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Annexin A3 and cancer

Annexin A3 and cancer ONCOLOGY LETTERS 22: 834, 2021 Annexin A3 and cancer (Review) * * CHAO LIU , NANNAN LI , GUIJIAN LIU and XUE FENG Clinical Laboratory, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China Received August 5, 2021; Accepted September 29, 2021 DOI: 10.3892/ol.2021.13095 Abstract. Annexin A3 (ANXA3), an annexin family member, been extensively studied due to their association with the devel‑ contains 36 kDa and 33 kDa isoforms. Similar to other annexin opment of human diseases. This group contains 12 members members, ANXA3 plays an important role in the development (annexins A1A ‑ 11 and annexin A13). The structure of annexins of human diseases. Recent studies have reported that abnormal is similar; they are composed of a highly conserved Ct ‑ erminus ANXA3 expression is closely associated with the develop‑ and a variable N‑terminus. The C‑terminal protein core ment, progression, metastasis, drug resistance and prognosis contains four annexin repeats, each composed of 698 ‑ 0 amino of several malignant tumours, such as breast cancer, lung acid residues (4). The N‑terminal domain is highly variable, cancer and hepatocellular carcinoma. ANXA3 exerts its role in which the diversity of the amino acid sequence and length by regulating cell proliferation, migration and apoptosis via the result in the difference of functions among all annexin family phosphatidylinositol3 ‑ kinase /Akt, nuclear factor‑ κB (NF‑ κB), members (4,5). Recent studies have reported that annexins play cJ ‑ UN Nte ‑ rminal kinase, extracellular signalr ‑ egulated kinase an important role in tumour development and progression, cell and hypoxiai‑ nducible factor1 s ‑ ignalling pathways. ANXA3 proliferation and apoptosis, invasion and metastasis, drug resis‑ may act as a novel target for the early diagnosis and treatment tance and angiogenesis (6,7). of tumours. The present review summarises the recent progress Annexin A3 (ANXA3), a member of the annexin family , is also in the role of ANXA3 and its regulatory pathways in tumours. known as lipocortin III or placental anticoagulant protein III (3). ANXA3 is considered a new angiogenesis factor (8,9), which participates in the liver regeneration process (10,11). ANXA3 is Contents also closely associated with the development of human diseases, such as cancer and ina fl mmation (3,12). 1. Introduction 2. ANXA3 and tumour Structure of ANXA3. ANXA3 belongs to the annexin family, 3. Pathways by which ANXA3 exerts its role whose encoding gene is in human chromosome 4q13‑q22 (12). 4. Conclusion and prospects Previous studies have demonstrated that the molecular structures of ANXA3 and ANXA5 are highly homologous (13,14). The 2+ Ca binding sites of both annexins lie on the convex face of the 1. Introduction conversed domains, each of which contain helices A and B (13). The crystal structure of ANXA3 resembles that of ANXA8, Annexins. Annexins are a wellk ‑ nown multigene family, which which owns a complete and middle‑length N‑terminal 2+ bind to phospholipids in a Ca ‑dependent manner (1). They region (14). This is because both annexins are found in promy‑ are divided into v fi e groups (groups A, B, C, D and E), and elocytic cells undergoing the differentiation process (14). The are expressed in mammals, invertebrate, Mycetozoa and fungi, C‑terminal region of ANXA3 consists of four conserved plants and Protista, respectively (13 ‑ ). Group A annexins have domains (domains II ‑ V), forming a circular queue; each of them is composed of v fi e α‑helices (helices A‑E). The N‑terminal region comprises 20 amino acid residues that can facilitate the modulation of phospholipid membrane binding and ion perme‑ ation via ANXA3. ANXA3 contains two special tryptophan Correspondence to: Mrs. Xue Feng or Dr Guijian Liu, Clinical residues, one situated in the Nt ‑ erminal segment (W5), while the Laboratory, Guang'anmen Hospital, China Academy of Chinese other is at the extremity of IIIAI ‑ IIB loops (W190) (151 ‑ 7). Both Medical Sciences, 5 Bei Xiange Road, Beijing 100053, P.R. China tryptophans can inu fl ence the interactions between ANXA3 Em ‑ ail: [email protected] 2+ and phospholipid membrane, Ca (1517 ‑ ). Em ‑ ail: [email protected] Contributed equally Two isoforms of ANXA3. Increasing evidence suggest that the ANXA3 protein has two forms, one has a molecular weight of Key words: Annexin A3, cancer, role, pathway 33 kDa, while the other has a molecular weight of 36 kDa (12). Previous studies have reported that most tumours only express the 36 kDa form of the ANXA3 protein, while some cells LIU et al: ANNEXIN A3 AND CANCER simultaneously express both forms of the ANXA3 protein or in urine samples between patients with UTUC and healthy just express either of the two forms (33 kDa or 36 kDa), such as controls. High ANXA3 expression in patients with UTUC HL‑60 myeloid cells, rat brain cells, prostate cancer cells, the was further detected via western blot analysis. Taken together, retinal and choroidal endothelial cells (182 ‑ 2). Le Cabec et al these n fi dings suggest that high ANXA3 expression is strongly detected the expression of both forms of the ANXA3 protein in associated with tumorigenesis of UTUC, and thus ANXA3 may the human leukaemic myeloblast HL‑60 cells via western blot act as a potential biomarker for diagnosing UTUC. analysis (18). The results indicated that the 33 kDa and 36 kDa isoforms of ANXA3 protein were synchronously present in ANXA3 and the development and progression of gastric cancer. undifferentiated HL‑60 cells. When HL‑60 cells were differen ‑ By performing quantitative PCR and western blot analyses, tiated along the neutrophilic pathway or monocytic pathway, the Yu et al (25) reported that ANXA3 expression is upregulated 33 kDa form of the ANXA3 protein was mainly expressed in in gastric cancer tissues compared with adjacent normal tissues blood neutrophils, while the 36 kDa form of the ANXA3 protein at both the protein and mRNA levels. The protein and mRNA was expressed in monocytes. Junker et al (20) determined that expression levels of ANXA3 decreased following transfec‑ rat brain cells express the 33 kDa and 36 kDa isoforms of the tion with small interfering (si)RNA. In addition, ANXA3 ANXA3 protein. Further study demonstrated that the expression knockdown suppressed the cell proliferation, migration and of the 33 kDa isoform of ANXA3 is signic fi antly upregulated in invasion of gastric cancer. Collectively, these findings suggest the rat brain following the occurrence of cerebral