, J. R., and Vedeler, A. Du, K., Ren, J., Fu, Z., Wu, X., Zheng, J., and Li, X. (2020). ANXA3 is upregulated by (2019). 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Annexin A protein family: Focusing on the occurrence, progression and treatment of cancer

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TYPE Review PUBLISHED 03 March 2023 DOI 10.3389/fcell.2023.1141331 Annexin A protein family: Focusing on the occurrence, progression OPEN ACCESS EDITED BY Masahide Takahashi, and treatment of cancer Fujita Health University, Japan REVIEWED BY 1† 1† 3† 1 Huhu Zhang , Zhe Zhang , Tingting Guo , Guang Chen , Liang Weng, Xiangya Hospital, Central South 1 3 2 1 Guoxiang Liu , Qinghang Song , Guichun Li , Fenghua Xu , University, China 1 1 1 1 1 Motoshi Suzuki, Xiaolei Dong , Fanghao Yang , Can Cao , Di Zhong , Shuang Li , Fujita Health University, Japan 1 1 1,4 1 Ya Li , Mengjun Wang , Bing Li * and Lina Yang * *CORRESPONDENCE Lina Yang, Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China, [email protected] Department of Traditional Chinese Medicine, The People’s Hospital of Zhaoyuan City, Yantai, China, 3 4 Bing Li, Health Science Center, Qingdao University, Qingdao, China, Department of Hematology, The Affiliated [email protected] Hospital of Qingdao University, Qingdao, China These authors have contributed equally to this work SPECIALTY SECTION The annexin A (ANXA) protein family is a well-known tissue-specific multigene This article was submitted to Cancer Cell Biology, 2+ family that encodes Ca phospholipid-binding proteins. A considerable amount a section of the journal of literature is available on the abnormal expression of ANXA proteins in various Frontiers in Cell and Developmental Biology malignant diseases, including cancer, atherosclerosis and diabetes. As critical regulatory molecules in cancer, ANXA proteins play an essential role in cancer RECEIVED 10 January 2023 ACCEPTED 23 February 2023 progression, proliferation, invasion and metastasis. Recent studies about their PUBLISHED 03 March 2023 structure, biological properties and functions in different types of cancers are CITATION briefly summarised in this review. We further discuss the use of ANXA as new class Zhang H, Zhang Z, Guo T, Chen G, Liu G, of targets in the clinical diagnosis and treatment of cancer. Song Q, Li G, Xu F, Dong X, Yang F, Cao C, Zhong D, Li S, Li Y, Wang M, Li B and Yang L (2023), Annexin A protein family: KEYWORDS Focusing on the occurrence, progression annexin a protein family, structure, cancer progression, biomarker, treatment, inhibitor and treatment of cancer. Front. Cell Dev. Biol. 11:1141331. doi: 10.3389/fcell.2023.1141331 1 Introduction COPYRIGHT © 2023 Zhang, Zhang, Guo, Chen, Liu, Song, Li, Xu, Dong, Yang, Cao, Zhong, Li, ANXs are proteins that are encoded by a highly conserved multigene family and are Li, Wang, Li and Yang. This is an open- widely found in animals, plants and protists (Geisow et al., 1987). In 1978, ANXs were given access article distributed under the terms of the Creative Commons Attribution different names based on their different biochemical properties and were divided into five License (CC BY). The use, distribution or categories: A, B, C, D and E . The ANXA protein family in humans contains 12 species, reproduction in other forums is ANXA1– ANXA11 and ANXA13 (Croissant et al., 2021), all of which are small soluble permitted, provided the original author(s) and the copyright owner(s) are credited proteins. They are uniquely expressed in specific tissues; for example, ANXA3 induces and that the original publication in this human umbilical vein endothelial cell migration and tubulogenesis (Park et al., 2005), journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Abbreviations: ALL, Acute lymphoblastic leukemia; ANXA, Annexin A; ANXs, Annexins; ATP, Adenosine triphosphate; Bcl-2, B-cell lymphoma-2; EGFR, Epidermal growth factor receptor; EMT, Epithelial- mesenchymal transition; ERK, Extracellular signal-regulated kinase; FHIT, Fragile histidine triad; GBM, Glioblastoma multiforme; HIF, Hypoxia Inducible Factor; HepG2, Human hepatocellular carcinomas; HPV, Human papillomavirus; IL-6, Interleukin-6; JAK2, Janus-family tyrosine kinase 2; MAPK, Mitogen- activated protein kinase; MEK, MAPK/ERK kinase; MMPs, Matrix metalloproteinases; MYC, Myelocytomatosis oncogene cellular homolog; PI3K, Phosphoinositide 3 kinase; AKT, AKT8 virus oncogene cellular homolog; RRM2, Ribonucleotide reductase M2 subunit; STAT3, Signal transducer and activator of transcription 3; TAGLN, Transgelin; NF-κB, Nuclear factor κ B; TFP, Trifluoperazine; NBC, Triple negative breast cancer; TSG, Tumor necrosis factor-stimulated gene; VEGF, Vascular endothelial growth factor. Frontiers in Cell and Developmental Biology 01 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 2+12 ANXA4 is specifically expressed in cochlear and vestibular hair cells in the presence of Ca . This binding is, however, reversible. The 2+ (Li et al., 2021a), while, while ANXA5 participates in the activation removal of Ca reveals the N-terminus hidden in the centre of the of immune T cells (Hu et al., 2020). C-terminus (Rintala-Dempsey et al., 2008). The coordination of Tissue-specific ANXA proteins exist in different cancers, ANXA to calcium ions requires the involvement of water molecules including hepatocellular carcinoma (Dong et al., 2014), gastric to ensure the two ligands remain stable (Rintala-Dempsey et al., 2+ cancer (Wang et al., 2013), breast cancer (Sharma et al., 2012), 2008). Besides Ca , the N-terminal of ANXA has multiple binding ovarian cancer (Manai et al., 2020) and lung cancer (Zhou et al., sites, including interacting partners. For instance, the S100 family, 2+ 2021a). In addition, numerous studies have indicated that ANXA is which comprises electron chiral Ca binding proteins (Bharadwaj expressed irregularly in disparate cancers. For instance, ANXA2 is et al., 2013), functions to regulate cell proliferation, membrane elevated in breast cancer and stimulates fibrinolytic enzyme transport and calcium homeostasis (Donato et al., 2013). The production, which results in angiogenesis and metastasis. In S100–ANXA interaction has been shown to play a role in contrast, ANXA6 expression is downregulated in primary gastric membrane fusion by linking an S100 protein to two ANXA cancer tissues and directly inactivates the Ras/MAPK signalling proteins on a phospholipid membrane (Rintala-Dempsey et al., pathway (Wang et al., 2013) to inhibit gastric cancer growth. 