ischaemia (20). that ANXA3 may participate in the tumorigenesis of gastric Using two‑dimensional electrophoresis combined with western cancer by acting as an oncogene. Researchers evaluated the blotting, Bianchi et al (23) detected ANXA3 protein expression expression intensity of ANXA3 in 80 gastric cancer tissues in primary cell cultures, which were isolated from 20 matched and investigated its association with prognosis, proliferation human renal cortical and renal cell carcinoma (RCC) tissues. and apoptosis of gastric cancer by tissue microarray combined The results demonstrated that the 33 kDa and 36 kDa isoforms with immunohistochemistry (26). The results demonstrated of the ANXA3 protein were both expressed. Compared with that ANXA3 expression was higher in gastric cancer compared renal cortical cultures, expression of the ANXA3 33 kDa form in with the controls, which was positively associated with tumour RCC cultures signic fi antly increased, whereas expression of the volume and TNM stage. 36 kDa form of the ANXA3 protein and total ANXA3 protein Ki3 ‑ 4 is a well‑known proliferating cell nuclear antigen, signic fi antly decreased. Furthermore, tissue microarray analysis and its function is strongly associated with mitosis (27). The revealed that ANXA3 protein expression is downregulated in proliferation index of Ki3 ‑ 4 is frequently used to estimate the RCC tissues compared with normal renal cortical tissues. malignant proliferation of tumour cells in the clinic setting (27). Increasing evidence suggest that generation of the 33 kDa Bcl2 i ‑ s an important indicator of the apoptotic signalling and 36 kDa isoforms of the ANXA3 protein has no association pathway, and is an antiapoptotic member of the Bcl2 ‑ protein with post‑translational modic fi ations, such as phosphorylation family (28). Upregulated ANXA3 expression causes alterations and N‑glycosylation (18). The mRNAs encoding ANXA3, in the expression levels of Ki‑34 and Bcl‑2, which signic fi antly which result from the alternative splicing of exon III, produce decreases the overall survival of patients with gastric cancer (26). two ANXA3 transcripts, including the 36 kDa isoform of the Upregulated ANXA3 expression was associated with a poor ANXA3 protein of a fulll ‑ ength protein and the 33 kDa isoform prognosis among 183 patients with gastric cancer (29). Inhibition of the ANXA3 protein, lacking the first 39 amino acid residues of ANXA3 suppresses tumorigenicity in vivo and suppresses of the N‑terminal region (18,21,23) (Fig. 1). The generation the proliferation, clone formation, migration and invasion of model of the two ANXA3 transcripts is similar to that of the gastric cancer cells (29). Taken together, these n fi dings suggest remaining members of the annexin family (2). that ANXA3 may serve as an independent marker of poor prognosis of gastric cancer. Recently, it has been demonstrated 2. ANXA3 and tumour that ANXA3 expression in the Ochratoxin A (OTA) induces the malignant transformation of human gastric epithelium cells ANXA3 and the development and progression of tumour. It (GES1 ‑ ) compared with normal GES1 c ‑ ells (30). The prolif ‑ has been reported that abnormal ANXA3 protein expression erative, migratory and invasive abilities of OTA‑GES1 ‑ T cells is closely associated with the development and progression of weaken following ANXA3 knockdown (30). Overexpression tumour. Overexpression of ANXA3 promotes the development of ANXA3 promotes the carcinogenesis of gastric cancer by and progression of tumours, such as upper tract urothelial cancer regulating the cell proliferation and apoptosis of gastric cancer. (UTUC), gastric carcinoma, hepatocellular carcinoma (HCC), However, further studies are required to determine the molec‑ breast cancer and osteosarcoma, whereas ANXA3 knockdown ular mechanisms underlying the contribution of ANXA3 to the suppresses the tumorigenesis of prostate carcinoma (24‑44) carcinogenesis of gastric cancer. (Table I). ANXA3 and the development and progression of HCC. ANXA3 ANXA3 and the development and progression of upper expression was detected in 20 pairs of HCC tumour tissues and tract urothelial cancer. Lu et al (24) investigated ANXA3 the corresponding normal tissues via immunohistochemical expression in urine samples and tissues, which were collected staining (31). The results demonstrated that ANXA3 expression from 13 patients with UTUC and 20 healthy individuals, was upregulated in 74% of HCC tumour tissues, suggesting that using non‑fixed volume stepwise weak anion exchange ANXA3 is strongly associated with the development of HCC. chromatography coupled with two‑dimensional electrophoresis This result was concordant with that of other groups (32,33). assay. The results revealed 55 differential expression proteins Western blot and quantitative PCR analyses were performed to ONCOLOGY LETTERS 22: 834, 2021 Table I. Role of Annexin A3 in the development and progression of cancer. Cancer Expression Role (Refs.) Upper tract urothelial cancer Upregulation in urine samples and tissues Strong association with tumorigenesis (24) Gastric cancer Upregulation in tumour tissues Promotes proliferation and (26) inhibits apoptosis of cells Hepatocellular carcinoma Upregulation in tumour tissues Enhances the proliferation, colony (31‑35) formation and migration of cells Prostate cancer Downregulation in tumour tissues Negatively associated with (38‑41) the pT stage and Gleason score Breast cancer Upregulation in tumour cells Promotes the proliferation (42,43) and colony formation of cells Osteosarcoma Upregulation in osteosarcoma cell lines Inhibits the apoptosis of cells (44) Figure 1. Diagram of the two isoforms of ANXA3. The 33 kDa and 36 kDa ANXA3 proteins. ANXA3 contains an N terminal, four annexin repeat domains (Ⅰ‑Ⅳ) and a C terminal. The 33 kDa isoform of ANXA3 lacks the first 39 amino acid residues of the N‑terminal region, unlike the 36 kDa isoform. ANXA3, Annexin A3; aa, amino acids. detect ANXA3 expression in 34 matched HCC tissues of and Nt‑ erminal kinase (JNK) signalling pathway (33). Recently, it adjacent normal liver tissues (32). The results demonstrated that has been reported that ANXA3 can promote tumorigenicity ANXA3 expression was notably higher in HCC tumour tissues in HCC by remodelling the immune microenvironment by compared with normal liver tissues, at both protein and mRNA regulating the infiltrated neutrophil‑lymphocyte ratio (iNLR) levels, which was further confirmed via immunohistochemistry and the release of chemokines, CXCL8 and CCL25 from HCC staining. ANXA3 expression was elevated in almost 58.1% cells (36). High ANXA3 expression is associated with high of 155 clinical primary HCC samples. Upregulated ANXA3 iNLR, and high risk of mortality in patients with HCC (36). expression was positively associated with tumour size of HCC, Taken together, these findings suggest that ANXA3 may be a advanced clinical stage and number of lesions, but was negatively potential diagnostic marker and therapeutic target for HCC (37). associated with the prognosis of HCC. Further functional inves‑ tigations demonstrated that upregulated ANXA3 expression ANXA3 and the development and progression of prostate enhanced cell proliferation, colony formation, cell migration cancer. A previous study identie fi d that ANXA3 is one of the and invasion of HCC. Conversely, downregulation of ANXA3 four proteins whose expression signic fi antly differs between significantly suppressed these cell behaviours. Collectively, 31 prostate cancer tissues and matched benign tissues on differ‑ these n fi dings suggest that ANXA3 may severe as an indepen ‑ ential radioactive quantic fi ation (38). Immunohistochemistry dent prognostic factor for patients with HCC. ANXA3 may play analysis further demonstrated that ANXA3 expression was an oncogenic role in promoting tumorigenesis of HCC, and thus lower in the cancer group compared with the benign group, and is considered a novel target for HCC therapy (32). A previous low ANXA3 expression was dependent on the Gleason pattern study demonstrated that ANXA3 expression is higher in 50.6% of prostate cancer with a negative correlation. Köllermann et al of primary HCC clinical samples compared with matched adja‑ and Jeun et al also provided powerful data regarding the asso‑ cent normal liver samples (33). ciation between ANXA3 and prostate cancer (39,40). These The cancer stem cell (CSC), which has the capacity for authors examined altered ANXA3 expression in prostate tumour initiation, self‑renewal and differentiation, has recently cancer, benign epithelium and highg ‑ rade prostatic intraepi ‑ been considered to contribute to the recurrence and metastasis of thelial neoplasia (PIN) tissues using immunohistochemistry HCC (34). CD133 is a molecular indicator of CSCs in HCC and is and tissue microarray. The results demonstrated that ANXA3 used to obtain HCC steml ‑ ike cells isolated from HCC cells (35). expression was notably downregulated in prostate cancer tissues Pan et al reported that compared with non‑CSCs, CSCs derived compared with benign epithelium and highg ‑ rade PIN tissues, from Huh7 cells highly expressed endogenous ANXA3 (32). and ~27.2% of prostatic cancer samples negatively expressed In addition, ANXA3 plays an essential role in conferring the ANXA3. Downregulated ANXA3 expression was negatively stemness of HCC by inhibiting the hypoxiai‑ nducible factor associated with the pT stage and Gleason score of prostate (HIF)‑1 α/NOTCH pathway (34). Tong et al demonstrated that cancer but positively associated with poor prognosis of prostate both endogenous and exogenous ANXA3 proteins can maintain cancer, suggesting that ANXA3 may be used as a marker for the the CSC characteristics of HCC cells and facilitate selfr ‑ enewal early diagnosis of prostate cancer. Other studies have reported and proliferation of HCC CSCs by downregulating the cJ ‑ UN the value of ANXA3 in diagnosing prostate cancer (40,41). LIU et al: ANNEXIN A3 AND CANCER Table II. Role of Annexin A3 in cancer resistance to drugs. Cancer Drugs Resistance (Refs.) Hepatocellular carcinoma Cisplatin, 5‑fluorouracil, staurosporine and sorafenib Increase (33,34,45) Ovarian carcinoma Platinum and cisplatin Increase (46‑48) Lung cancer Platinum, cisplatin and oxaliplatin Increase (49,50) Prostate cancer Cyclophosphamide Increase (51) Breast cancer Doxorubicin Increase (52) Colorectal cancer Oxaliplatin Increase (53) Western blot analysis was performed to detect ANXA3 protein ANXA3 and the drug resistance of tumours. Recently, it has expression in the urine samples of 590 patients, of whom been suggested that ANXA3 may exert an important inu fl ence 367 had prostate cancer and 223 had an unverie fi d adenocar ‑ on the drug resistance of different types of tumours, such as cinoma (41). The results demonstrated that the sensitivity and HCC, ovarian carcinoma, lung adenocarcinoma (LADC) and specificity of ANXA3 as a diagnostic marker for prostate prostatic carcinoma (Table II). cancer exceeded that of tPSA, since patients had negative n fi d ‑ ings on digital rectal examination and low prostate‑specic fi Role of ANXA3 in HCC drug resistance. To study the role of antigen concentration (21 ‑ 0 ng/ml). A recent study reported that ANXA3 in drug resistance, the expression of ANXA3 was ANXA3 expression in urine is clinically associated with the changed in different HCC cell lines by overexpressing ANXA3 actual tumour volume (40). Collectively, these n fi dings suggest or by targeting the ANXA3‑specific shRNA vectors (32). that the quantic fi ation of ANXA3 expression in urine samples Results of the in vitro drug sensitivity assay and in vivo tumour may be used as a specic fi marker for the early diagnosis of growth suppression assay indicated that overexpression of prostate cancer. ANXA3 notably enhanced the drug resistance of HCC cells to cisplatin and 5‑u fl orouracil (5‑FU), while ANXA3 knock ‑ ANXA3 and the development and progression of breast down significantly decreased the resistance to these drugs. cancer. ANXA3 expression is higher in breast cancer cell lines Thus, ANXA3 may play an important role in the occurrence (MDAM ‑ B 231, HCC‑69 and HCC1 ‑ 954) compared with other of drug resistance in patients with HCC, and may serve as cell types (42). ANXA3 knockdown inhibits the proliferation an innovative target for HCC treatment. Tong et al (33) and colony forming ability of MDAM ‑ B 231 cells in vitro (42). reported that increased ANXA3 expression resulted in the In another study, the inu fl ence of ANXA3 on the incidence of occurrence of drug resistance among patients with HCC to breast cancer was evaluated using a nude mouse model bearing cisplatin, 5‑FU and staurosporine both in vitro and in vivo. a subcutaneous tumour in vivo (43). The volume and weight of Another study investigated the role of ANXA3 in the tumours in the ANXA3 silencing group was smaller compared resistance of HCC cells to 5‑FU (32). They established the with the control group. Furthermore, the level of red blood Bel7302/5‑FU cell line, which is resistant to 5‑FU, and its vessels was relatively low in the ANXA3 silencing group. The parental Bel7302 cell