2008). Because of these different sequences in the N-terminal, Aside from ANXA2 and ANXA6, other ANXA family proteins ANXA members display distinctive properties and diverse can be used as markers of tumour occurrence and development as functions. ANXA3 has a strong binding ability to phospholipids they affect a variety of signal pathways, such as cancer cell invasion, via the substitution of classical Trp-5 with alanine (Hofmann et al., migration, apoptosis and autophagy. Furthermore, some ANXA 2000), while ANXA1 phosphorylates diverse protein residues via its proteins cause drug resistance and are thus potential therapeutic N-terminal kinases characteristic (Rosengarth et al., 2001). targets for tumours. A discussion of ANXA and their inhibitors may Generally, these subtle changes do not affect their basic structure provide better strategies for the early diagnosis, clinical treatment of ANXA proteins. and prognosis of cancer. 3 The role of ANXA protein family in 2 The molecular structure of ANXA cancer progression protein family 3.1 The role of ANXA protein family in cell The ANXA protein family contains structural and biological proliferation features. Structurally, the C-terminal region is conserved, with most membrane-bound proteins consisting of four fragments of around The ANXA protein family can inhibit tumour proliferation by 70 amino acids each, which are internally and intrinsically affecting cell membrane and cytoskeleton formation. In homologous to the membrane-bound proteins. An exception is nasopharyngeal carcinoma, decreased ANXA1 leads to the the ANXA6 protein, which has eight core fragments that form a upregulation of S100A9/vimentin, which increases tumour high alpha helix and a closely spaced disc-like structure (Figure 1) invasion by regulating the function of the cytoskeletal proteins (Li et al., 2022). (Xiao et al., 2017). When ANXA2 expression is effectively The biological functions of the superfamily members differ inhibited, the growth and motility of both the human colorectal depending on the N-terminal domain, which is where most of cancer cell line CACO2 and human hepatocellular carcinoma cell their post-translational modifications occur (Wang et al., 2019). line SMMC7721 are significantly reduced, and the motility- In biology, the ANXA protein family is a group of calcium- associated microstructures, such as pseudopods and filamentous dependent phospholipid-binding proteins, so called because they pseudopods, as well as the polymerisation of microfilaments and only bind to phospholipid membranes with conformational changes microtubules, are significantly inhibited (He et al., 2019). FIGURE 1 Schematic diagram of ANXA protein structure. ANXA consists of two regions, one of which is the C-terminus, the characteristic highly conserved core structural domain that usually consists of four repetitive sequences (A), while ANXA6 has eight repetitive sequences (B), each of which contains a calcium-binding motif. Another region is the N-terminal, where the amino acid arrangement order and length of each ANXA varies. Frontiers in Cell and Developmental Biology 02 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 FIGURE 2 Signaling pathways of ANXA protein family regulating tumor cell proliferation. Except for ANXA6, the rest of the ANXA protein family was overexpressed and promoted the proliferation of tumor cells. The members of the ANXA protein family play the opposing roles of promoting and inhibiting tumour proliferation through their participation in or activation of signalling pathways. The exceptions are ANXA5, ANXA6, ANXA10 and ANXA11, which play roles in several tumour types, while other ANXA members promote tumour cell proliferation (Grewal et al., 2010; Li et al., 2018a; Liu et al., 2019; Liu et al., 2020; Liu et al., 2021a; Zhou et al., 2021a; Zhou et al., 2021b; Gu et al., 2021; Huang et al., 2021; Ju et al., 2021; Wei and Zhu, 2021). In hepatocellular carcinoma, the overexpression of ANXA2 (Zhang et al., 2013), ANXA3 (Guo et al., 2021a), ANXA4 (Liu et al., 2017), ANXA5 (Sun et al., 2018) and ANXA11 (Liu et al., 2019) promotes proliferation because ANXA2–ANXA5 affect Wnt/β-catenin, MEK-ERK, PI3K/AKT-HIF-α and other pathways. It is worth mentioning that ANXA4 may be a key factor in hepatocellular carcinoma FIGURE 3 tumorigenesis (Liu et al., 2017), as downregulating Regulation of the ANXA protein family in the cell cycle. Members ANXA4 expression can inhibit hepatocellular carcinoma of the ANXA protein family promotes tumor cell cycle progression. proliferation and tumorigenesis in vitro and in vivo. Similarly, in lung cancer, the overexpression of ANXA8 activates the EGFR/ AKT/mTOR signalling pathway to promote proliferation (Zhou et al., 2021a), while in thyroid cancer, increased ANXA1 promotes studies have demonstrated that ANXA proteins are involved in the thyroid cancer proliferation by mediating IL-6/JAK2/STAT3 (Zhao regulation of tumour proliferation, and these studies may provide new ideas and directions for research on tumour prevention and et al., 2021). In contrast, the overexpression of the ANXA10 gene targeted therapies depending on the understanding of their role in significantly inhibits HepG2 cell proliferation in vitro, and its the pathogenesis of malignant tumours (Figure 2). downregulation inhibits papillary thyroid cancer proliferation; it acts directly on TSG101 by inactivating