line, which is sensitive to 5‑FU (32). proliferation rate was lower; however, the G /G cell ratio was Using the quantitative proteomic method bearing isobaric 0 1 higher in the transfection group compared with the control labelling combined with 2D LC‑MS /MS, ANXA3 expres‑ group (43). ANXA3 expression was associated with the size sion was identie fi d to be higher in Bel7302 /5‑FU compared of the tumour and diseasef ‑ ree survival in 30 patients with with Bel7302, which was further validated via western primary breast cancer (42). Taken together, these findings blot and quantitative PCR analyses. Furthermore, ANXA3 suggest that ANXA3 plays an important role in the initiation knockdown in 5‑FU‑resistant Bel7302 /5‑FU cells notably and progression of breast cancer, and thus may be used as a decreased the drug resistance of HCC cells to 5‑FU, cisplatin potential therapeutic target for breast cancer. and adriamycin. A recent study demonstrated that ANXA3 expression is higher in sorafenib‑resistant HCC cells, HepG2 ANXA3 and the development and progression of osteo‑ and Huh7, and sorafenib‑resistant patient‑derived HCC sarcoma. ANXA3 expression is higher in osteosarcoma xenografts (45). Patients with low ANXA3 expression had cell lines, HOS and U2OS, compared with osteoblasts (44). a better prognosis after receiving sorafenib treatment than To further examine the role of ANXA3 in osteosarcoma those with high ANXA3 expression. Furthermore, ANXA3 cells, ANXA3 siRNA was transfected into HOS, U2OS knockdown in the sorafenib‑resistant HCC cells, HepG2 and and osteoblasts. The mRNA and protein expression levels Huh7, suppressed the resistance of HCC cells to sorafenib (45). of ANXA3 were successfully inhibited following transfec‑ Further experiments demonstrated that antiA ‑ NXA3 therapy tion with siRNA. The results demonstrated that ANXA3 (antiA ‑ NXA3 monoclonal antibody) combined with sorafenib knockdown decreased the apoptotic rate of HOS and U2OS can increase the apoptotic rate compared with sorafenib alone cells by 3‑fold (44). These findings suggest that ANXA3 may in sorafenib‑resistant HCC cells (45). Taken together, these n fi d ‑ regulate the tumorigenicity by influencing the apoptosis of ings suggest that ANXA3 may be strongly associated with the osteosarcoma cells. multi‑drug resistance (MDR) in HCC. The association between ONCOLOGY LETTERS 22: 834, 2021 ANXA3 and drug resistance in HCC provides novel and impor‑ Role of ANXA3 in prostate cancer drug resistance. tant clues to further investigate MDR in other types of tumours. Thoenes et al (51) established an SCID mice model, developed a prostate cancer phenotype that is resistant to metronomic cyclo‑ Role of ANXA3 in ovarian carcinoma drug resistance. In phosphamide (CPA) and obtained samples of prostate cancer human ovarian cancer cell lines, which are resistant to platinum, PC3D ‑ 3 and PC4D ‑ 4 cell lines that are resistant to CPA and ANXA3 expression was reported to be higher than that in human parental prostate cancer PC3D ‑ 3 cell lines. The results demon ‑ epithelial ovarian cancer cell lines. ANXA3 expression notably strated that ANXA3 expression in prostate cancer PC3D ‑ 3 and increased in tumour tissues obtained from platinumr ‑ esistant PC4D ‑ 4 cell lines that are tolerant to CPA was higher than that patients with ovarian cancer than those obtained from plat‑ in parental prostate cancer PC3‑D3 cell lines. Furthermore, inum‑sensitive patients (46‑48). Yan et al (47) demonstrated ANXA3 expression was notably higher in xenografts treated that upregulated ANXA3 expression notably decreases the with CPA compared with groups without CPA treatment. These amount of cisplatin uptake and p53 expression induced by results indicate that high ANXA3 expression may enhance cisplatin, and ANXA3 knockdown significantly increases the drug resistance of prostate cancer to CPA, and can serve intracellular cisplatin concentrations in ovarian cancer cells. as a novel biomarker for predicting chemoresistance in prostate These results suggest that the upregulation of ANXA3 expres‑ cancer. sion may be the specic fi mechanism responsible for the increase in ovarian cancer chemoresistance to cisplatin; however, the Role of ANXA3 in breast cancer drug resistance. Doxorubicin precise mechanism of ANXA3 leading to cisplatin resistance (Dox) is widely used for the treatment of breast cancer. To in ovarian cancer requires further investigation. Another study further investigate the role of ANXA3 in the resistance of breast indicated that ANXA3 was detected in the ovarian cancer cancer to Dox, ANXA3 expression was inhibited in the human cell culture medium (48). The amount of secreted ANXA3 is breast cancer cell line, MDAM ‑ B2 ‑ 31 and mouse mammary dependent on the expression level of ANXA3 in ovarian cancer cancer cell line, 4T1, and ANXA3 silencing cells were treated and the degree of ovarian cancer chemoresistance to cisplatin. with Dox (52). Flow cytometric analysis demonstrated that there The research demonstrated that there were more elliptical was increased Dox accumulation in ANXA3 silencing cells vesicles containing different concentrations of drugs in the compared with normal cells (52). To further investigate the role cytoplasm of platinumr ‑ esistant ovarian cancer cell lines than in of ANXA3 in the resistance of breast cancer to Dox in vivo, platinums ‑ ensitive parental ovarian cancer cell lines (48). Part ANXA3 silencing and normal MDA‑MB2 ‑ 31 and 4T1 cells of the elliptical vesicles can fuse with the cell membrane, which were transplanted into the BALB/c mice. When the tumour size suggests that ANXA3 expression may be owing to exocytosis reached to 23 ‑ mm, the mice were treated with Dox. The results and the release of exosomes. These results demonstrate that demonstrated that ANXA3 silencing enhanced the sensitivity ANXA3 increases the chemoresistance of ovarian cancer of Dox to breast cancer (52). Thus, ANXA3 may inu fl ence the to platinum by increasing the aggregation of vesicles and the resistance of breast cancer to Dox by regulating the cellular exocytosis of vesicles containing drugs. Thus, ANXA3 may be accumulation of Dox. a valuable target for the chemical therapy of ovarian cancer. Role of ANXA3 in colorectal cancer drug resistance. Ox is Role of ANXA3 in lung cancer drug resistance. A previous used as a chemotherapy drug for colorectal cancer (CRC) (53). study investigated ANXA3 expression in lung cancer A549 To determine the role of ANXA3 on Ox resistance in CRC, cells, with and without platinum resistance, and LADC two CRC cell lines, HCT116 and SW480, were treated tissues (49). The results demonstrated that ANXA3 expression with Ox and exhibited resistance to Ox (HCT116/Ox and in platinum‑resistant lung cancer A549 cells was signic fi antly SW480/Ox) (53). The halfm ‑ aximum inhibitory concentration higher than that in the nonr ‑ esistant groups, at both the protein values of Ox in HCT116/Ox and SW480/Ox cells were higher and mRNA levels. In addition, ANXA3 expression was also than that in their parental cells, suggesting that HCT116/Ox detected in platinum‑resistant LADC tissues, suggesting and SW480/Ox were resistant to Ox. Furthermore, ANXA3 that ANXA3 may play an important role in the resistance of expression in HCT116/Ox and SW480/Ox was higher LADC to cisplatin. Platinumr ‑ esistant lung cancer A549 cells compared with HCT116 and SW480 cells, suggesting that were further treated with a molecular compound that can ANXA3 is associated with Ox resistance in CRC cells. Further bind with ANXA3. Analysis demonstrated that cell viability experiments demonstrated that ANXA3 silencing suppressed of cisplatin‑resistant LADC signica fi ntly reduced, suggesting Ox resistance in CRC via the mitogena ‑ ctivated protein kinase that the compound targeting ANXA3 can induce cell death in signalling pathway (53). Collectively, these results suggest that platinumr ‑ esistant lung cancer A549 cells. Thus, ANXA3 may ANXA3 plays an important role in CRC resistance to Ox. be a novel therapeutic target to circumvent cisplatin resistance Thus, clinical studies are required to determine the role of in patients with LADC (49). A recent study demonstrated that ANXA3 in CRC resistance to Ox. ANXA3 expression is higher in oxaliplatin (Ox)r ‑ esistant A549 lung cancer cells (A549/Ox) compared with normal A549 cells, Role of ANXA3 in tumour metastasis. Recent studies have which suggests that ANXA3 may be associated with lung demonstrated that altered ANXA3 expression is closely associ‑ cancer cell resistance to Ox (50). Further experiments demon‑ ated with the metastasis of different types of cancer (Table III). strated that ANXA3 knockdown in A549/Ox cells can enhance ANXA3 expression is higher in different types of cancer tissues the effect of Ox on lung cancer cells (50). Collectively, these compared with controls, such as breast, lung, gallbladder and findings suggest that ANXA3 knockdown can suppress the colon cancer tissues. Overexpression of ANXA3 promotes resistance of lung cancer cells to Ox. cancer metastasis. ANXA3 expression is downregulated in LIU et al: ANNEXIN A3 AND CANCER Table III. Role of Annexin A3 in the metastasis of cancer. Cancer Expression Role (Refs.) Breast cancer Upregulation in patients with May promote metastasis (54‑57) lymph node metastasis Lung cancer Upregulation in patients with metastasis May promote lymph node metastasis (58,59) Papillary thyroid carcinoma Downregulation in patients with metastasis Significantly associated with metastasis (60) Gallbladder carcinoma Upregulation in patients with metastasis May promote metastasis (61,62) Colon cancer Upregulation in patients with cancer May promote metastasis (63‑68) via the HIF‑1 α pathway Pancreatic cancer Upregulation in patients with Promotes epithelial‑to‑mesenchymal (69) pancreatic cancer transition and lymph node metastasis HIF, hypoxia‑inducible factor. papillary thyroid carcinoma compared with normal tissues, cancer cells (59). These results suggest that ANXA3 expression which promotes cancer metastasis (54‑69). may promote lymph node metastasis of lung cancer. Thus, ANXA3 may be used as a novel biomarker for predicting the Role of ANXA3 in breast cancer metastasis. Previous studies metastasis and prognosis of lung cancer. have reported that ANXA3 is expressed in several human breast cancer cell lines and 60 breast cancer tissues (42,54). Western Role of ANXA3 in papillary thyroid carcinoma metastasis. blot and immunohistochemistry analyses demonstrated that Jung et al (60) analysed the differential protein expression of ANXA3 is highly expressed in MCF7 a ‑ nd MDA‑MB‑435 25 pairs of papillary thyroid carcinomas and corresponding cells, and breast cancer tissues (54). Other studies have reported normal tissues by performing two‑dimensional electrophoresis, the high ANXA3 expression in breast cancer cells, and ANXA3 mass spectrometry, western blot, northern blot and immunohis‑ silencing signic fi antly suppresses the migration and invasion of tochemical analyses, and found that ANXA3 expression was breast cancer cells (42,55). ANXA3 was positively expressed in lower in papillary thyroid carcinoma compared with the controls, 27/35 patients with lymph node metastasis, and only positively at both mRNA and protein levels. Immunohistochemistry expressed in 12/25 patients without lymph node metastasis (54). analysis demonstrated that ANXA3 expression in papillary Further analysis demonstrated that the diseasef ‑ ree survival and thyroid carcinoma with lymph node metastasis decreased, but overall survival times of patients with ANXA3p ‑ ositive breast the differences were not signic fi ant. However, ANXA3 expres ‑ cancer were signic fi antly shorter compared with patients with sion was signic fi antly lower in papillary thyroid carcinoma with ANXA3n ‑ egative breast cancer. However, ANXA3 expression lymph node metastasis. Papillary thyroid carcinoma tissues is not associated with age, hormone receptor, tumour grade and without lymph node metastasis had a staining score of >3, while histology (54). Further studies also confirmed that ANXA3 those with lymph node metastasis had a staining score of ≤3. expression is positively associated with the diseasef ‑ ree survival Further analysis revealed that ANXA3 expression was high in and overall survival of lymph node metastasis in patients with 61.1% of papillary microcarcinoma tissues without lymph node breast cancer (42,56). ANXA3 expression is higher in patients metastasis; however, the expression of ANXA3 was low in with triple‑negative breast cancer, which frequently metasta ‑ 67.2% of papillary thyroid carcinoma tissues with lymph node sises compared with other types of cancer (56,57). These results metastasis. These results suggest that low ANXA3 expression is suggest that high ANXA3 expression may promote the metas‑ signic fi antly associated with the metastasis of papillary thyroid tasis of breast cancer. ANXA3 is an independent factor of poor carcinoma; thus, it may be used as one of the negative predictive prognosis in breast cancer, and thus may be a novel potential indexes of papillary thyroid carcinoma. therapeutic target for predicting