the MAPK/ERK signalling pathway (Wei and Zhu, 2021). In gastric cancer, different ANXA 3.2 The role of the ANXA protein family in the proteins show either proliferation promoting or inhibiting effects. cell cycle For instance, ANXA2 directs the interaction of the protein YES1 and involves the EphA2-YES1-ANXA2 pathway (Mao et al., 2021), The cell cycle is a complex process involving many regulatory which promotes gastric cancer progression and metastasis, while ANXA6 (Wang et al., 2013) suppresses gastric cancer progression by proteins that guide cells through specific sequences of events that inhibiting Ras/MAPK signalling. Moreover, increased culminate in the production of two daughter cells (Schafer, 1998). ANXA5 inhibits cervical cancer proliferation by regulating the The ANXA protein family plays critical roles in cell cycle regulation expression of Bcl-2 and Bax (Li et al., 2018a). A large number of in a complex manner (Figure 3). ANXA1 promotes G /G phase 0 1 Frontiers in Cell and Developmental Biology 03 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 cyclic arrest in leukaemic K562 and U937 cells and promotes apoptosis in leukaemia (Tsai et al., 2013; Sabran et al., 2019). In one study, silencing ANXA1 in hypopharyngeal carcinoma not only significantly decreased the proportion of G /G phase cells, but 0 1 significantly increased the proportion of S phase cells, which enhanced cell activity and promoted cell cycle progression (Li et al., 2021b). ANXA2 regulates c-Myc expression by binding to the 5′UTR of 2+ its mRNA in a Ca -dependent manner at the two pseudoknots of the internal ribosome entry site. Thus, downstream cyclinD1, a cell cycle regulator protein, is affected, which leads to cell proliferation and a high proportion of S-phase cells (Strand et al., 2021; Sun and Zhang, 2021). The downregulation of ANXA2 stalls cells in the G phase or S-G /M phase in gastric cancer (Sun et al., 2013) and glioblastoma multiforme (Maule et al., 2016), respectively. A study FIGURE 4 showed that the ANXA3 silencing group had a lower proliferation Regulation of ANXA protein family in apoptosis and autophagy. rate in breast cancer and a higher cell ratio in the G /G compared to 0 1 ANXA1 promoted cellular autophagy and ANXA6 inhibited cellular the control group (Li et al., 2018b). In oncogenic human autophagy. In terms of apoptosis, except for ANXA10, which had a dual role, the rest of the ANXA protein family inhibited tumor cell papillomavirus-positive non-small cell lung cancer, ANXA4 is apoptosis. mediated by HPV16E7 and HPV16E6/E7, promotes cell proliferation and regulates the cell cycle and mitosis (Ciotti et al., 2009). Meanwhile, the combination of epigallocatechin gallate and quercetin enhance ANXA5 to effectively inhibit colorectal cancer arrest at the G stage (Xue et al., 2009; Al-Ghamdi et al., 2021). tumour cell line 168FARN, the knockdown of ANXA1 inhibited the Furthermore, the overexpression of ANXA9 has been found to invasion and metastasis of breast cancer (Tu et al., 2017), with less increase the migration of gastric cancer and form larger and expression of epithelial–mesenchymal transition (EMT) markers, more cell clones, which decrease in the G phase and increase in wave proteins and myosin light-chain kinase. the S and G phases (Zhou et al., 2021b). ANXA10 is frequently In addition to ANXA1, the ANXA proteins ANXA2, found to be highly expressed in human oral cancer, and this high ANXA9 and ANXA10 are associated with tumour cell adhesion, expression may promote G phase cell cycle progression by invasion and metastasis (Xu et al., 2015; Yu et al., 2018; Sun et al., activating the ERK/MAPK signalling pathway, which in turn 2019). Once ANXA2 binds to fibrinogen and tissue-type fibrinogen results in the reduced expression of member-dependent kinases activators, it can activate metalloproteinase (MMPs), which will in of cell cycle proteins (Shimizu et al., 2012). To date, most studies turn disrupt the integrity of the extracellular matrix, resulting in have described ANXA protein family members as promoting the cell tumour invasion and metastasis (Xu et al., 2015). Accordingly, in cycle in cancer, although little is known about the associated gastric cancer HGC-27 cells, the inhibition of ANXA2 was found to mechanisms. Future investigations regarding the impact of significantly reduce the migration and secretion of MMPs and ANXA proteins on the regulation of the cell cycle would inhibit cancer invasion and metastasis (Han et al., 2017). certainly inspire more exploration of their biological effects. Similarly, Shi et al. (2020) Found that TAGLN2–ANXA2 interaction induces invasion and metastasis in hepatocellular carcinoma. In oesophageal cancer, the overexpression 3.3 The role of ANXA protein family in of ANXA2 promotes ESCC cell invasion in vitro and metastasis in invasion and metastasis vivo through the activation of the MYC-HIF-1α-VEGF cascade (Ma et al., 2018). More meaningfully, some clinical studies have shown Invasion describes the occupation of adjacent normal tissues by the relationship between the expression levels of ANXA2 and the cancer cells after leaving the tumour parent body, and metastasis is invasion and metastasis of prostate cancer. ANXA2 can therefore be the spread of tumour cells from the primary site to distant organs used as a prognostic biomarker for aggressive prostate cancer (Tan (Hart and Fidler, 1980). Increasing evidence has elucidated the et al., 2021). ANXA9 expression levels have been correlated with the critical role of the ANXA protein family in cancer invasion and depth of invasion and lymphatic metastasis of colorectal cancer (Yu metastasis (Xu et al., 2015). Proteomics technology has revealed that et al., 2018). Patients with colorectal cancer and positive ANXA1 mainly regulates the processes related to tumour cell ANXA9 expression were found to have a poorer prognosis, skeletal remodelling and immune responses, thus affecting the which indicates