breast cancer metastasis (56,57). Role of ANXA3 in gallbladder carcinoma metastasis. Role of ANXA3 in lung cancer metastasis. The differential Tan et al (61) performed two‑dimensional electrophoresis and protein expression between LADC tissues with and without mass spectrometry to evaluate the differential protein expres‑ lymph node metastasis were identified using fluorescence sion of ANXA3 between six pairs of gallbladder carcinoma differential gel electrophoresis and mass spectrometry and benign gallbladder tissues. Immunohistochemical analysis analysis (58). Western blot and immunohistochemistry analyses demonstrated that high ANXA3 expression was closely associ‑ demonstrated that the expression of ANXA3 was higher in ated with tumour grade, lymph node metastasis and postoperative the metastasis group compared with the nonm ‑ etastasis group. survival of gallbladder carcinoma. Similarly, Wang et al (62) Further analysis indicated that high ANXA3 expression performed western blot and reverse transcription‑quantitative increased the postoperative recurrence rate and decreased the PCR analyses, and reported that ANXA3 expression was average and overall survival rate of patients with LADC, which signic fi antly higher in GBC‑SD18H cells, with high metastatic was not associated with sex, age, tumour size and differentiation. potential, compared with GBC‑SD18L cells, with low metastatic In addition, ANXA3 silencing inhibits the invasion of lung potential (62). Collectively, these results suggest that ANXA3 ONCOLOGY LETTERS 22: 834, 2021 may promote gallbladder carcinoma metastasis. Thus, ANXA3 with ANXA3 shRNA and LY294002, ANXA3 expression may be used as a therapeutic target for gallbladder carcinoma. decreased, but the PI3K/Akt pathway was not activated (71). This suggests that ANXA3 may regulate cellular behaviour in Role of ANXA3 in colon cancer metastasis. The mRNA levels individuals with AMI via the PI3K/Akt pathway. Thus, ANXA3 of ANXA3 in the blood of patients with colon cancer was may play an important role in the development of cancer via the signic fi antly higher compared with healthy controls (63,64). PI3K/Akt pathway. Another study reported that ANXA3 expression was upregu‑ lated in colon cancer tissues, suggesting that ANXA3 may be NF‑ κB signalling pathway. ANXA3 expression is upregu‑ closely associated with colon cancer (65). Xie et al analysed lated in breast cancer tissues compared with paracancerous ANXA3 and HIF‑ α expression and their association with the tissues (52). High ANXA3 expression is associated with poor clinicopathological characteristics and prognosis of 60 patients overall survival, suggesting that ANXA3 may play an impor‑ with colon cancer (65,66). The results demonstrated that tant role in the development of breast cancer (52). To further 65 and 47% of patients with colon cancer had high ANXA3 evaluate its role in breast cancer, shRNA‑targeted ANXA3 and HIF‑ α expression, respectively, and ANXA3 was closely was transfected in vivo and vitro. The results demonstrated that associated with tumour size and Dukes' staging. HIF‑ α is as ANXA3 silencing inhibited cell invasion, whilst promoting key regulator of tumour angiogenesis (67,68). It can stimulate cell proliferation (52). This result remains controversial, as it is vascular endothelial growth factor (VEGF) expression in difc fi ult to determine whether the protein is ‘good’ or ‘bad’ for tumours (67,68). The expression patterns of ANXA3 and HIF‑ α the development of breast cancer. Further experiments indicated were similar, and their expression was closely associated. These that ANXA3 knockdown inhibited the NF‑ κB pathway by results suggest that high ANXA3 expression promotes the increasing IκBα expression, which is a cellular protein (52,72). development and metastasis of colon cancer, which may induce NF‑ κB plays an important role in the EMT process in a breast angiogenesis via the HIF‑ α signalling pathway. cancer model (73). ANXA3 silencing regulates the EMT process via the NF‑ κB pathway. Blockade of the IκBα pathway can alle‑ Role of ANXA3 in pancreatic cancer metastasis. Quantitative viate the EMT process induced by ANXA3 knockdown (73). PCR and western blot analyses demonstrated that ANXA3 These results suggest that ANXA3 may play roles in the devel‑ was highly expressed in 115 patients with pancreatic cancer opment of other types of cancer via the NF‑ κB pathway, which (PC) (69). ANXA3 silencing inhibits epithelialt ‑ om ‑ esenchymal should be validated by further studies. transition (EMT) and lymph node metastasis (69). In addition, ANXA3 knockdown suppresses the migratory and invasive JNK signalling pathway. ANXA3 is closely associated with abilities of PC cells in vitro (69). The suppression of lymph HCC. ANXA3 expression in the sera of patients with HCC is node metastasis by ANXA3 silencing has also been confirmed associated with their clinical features (8). Excessive ANXA3 in tumour xenografts in vivo (69). Taken together, these results expression plays an important role in promoting cancer and suggest that ANXA3 silencing can inhibit the metastasis of PC. inducing stem cell features in live CD133 liver CSCs (33). Thus, ANXA3 may be a potential therapeutic target for PC ANXA3 exerts its role by enhancing the JNK signalling metastasis. pathway, thus increasing JNK kinase activity and its expres‑ In conclusion, ANXA3 plays an important role in the devel‑ sion (33). Blockade of ANXA3 with a monoclonal antibody can opment, metastasis and drug resistance of different types of reduce tumour growth and selfr ‑ enewal in vitro and in vivo (33). cancer. However, the pathways by which ANXA3 exerts its role Cancer‑related fibroblasts (CAFs), which are found within remain unclear. cancer cells, have a signic fi ant effect on the proliferation, metas ‑ tasis, chemoresistance and invasion of cancer cells (74). ANXA3 3. Pathways by which ANXA3 exerts its role expression is higher in CAFs in tumour tissues compared with normal b fi roblasts (74). The CAF‑conditioned medium Phosphatidylinositol3 k ‑ inase (PI3K) /Akt signalling pathway. can increase ANXA3 expression in lung cancer cells, which The PI3K/Akt signalling pathway plays an important role in cell increases cisplatin resistance. Conversely, ANXA3 knockdown proliferation, metabolism and migration (70). AMI is a conse‑ in lung cancer increases cisplatin sensitivity. ANXA3 plays an quence of coronary atherosclerotic heart disease, which can lead important role in the chemoresistance of lung cancer by regu‑ to the reduction of myocardial cells (71). An AMI rat model