that ANXA9 could be an independent risk factor invasive migration of cancer cells (Tu et al., 2017). Of particular for survival. In extrahepatic cholangiocarcinoma, ANXA10 can interest, ANXA1 plays dual roles with regard to invasion and induce tumour proliferation, EMT facilitation and tumour metastasis among different tumour cells (Liu et al., 2014; Swa metastasis (Sun et al., 2019). A large number of preclinical and et al., 2015). A study showed that the inhibition of ANXA1 in clinical studies have demonstrated that most ANXAs exhibit nasopharyngeal carcinoma increased the trauma-healing ability of obviously invasive and metastatic properties. This may provide the cells, and the activation of the ANXA1 gene decreased the an explanation for cancer survival via the broken host immune trauma-healing rate by 70%. Conversely, in the mouse mammary defence and distant cancer growth. Accordingly, inhibiting Frontiers in Cell and Developmental Biology 04 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 ANXA-associated targets may offer new approaches to mitigate 3.6 Summary cancer metastasis and improve patient survival. There is a growing consensus that ANXA proteins play a role in cancer and that the ANXA protein family is involved in tumour cell 3.4 The role of ANXA protein family in cell proliferation, cell cycle regulation, invasive metastasis, apoptosis and apoptosis autophagy in numerous cancers (Table 1). The consensus thus far is that ANXA proteins in tumour cells may be mediators of Apoptosisisanordered andcoordinated cellular process that tumorigenesis, proliferation and metastasis, that is, ‘angels of life’ occurs under physiological and pathological conditions (Wong, for some tumours and ‘demons of death’ for others. This summary 2011). Evidence suggests that the ANXA protein family has a dual therefore provides an exciting opportunity for the treatment of role in tumour cell apoptosis, namely, anti-apoptotic and pro- various cancers. apoptotic activity (Figure 4)(Huang et al., 2008; Liu et al., 2012; Wei and Zhu, 2021). ANXA2 silencing significantly decreases the mRNA and protein expression of Bcl-1 and promotes apoptosis 4 The role of ANXA protein family as a in osteosarcoma through the AKT signalling pathway and, in biomarker in cancer diagnosis lung cancer, by the activity of p53 (Huang et al., 2008; Pan et al., 2018). The upregulation of ANXA4 enhances its interaction with Previous studies have confirmed that the ANXA protein family NF-κB p50, activates the NF-κB signalling pathway, promotes is significantly associated with tumour development and can be used cell cycle progression and inhibits apoptosis (Liu et al., 2020). as a biomarker for cancer diagnoses. Through an in vitro study of ANXA7 knockdown reduces mRNA, the protein levels of LEPR 268 lung cancer patients, Rong et al. (2014) found that the and the intracellular signalling pathways of the ERK1/2, JAk2/ expression of ANXA1 in the cancer tissues and serum of lung STAT3 and PI3K-related proteins, thereby promoting apoptosis cancer patients was significantly higher than normal. Elevated in hepatocellular carcinoma (Huang et al., 2021). While serum ANXA1 was noted to closely correlate with the clinical ANXA10 plays a diverse role in different tumours, in manifestations in these patients. A large number of studies have hepatocellular carcinoma, the overexpression of also demonstrated that, in addition to lung cancer, ANXA10 significantly promotes apoptosis. Conversely, in ANXA1 expression is upregulated in a variety of cancers, papillary thyroid cancer, the knockdown of including hepatocellular carcinoma (Zhuang et al., 2019), ANXA10 promotes apoptosis by inhibiting the MAPK/ERK colorectal cancer (Liang and Li, 2021), pancreatic cancer (Novizio signalling pathway through the downregulation of TSG101 et al., 2021), melanoma (Delorme et al., 2021), and endometrial (Liu et al., 2012; Wei and Zhu, 2021). Although studies have cancers (Aboulouard et al., 2021). By constructing a risk model, shown the functional diversity of ANXA proteins in apoptosis, a Liang and Li (2021) found that ANXA1 expression levels were deeper understanding of ANXA would make an important associated with the level of immune infiltration in colorectal contribution to the field of cancer treatment by enhancing cancer. ANXA1 could therefore be used as a biomarker for apoptosis. colorectal cancer diagnoses and as an independent prognostic indicator for patients. Further, other ANXA protein family members have shown abnormal expression in many cancers. 3.5 The role of ANXA protein family in For example, the high expression of ANXA3 has been closely autophagy associated with upper tract urothelial carcinoma (Lu et al., 2014; Liu et al., 2021a), and patients with higher ANXA3 have been Autophagy is a catabolic process involving the lysosomal found to have a higher rate of postoperative recurrence (Liu renewal of proteins and organelles to maintain cellular et al., 2021a). Additionally, ANXA5 is significantly expressed in homeostasis and reduce metabolic stress (Lozy and Karantza, non-papillary bladder cancer (Wu et al., 2021), and lung cancer 2012). Autophagy is one of the most important programmed cell patients with high Cir–ANXA seven expression tend to have a death mechanisms, and the ANXA protein family has a poorer prognosis (Wang, 2021). Meanwhile, considerable impact on autophagy (Figure 4). ANXA ANXA8 expression has been noted as significantly more regulates the formation of vesicular lipid membranes and enhanced in ovarian malignant tissues than benign tumours promotes cellular cytokinesis (Xi et al., 2020). Respective and normal ovarian tissues and is associated with a poor members of the ANXA protein family have different effects prognosis (Gou et al., 2019), and ANXA10 has recently been on autophagy in various cancers. ANXA1 inhibits cellular shown to be a prognostic biomarker for papillary thyroid cancer autophagy and promotes tumour invasion and metastasis as well as a potential therapeutic target (Liu et al., 2021b). through PI3K/AKT signalling activation in nasopharyngeal Similarly, ANXA13 expression is upregulated in colorectal carcinoma (Zhu et al., 2018). In contrast, autophagy induced cancer and promotes the invasion of cancer (Jiang et al., by ANXA6 in cervical cancer may be related to the inhibition of 2017). This suggests that ANXA has already been used as a the PI3K-AKT and ERK signalling pathways of mTOR diagnostic biomarker in a variety of cancers. More specifically, activation (Sun et al., 2020). Elucidating the molecular due to its unique structure, ANXA6 may act as either a tumour mechanism of ANXA in autophagy may assist in identifying suppressor or a tumour promoter depending on the type and new therapeutic targets and developing novel treatment stage of cancer. ANXA6 expression has been reported to strategies. be upregulated in cancers such as pancreatic cancer Frontiers in Cell and Developmental Biology 05 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 TABLE 1 The role of ANXA family proteins in cancer progression. Member Cancer type Type cell Expression Effect Reference patterns ANXA1 Thyroid carcinoma TPC-1 mRNA and protein High ANXA1 expression promotes Zhao et al., (2021) the proliferation of thyroid cancer cells Nasopharyngeal 5–8F 6–10B Protein ANXA1 promotes migration, Xiao et al., (2017), Liu et al., carcinoma invasion, and metastasis of (2014) Zhu et al., (2018) nasopharyngeal carcinoma cells, and autophagy activation inhibits metastasis of nasopharyngeal carcinoma with high ANXA1 expression Hypopharyngeal FaDu mRNA and protein Silencing ANXA1 inhibited apoptosis Li et al., (2021b) carcinoma and increased the proportion of S- phase cells Leukemic K562 U937 mRNA and protein ANXA1 induces apoptosis and G /G Sabran et al., (2019) 0 1 phase cycle arrest in K562 and U937 cells Breast cancer 168FARN Protein The expression of vimentin and Tsai et al., (2013) myosin light chain kinase decreased after inhibiting ANXA1 ANXA2 Colorectal Cancer ATCC mRNA and protein Significant reduction in growth and He et al., (2019) motility of colorectal cancer when ANXA2 expression was inhibited Inhibition of ANXA2 Gastric carcinoma HGC-27; MKN45 Protein significantly reduces cell Han et al., (2017); Mao et al., proliferation, migration and matrix (2021) metalloproteinase secretion Glioblastoma Primary GBM cells Protein ANXA2 knockdown stalled the cell Maule et al., (2016) cycle in S-G2/M phase Esophageal cancer KYSE Protein Overexpression of ANXA2 activates Ma et al. (2018) the MYC-HIF1A-VEGF cascade through Prostate cancer Tissue Protein High expression of ANXA2 promotes Tan et al. (2021) invasion and metastasis Hepatocellular carcinoma Huh-7 QGY-7703; mRNA and protein TAGLN2-Annexin A2 interactions He et al., (2019), Zhang et al., HepG2; SMMC-7721 induce invasion and metastasis, (2013), Shi et al., (2020) shRNA-mediated ANXA2 silences inhibit proliferation, invasion, migration, and tumorigenic potential of hepatoma Lung cancer BE1 Protein Knockdown of ANXA2 promotes Huang et al., (2008) apoptosis and inhibits cell proliferation in lung cancer cells Osteosarcoma U-2 OS mRNA and protein ANXA2 promotes OS cell Pan et al., (2018) proliferation, migration, and invasion, and inhibits apoptosis ANXA3 Hepatocellular carcinoma HepG2 Protein ANXA3 promotes proliferation and Guo et al., (2021a) angiogenesis of hepatocellular carcinoma Breast carcinoma MDA-MB-231 Protein After ANXA3 silencing, the Li et al., (2018b) proportion of G0 / G1 phase cells increased and cell proliferation rate decreased ANXA4 ovarian clear cell ES-2 RMG-1 Protein ANXA4 promotes cell proliferation Liu et al., (2020) carcinoma and inhibits cell apoptosis (Continued on following page) Frontiers in Cell and Developmental Biology 06 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 TABLE 1 (Continued) The role of ANXA family proteins in cancer progression. Member Cancer type Type cell Expression Effect Reference patterns Hepatocellular carcinoma SMMC-7721 mRNA and protein Down-regulation of ANXA4 Liu et al., (2017) expression inhibits hepatocellular carcinoma cell proliferation and tumorigenesis Lung cancer A549 Protein ANXA4 is mediated by HPV16E7 Ciotti et al., (2009) and HPV16E6/E7, promotes cell proliferation, and regulates cell cycle and mitosis ANXA5 Cervical carcinoma HeLa Protein Increased ANXA5 expression Li et al., (2018a) inhibits the proliferation and metastasis of cervical cancer cells ANXA5 Hepatocarcinoma Tissue Protein overexpression promotes clinical Sun et al., (2018) progression and lymphatic metastasis in hepatocellular carcinoma Colorectal cancer ATCC mRNA and protein In colorectal cancer, ANXA5 is Xue et al., (2009) inhibited, resulting in G phase arrest ANXA6 Gastric cancer MKN28 mRNA and protein ANXA6 plays an oncogenic role in Wang et al., (2013) gastric cancer cells Cervical cancer HeLa Protein In cervical cancer, ANXA6 induces Sun et al., (2020) autophagy ANXA7 Hepatocellular carcinoma Hca-F Hca-P mRNA and protein ANXA7 promotes the proliferation, Huang et al. (2021) migration and invasion of lymphatic metastatic cells from hepatocellular carcinoma and inhibits their apoptosis. ANXA8 Lung cancer A549 Protein Overexpressed ANXA8 promotes the Zhou et al. (2021a) proliferation of lung cancer cells ANXA9 Gastric cancer HGC-27 mRNA and protein Overexpression of ANXA9 increased Zhou et al., (2021b) the number of gastric cancer cells migrating Colorectal cancer Caco-2; HCT116; SW620 mRNA and protein The expression level is correlated Yu et al., (2018) with the invasion depth and lymphatic metastasis of colorectal cancer ANXA10 Thyroid carcinoma BCPAP; TPC-1; KTC-1 mRNA and protein ANXA10 inhibits PTC cell Wei and Zhu, (2021) proliferation and promotes PTC cell apoptosis by binding with TSG101 Hepatocellular carcinoma HepG2 mRNA and protein Overexpression of ANXA10 gene Liu et al., (2012) inhibits proliferation and promotes