was lating JNK activity. Using the specic fi JNK activity inhibitor constructed (71). ANXA3 shRNA was transfected into different can retard the effect of ANXA3 on cisplatin resistance. Thus, groups of rats to inhibit ANXA3 expression. The results ANXA3 expression promotes HCC and lung cancer via the demonstrated that ANXA3 silencing alleviated the inflam‑ JNK signalling pathway (74). Another study reported that mation reaction by reducing the expression of ina fl mmatory ANXA3 silencing ameliorates the intracranial aneurysm by markers, such as interleukin (IL)‑6, tumour necrosis factor α inhibiting the JNK signalling pathway (75). Thus, ANXA3 may (TNF‑ α) and nitric oxide (NO). Furthermore, transfection with exert its role in different types of cancer and diseases via the ANXA3 shRNA increased the mRNA and protein expression JNK signalling pathway. levels of Bcl2 ‑ , bFGF and VEGF, and phosphorylation of Akt. These findings suggest that ANXA3 silencing may regulate cell Extracellular signal‑regulated kinase (ERK) signalling behaviour via the PI3K/Akt signalling pathway. LY294002, an pathway. Quantitative proteomics analysis demonstrated that inhibitor of the PI3K/Akt signalling pathway, can activate the ANXA3 expression is higher in LADC tissues (76). Furthermore, PI3K/Akt signalling pathway and alleviate ina fl mmation, which ANXA3 knockdown inhibits the proliferation, invasion, migra‑ is caused by ANXA3 silencing (71). In animals transfected tion and metastases of LADC cells in vivo and in vitro (76). LIU et al: ANNEXIN A3 AND CANCER Figure 2. Signal transduction pathways by which ANXA3 exerts its role. ANXA3 exerts its role by regulating cell proliferation, migration and apoptosis by downregulating the PI3K/Akt signalling pathway and upregulating the NF‑ κB, JNK, ERK and HIF1 s ‑ ignalling pathways. ANXA3, Annexin A3; PI3K, phosphatidylinositol3 ‑ kinase; NF‑ κB, nuclear factor‑ κB; JNK, cJ ‑ UN N‑terminal kinase; ERK, extracellular signal‑regulated kinase; HIF, hypoxiai ‑ nducible factor. However, the molecular mechanism by which ANXA3 knock‑ as prostate cancer, upper tract urothelial carcinoma, gastric down affects LADC cells remains unclear. It has been reported cancer, hepatocellular cancer, ovarian cancer, lung cancer, that ANXA3 silencing can reduce the phosphorylation of MEK breast cancer and gallbladder cancer. Its altered expression is and ERK (76). Thus, ANXA3 may exert its role via the ERK a potential biomarker for tumour staging, grading, metastasis signalling pathway. In addition, ANXA3 expression is higher in and prognosis of patients. Thus, it may be used as a novel two CRC cell lines, HCT116/Ox and SW480/Ox, which develop target for the treatment and diagnosis of tumour. ANXA3 Ox resistance. ANXA3 silencing can reduce the proliferation, exerts its role via the PI3K/Akt, NF‑ κB, JNK, ERK and migration, invasion, migration and metastases of CRC cells, HIF1 s ‑ ignalling pathways (Fig. 2). In addition, ANXA3 has but promote cell apoptosis. Furthermore, ANXA3 knockdown two isoforms (33 kDa and 36 kDa ANXA3 proteins), and the can reduce the phosphorylation of ERK and JNK. The ERK expression patterns of these two isoforms vary in different inhibitor can reverse the changes caused by ANXA3 knock‑ types of cells. Further studies are required to verify the func‑ down (53). Taken together, these n fi dings suggest that ANXA3 tion of ANXA3 and its two isoforms in tumours and their may exert its role via the ERK signalling pathway in lung cancer mechanisms. and CRC. Acknowledgements HIF1 s ‑ ignalling pathway. ANXA3 expression is higher in the sera of patients with melanoma compared with healthy Not applicable. controls (77). In addition, ANXA3 expression has a close association with the overall survival of patients with Funding melanoma, suggesting that ANXA3 may play an important role in melanoma. Overexpression of ANXA3 can promote No funding was received. the proliferation and migration of human melanoma WM1 ‑ 15 cells. Conversely, ANXA3 knockdown inhibits cell Availability of data and materials proliferation and migration (77). Furthermore, ANXA3 exerts its role by activating HIF1 ‑ α (77). Another study reported that Not applicable. ANXA3 increases the migration and tube formation of human umbilical vein endothelial cells (9). Furthermore, ANXA3 can Authors' contributions induce VEGF production via the HIF1 p ‑ athway (9). Thus, ANXA3 may play certain roles in cancer and the angiogenesis CL and NL performed the literature review and drafted the process via the HIF1 p ‑ athway. It also plays an important role initial manuscript. GL and XF critically revised the manu‑ in the maintenance of cancer steml‑ ike cells /canceri ‑ nitiating script for important intellectual content. Data authentication cells via the HIF pathway (78). is not applicable. All authors have read and approved the manuscript. 4. 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Tan Y, Meng HP, Wu Q, Wang FQ and Wu HR: Proteomic study International (CC BY-NC-ND 4.0) License. of gallbladder cancer, with special reference on the expression and signic fi ance of annexin A3. Zhonghua Bing Li Xue Za Zhi 39: 3823 ‑ 86, 2010 (In Chinese). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Oncology Letters Pubmed Central

Annexin A3 and cancer

Liu, Chao; Li, Nannan; Liu, Guijian; Feng, Xue
Oncology Letters , Volume 22 (6) – Oct 14, 2021
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10.3892/ol.2021.13095
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Abstract

ONCOLOGY LETTERS 22: 834, 2021 Annexin A3 and cancer (Review) * * CHAO LIU , NANNAN LI , GUIJIAN LIU and XUE FENG Clinical Laboratory, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China Received August 5, 2021; Accepted September 29, 2021 DOI: 10.3892/ol.2021.13095 Abstract. Annexin A3 (ANXA3), an annexin family member, been extensively studied due to their association with the devel‑ contains 36 kDa and 33 kDa isoforms. Similar to other annexin opment of human diseases. This group contains 12 members members, ANXA3 plays an important role in the development (annexins A1A ‑ 11 and annexin A13). The structure of annexins of human diseases. Recent studies have reported that abnormal is similar; they are composed of a highly conserved Ct ‑ erminus ANXA3 expression is closely associated with the develop‑ and a variable N‑terminus. The C‑terminal protein core ment, progression, metastasis, drug resistance and prognosis contains four annexin repeats, each composed of 698 ‑ 0 amino of several malignant tumours, such as breast cancer, lung acid residues (4). The