apoptosis of HepG2 cells in vitro Oral cancer HSC-2; HSC-3; KON mRNA and protein ANXA10 promotes G phase cell Shimizu et al., (2012) cycle progression in oral cancer Extrahepatic QBC-939; FRH-0201 mRNA and protein Induction of proliferation, EMT Sun et al., (2019) cholangiocarcinoma facilitation and tumor metastasis ANXA11 Hepatocellular carcinoma Huh7; HCCLM3 mRNA and protein ANXA11 promotes metastasis and Liu et al. (2019) the EMT pathway in hepatocellular carcinoma (Leca et al., 2016), ovarian cancer (Noreen et al., 2020), female (TNBC) (Korolkova et al., 2020). Such studies offer some thyroid cancer (Lee et al., 2018), and esophageal important insights for the use of ANXA6 as a biomarker for adenocarcinoma (Zaidi et al., 2014), but downregulated in the progression of these cancers (Table 2). In addition, hepatocellular carcinoma (Meier et al., 2016), gastric cancer ANXA1 expression is significantly increased in small cell lung (Wang et al., 2013), breast cancer (Sakwe et al., 2011), cervical cancer patients with bone metastases than without bone cancer (Lomnytska et al., 2010) and triple negative breast cancer metastases (Chen et al., 2021). The elevation of ANXA1 has Frontiers in Cell and Developmental Biology 07 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 TABLE 2 The role of ANXA as a biomarker in cancer diagnosis. Member Cancer type ANXA protein expression Ref ANXA1 Hepatocellular carcinoma High expression Zhuang et al. (2019) Colorectal cancer High expression Liang and Li (2021) Pancreatic cancer High expression Novizio et al. (2021) Melanoma High expression Delorme et al. (2021) Endometrial cancer High expression Aboulouard et al. (2021) ANXA2 Lung cancer High expression Leca et al. (2016) ANXA3 Upper tract urothelial carcinoma High expression Lu et al. (2014), Liu et al. (2021a) ANXA5 Non-papillary bladder cancer High expression Wu et al. (2021) ANXA6 Pancreatic cancer High expression Leca et al. (2016) Ovarian cancer High expression Noreen et al. (2020) Female thyroid cancer High expression Lee et al. (2018) Esophageal adenocarcinoma High expression Zaidi et al. (2014) Hepatocellular carcinoma Low expression Meier et al. (2016) Gastric cancer Low expression Wang et al. (2013) Breast cancer Low expression Sakwe et al. (2011) Cervical cancer Low expression Lomnytska et al. (2010) Triple-negative breast cancer Low expression Korolkova et al. (2020) ANXA7 Lung cancer High expression Wang (2021) ANXA8 Ovarian cancer High expression Gou et al. (2019) ANXA10 Papillary thyroid cancer High expression Liu et al. (2021b) ANXA13 Colorectal cancer High expression Jiang et al. (2017) been detected in colorectal cancer patients with micro-metastases cancer (Gaudio et al., 2013; Wei et al., 2015; Gaudio et al., 2016). in the anterior lymph nodes than in matched individuals with However, ANXA4 can bind to the N-terminal part of the Fhit protein, a normal lymph nodes (He et al., 2010). ANXA3 expression was tumour suppressor gene, to form an ANXA4–Fhit complex, which also found to be higher in lung cancer patients with lymph node specifically prevents cytoplasmic translocation and generates drug metastases than those without metastases. Accumulating resistance (Huebner and Croce, 2001; Gaudio et al., 2013; Wei et al., evidence thus suggests that AXNA may be used as a potential 2015). Not only is the Fhit protein closely associated with ANXA4 and biomarker for cancer metastasis (Liu et al., 2021a). drug resistance, but also ATP7A. Toosendanin targets ANXA4/ATP7A to reduce the binding of ANXA4 to ATP7A and to mediate the sensitisation of non-small cell lung cancer to cisplatin (Zheng et al., 5 The role of ANXA protein family in 2018). Additionally, a vitro drug sensitivity assay demonstrated that the cancer treatment overexpression of ANXA3 significantly enhanced the resistance of hepatocellular carcinoma cells to cisplatin (Tong et al., 2015; Liu 5.1 Role of ANXA protein family in therapy et al., 2021a), 5-fluorouracil (Pan et al., 2015; Tong et al., 2015; Liu resistance et al., 2021a) and adriamycin (Liu et al., 2021a). A previous study found that the secretion of ANXA6-containing exosomes promoted paclitaxel Therapy resistance is one of the fundamental reasons for cancer resistance in breast cancer cells as well as cancer progression in a YAP1- progression. It is primarily driven by tumour cells’ intrinsic dependent manner (Guo et al., 2021b). At thesametime, reduced mechanisms. Previous studies have shown that ANXA promotes ANXA6 expression has been shown to sensitise TNBC cells to therapy resistance to a large number of drugs, which suggests that tyrosinase inhibitors (Korolkova et al., 2020), and Hsa-miR-105- ANXA plays an important role in treatment resistance. For example, 1 expression can be downregulated in cisplatin-resistant ovarian ANXA4 was found to be overexpressed in paclitaxel-resistant lung cancer cells by targeting ANXA9 (Kou et al., 2021). The cancer (Wei et al., 2012; Matsuzaki et al., 2014; Wei et al., 2015; Yao aforementioned information reveals a possible mechanism by which et al., 2016). In normal conditions, paclitaxel induces the translocation tumour cells become resistant to some anticancer drugs by affecting of ANXA4 to the cytoplasmic membrane and promotes apoptosis in ANXA proteins. Frontiers in Cell and Developmental Biology 08 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 TABLE 3 Inhibitors of ANXA family protein. Member Inhibitors Inhibitor Effect Ref type ANXA1 N-t-Boc-Met-Leu-Phe(BOC-1) Compound Binds competitively to FRP2 receptors Liu et al. (2015), Vago et al. (2016), Bai et al. (2020) ANXA2 RatRib120 Nucleases Target ANXA2 mRNA Aareskjold et al. (2019) 2-[5-(4,6-dimethyl-pyrimidin-2-ylsulfanylmethyl)-4-furan-2- Compound Acts on the N-terminal of ANXA2 to inhibit Reddy et al. (2014) ylmethyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-substituted (R)- the inhibitor compound of ANXA2 bound to acetamide analogues and 3,4,5-trisubstituted-1,2,4-triazole S100A10 and inhibits ANXA2 itself analogues 2+ ANXA5 Benzothiazolecipine K201 Compound Binds to ANXA5 and inhibits its Ca channel Kaneko et al. (1997), activity Gerke and Moss (2002) 2+ La Cation block the synexin channel of ANXA5 Rojas et al. (1990) 2+ ANXA7 La Cation block the synexin channel of ANXA7 Burns et al. (1989) 2+ Cd (>10 nM) Cation block the synexin channel of ANXA7 Pollard and Rojas (1988) Nifedipine (>300 nM) Compound block the synexin channel of ANXA7 Pollard and Rojas (1988) ANXA8 all-trans-retonoic acid Compound Down-regulation of highly expressed Chang et al. (1992) ANXA8 in acute promyelocytic leukemia patients Pan-inhibitors Derivatives of phenothiazine, especially trifluoperazine (TFP) Compound Inhibits the repair function of cell membrane or Heitmann et al. (2021) of ANXA plasma membrane by impairing the function of ANXA Besides the traditional drugs mentioned above, some novel ANXA sheds light on the utilisation of ANXA against drug targeted drugs have been found to produce resistance by affecting resistance and potential improvements in treatment efficacy. ANXA proteins. Xiong et al. noted that upregulation of the ribonucleotide reductase M2 subunit (RRM2) causes resistance to sunitinib in renal cancer cells because it 5.2 Role of ANXA protein family in stabilises ANXA1 and activates the AKT pathway modulation of therapy efficiency independently of its nucleotide reductase activity (Xiong et al., 2021). Spijkers-Hagelstein et al. found that As previously discussed, the ANXA protein family plays critical role ANXA2 was associated with glucocorticoid resistance in in the development of cancer, so ANXA proteins have become viable children with acute lymphoblastic leukaemia (ALL). The new targets for cancer treatment. Natural compounds are one of the downregulation of ANXA2 expression significantly increased directions that may be used to effect the use of ANXA2 in treatment. the sensitivity of ALL cells to glucocorticoids and prednisolone, For instance, the ginsenosides Rg5 and Rk1 can specifically bind to and when ANXA2 was overexpressed in ALL cells, Src kinase ANXA2. This interaction can inhibit NF-κB activity, downregulate activity was enhanced, which resulted in glucocorticoid apoptosis inhibitory proteins, activate caspases and promote apoptosis resistance. Meanwhile, the downregulation of (Wang et al., 2018). Picrasidine, a plant alkaloid purified from the ANXA2 blocked this process, leading to increased sensitivity traditional Chinese medicine bitter ginseng, has been shown to achieve to prednisolone and thus improved therapeutic efficacy. anti-tumour activity by targeting ANXA2 (Wang et al., 2017), and cicer Recently, ANXA2 has also been reported as a drug arietinum lectin inhibits the EGFR -mediated signalling pathway by resistance-associated protein in ovarian cancer (Cruz et al., blocking the binding of ANXA2 and galactose lectin-3, with apoptosis 2017). Furthermore, the knockdown of ANXA3 has been as a consequence, and inhibiting cancer proliferation and migration found to inhibit the resistance of hepatocellular carcinoma (Shetty et al., 2016). A researcher designed a cationic lipid-directed cells to sorafenib (Tong et al., 2018). The mechanism nanoparticle, which is essentially an ANXA2 shRNA carrier, and found involved the overexpression of ANXA3 in sorafenib-resistant that it can suppress tumour growth by silencing ANXA2 (Andey et al., hepatocellular carcinoma cells, which inhibited PKCd/p38- 2014). It has also been proposed that CBP12, a colorectal cancer binding associated apoptosis to promote cell survival. ANXA3 may peptide, can target ANXA2 with specificaffinity and thus has the therefore be important in the development of multidrug potential to become a novel targeted drug (Li et al., 2021c). In the resistance in hepatocellular carcinoma patients. Although the meantime, Du et al. found that ANXA3 and HIF-1α act together to mechanisms remain unclear, the anti-resistance function of promote colon carcinogenesis, while HIF-1α siRNA can inhibit the Frontiers in Cell and Developmental Biology 09 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 expression of HIF-1α and ANXA3 in transplantation tumour tissues affects the membrane-forming ability of ANXA and, to some (Du et al., 2020), Liu et al. demonstrated that miR-1253 upregulates the extent, impairs ANXA proteins from binding to membrane expression of the pro-apoptosis-related proteins Bax and caspase-3 and patches (Table 3)(Heitmann et al., 2021). Not only inhibitors, downregulates the expression of the anti-apoptosis-related protein but also their functions need deeper investigation. It remains an Bcl2 via the degradation of ANXA3 as its target, thereby promoting open question whether inhibitors are a potential target for cancer the apoptosis of cancer cells (Liu et al., 2021c). treatment and further, how to transferthisknowledge to clinical To date, a negligible number of studies addressing this area of application. research have been published. Future research involving drugs that target ANXA will undoubtedly inspire the development of new strategies that enhance therapy efficiency. 6 Conclusion and future directions Most of the numerous members of the ANXA protein family have 5.3 The inhibitors of the ANXA protein family been found to be associated with cancer, which is characterised by abnormal changes in the normal cellular pathway through the up- or Only a few studies are available on ANXA protein family inhibitors. downregulation of expression. Due to the individual characteristics of The downregulation of ANXA expression mainly uses gene knockout tumour cells and the various post-translational patterns of the ANXA and gene silencing. However, the identification of ANXA inhibitors protein family, members of the ANXA protein family trigger different would be beneficial as this would enable the targeting of ANXA proteins tumorigenesis and metastasis, thus leading to variable outcomes. A more forcancertreatment.Asdescribed previously with respecttotheir in-depth study of the ANXA protein family in the tumour 2+ structure, the functioning of ANXA proteins depends strictly on Ca , microenvironment, with careful consideration of the timing and and some ion channel blockers exert an inhibitory effect on ANXA approach to target selection, may suggest more biologically proteins (Kourie and Wood, 2000). In earlier studies, Pollard et al. meaningful clinical treatment strategies. In the early stages of cancer, 2+ found that concentrations of Ca greaterthan10 nMwereabletoblock high expression of ANXA proteins may promote metastasis. It is 2+ the synexin channel of ANXA7. While the non-activating Cd channel therefore important to consider the timing of the use of ANXA inhibitor nifedipine required concentrations greater than 300 mM proteins as clinical prognostic biomarkers. The expression of ANXA (Pollard and Rojas, 1988). Burns et al. pointed that the synexin proteins is significantly altered during cancer progression, so they can be 2+115,116 channel of ANXA5 was sensitive to 0.2 nM La .These ions used as diagnostic and prognostic biomarkers for certain cancers. and compounds inhibit ANXA function by blocking ion channels. Furthermore, targeting ANXA proteins has emerged as a promising Similarly, it was determined that benzothiazolecipine K201 could bind new strategy for cancer therapy. ANXA proteins are also closely 2+ to ANXA5 and inhibit its Ca channel activity because K201 was able associated with multidrug resistance in many cancers, including to inhibit the hinge movement of the ANXA5 module in a metastable cisplatin, paclitaxel and sorafenib resistance. If this could be a 2+ manner, thereby blocking Ca movement in ANXA5 (Kaneko et al., research direction and the sensitivity of cancer cells to drugs could be 1997; Gerke and Moss, 2002). In a recent study, Aareskjold et al. improved, it would undoubtedly be of significant help in cancer synthesised RatRib120, a nuclease, with the ability to stably integrate treatment. Currently, most of thedrugstudies involvingANXA with host DNA and enabled it to downregulate ANXA2 expression by proteins are still in the laboratory stage with only a few clinical targeting the ANXA2 mRNA (Aareskjold et al., 2019). In addition, applications. How to apply these findings to clinical treatment is thus ANXA8, which is highly expressed in patients with acute promyelocytic one of the future challenges in cancer research. Basic research on the leukaemia, was found to be inhibited by all-trans-retinoic acid, an ANXA protein family is currently relatively shallow, and many members inhibitor that can help patients with symptom relief (Chang et al., 1992). of this protein family have not been studied in an integrated manner with ANXA proteins characteristically bind to their receptors and relieve the aim of enhancing tumour prevention and treatment. Future research specific biological effects, so the inhibitors of ANXA receptors are key should focus on the role of the ANXA protein family in the tumour regulators of ANXA protein functions. n-t-Boc-Met-Leu-Phe is a classic microenvironment and consider tumour-related macrophages, tumour- ANXA1 receptor blocker (Liu et al., 2015; Vago et al., 2016; Bai et al., related fibroblasts and lymphatic metastasis to achieve the combination 2020) that competitively binds to the FRP2 receptor (Bai et al., 2020). In of cancer prevention and treatment. Moreover, such research should addition, due to the function of the interaction between ANXA and focus on drug screening, as well as drug resistance and its role in immune S100A10 in cancer, Reddy et al. screened 29 potential inhibitor suppression mechanisms, and aim to achieve precise treatments. compounds and determined that 2-[5-(4,6-dimethyl-pyrimidin-2- ylsulfanylmethyl)-4-furan-2-ylmethy l-4H-[1,2,4]triazol-3-ylsulfanyl]- N-substituted (R)-acetamide analogues and 3,4,5-trisubstituted-1,2,4- Author contributions triazole analogues were the two inhibitors that attached to the N-terminal of ANXA2 (Reddy et al., 2014). This attachment not HZ and TG contributed to the collection of data, preparation of only disrupted the interaction between ANXA and S100A10, but the figures and tables, and writing of the manuscript. GC and GL also inhibited ANXA2 activity. contributed to data collection and preparation of Figure 1. QS and A recent study found that phenothiazine derivatives, GL contributed to data collection and preparation of Figures 2, 3. especially trifluoperazine (TFP), are able to inhibit the repair FX, XD, and FY contributed to data collection and preparation of function of ANXA proteins at the cell membrane. TFP delays the Figure 4 and Table 1. CC and DZ contributed to data collection and accumulation of ANXA2-GFP at the damaged plasma preparation of Tables 2, 3. SL, YL, and MW reviewed the membrane, inhibits ANXA-mediated membrane curvature, manuscript. ZZ has revised the language and grammar of the Frontiers in Cell and Developmental Biology 10 frontiersin.org Zhang et al. 10.3389/fcell.2023.1141331 article. LY and BL contributed to the establishment of the structure Conflict of interest of this manuscript and acted as the supervisor. All authors read and approved the final manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding This work was supported by National Natural Science Publisher’s note Foundation of China (No.81803895) and Shandong Province Natural Science Foundation (ZR2021YQ57). All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the Acknowledgments reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or Figures 2, 3 and 4 were drawn by Figdraw (www.figdraw.com) endorsed by the publisher. References Aareskjold, E., Grindheim, A. K., Hollås, H., Goris, M., Lillehaug, J. R., and Vedeler, A. Du, K., Ren, J., Fu, Z., Wu, X., Zheng, J., and Li, X. (2020). ANXA3 is upregulated by (2019). 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