N‑terminal domain is highly variable, cancer and hepatocellular carcinoma. ANXA3 exerts its role in which the diversity of the amino acid sequence and length by regulating cell proliferation, migration and apoptosis via the result in the difference of functions among all annexin family phosphatidylinositol3 ‑ kinase /Akt, nuclear factor‑ κB (NF‑ κB), members (4,5). Recent studies have reported that annexins play cJ ‑ UN Nte ‑ rminal kinase, extracellular signalr ‑ egulated kinase an important role in tumour development and progression, cell and hypoxiai‑ nducible factor1 s ‑ ignalling pathways. ANXA3 proliferation and apoptosis, invasion and metastasis, drug resis‑ may act as a novel target for the early diagnosis and treatment tance and angiogenesis (6,7). of tumours. The present review summarises the recent progress Annexin A3 (ANXA3), a member of the annexin family , is also in the role of ANXA3 and its regulatory pathways in tumours. known as lipocortin III or placental anticoagulant protein III (3). ANXA3 is considered a new angiogenesis factor (8,9), which participates in the liver regeneration process (10,11). ANXA3 is Contents also closely associated with the development of human diseases, such as cancer and ina fl mmation (3,12). 1. Introduction 2. ANXA3 and tumour Structure of ANXA3. ANXA3 belongs to the annexin family, 3. Pathways by which ANXA3 exerts its role whose encoding gene is in human chromosome 4q13‑q22 (12). 4. Conclusion and prospects Previous studies have demonstrated that the molecular structures of ANXA3 and ANXA5 are highly homologous (13,14). The 2+ Ca binding sites of both annexins lie on the convex face of the 1. Introduction conversed domains, each of which contain helices A and B (13). The crystal structure of ANXA3 resembles that of ANXA8, Annexins. Annexins are a wellk ‑ nown multigene family, which which owns a complete and middle‑length N‑terminal 2+ bind to phospholipids in a Ca ‑dependent manner (1). They region (14). This is because both annexins are found in promy‑ are divided into v fi e groups (groups A, B, C, D and E), and elocytic cells undergoing the differentiation process (14). The are expressed in mammals, invertebrate, Mycetozoa and fungi, C‑terminal region of ANXA3 consists of four conserved plants and Protista, respectively (13 ‑ ). Group A annexins have domains (domains II ‑ V), forming a circular queue; each of them is composed of v fi e α‑helices (helices A‑E). The N‑terminal region comprises 20 amino acid residues that can facilitate the modulation of phospholipid membrane binding and ion perme‑ ation via ANXA3. ANXA3 contains two special tryptophan Correspondence to: Mrs. Xue Feng or Dr Guijian Liu, Clinical residues, one situated in the Nt ‑ erminal segment (W5), while the Laboratory, Guang'anmen Hospital, China Academy of Chinese other is at the extremity of IIIAI ‑ IIB loops (W190) (151 ‑ 7). Both Medical Sciences, 5 Bei Xiange Road, Beijing 100053, P.R. China tryptophans can inu fl ence the interactions between ANXA3 Em ‑ ail: [email protected] 2+ and phospholipid membrane, Ca (1517 ‑ ). Em ‑ ail: [email protected] Contributed equally Two isoforms of ANXA3. Increasing evidence suggest that the ANXA3 protein has two forms, one has a molecular weight of Key words: Annexin A3, cancer, role, pathway 33 kDa, while the other has a molecular weight of 36 kDa (12). Previous studies have reported that most tumours only express the 36 kDa form of the ANXA3 protein, while some cells LIU et al: ANNEXIN A3 AND CANCER simultaneously express both forms of the ANXA3 protein or in urine samples between patients with UTUC and healthy just express either of the two forms (33 kDa or 36 kDa), such as controls. High ANXA3 expression in patients with UTUC HL‑60 myeloid cells, rat brain cells, prostate cancer cells, the was further detected via western blot analysis. Taken together, retinal and choroidal endothelial cells (182 ‑ 2). Le Cabec et al these n fi dings suggest that high ANXA3 expression is strongly detected the expression of both forms of the ANXA3 protein in associated with tumorigenesis of UTUC, and thus ANXA3 may the human leukaemic myeloblast HL‑60 cells via western blot act as a potential biomarker for diagnosing UTUC. analysis (18). The results indicated that the 33 kDa and 36 kDa isoforms of ANXA3 protein were synchronously present in ANXA3 and the development and progression of gastric cancer. undifferentiated HL‑60 cells. When HL‑60 cells were differen ‑ By performing quantitative PCR and western blot analyses, tiated along the neutrophilic pathway or monocytic pathway, the Yu et al (25) reported that ANXA3 expression is upregulated 33 kDa form of the ANXA3 protein was mainly expressed in in gastric cancer tissues compared with adjacent normal tissues blood neutrophils, while the 36 kDa form of the ANXA3 protein at both the protein and mRNA levels. The protein and mRNA was expressed in monocytes. Junker et al (20) determined that expression levels of ANXA3 decreased following transfec‑ rat brain cells express the 33 kDa and 36 kDa isoforms of the tion with small interfering (si)RNA. In addition, ANXA3 ANXA3 protein. Further study demonstrated that the expression knockdown suppressed the cell proliferation, migration and of the 33 kDa isoform of ANXA3 is signic fi antly upregulated in invasion of gastric cancer. Collectively, these findings suggest the rat brain following the occurrence of cerebral ischaemia (20). that ANXA3 may participate in the tumorigenesis of gastric Using two‑dimensional electrophoresis combined with western cancer by acting as an oncogene. Researchers evaluated the blotting, Bianchi et al (23) detected ANXA3 protein expression expression intensity of ANXA3 in 80 gastric cancer tissues in primary cell cultures, which were isolated from 20 matched and investigated its association with prognosis, proliferation human renal cortical and renal cell carcinoma (RCC) tissues. and apoptosis of gastric cancer by tissue microarray combined The results demonstrated that the 33 kDa and 36 kDa isoforms with immunohistochemistry (26). The results demonstrated of the ANXA3 protein were both expressed. Compared with that ANXA3 expression was higher in gastric cancer compared renal cortical cultures, expression of the ANXA3 33 kDa form in with the controls, which was positively associated with tumour RCC cultures signic fi antly increased, whereas expression of the volume and TNM stage. 36 kDa form of the ANXA3 protein and total ANXA3 protein Ki3 ‑ 4 is a well‑known proliferating cell nuclear antigen, signic fi antly decreased. Furthermore, tissue microarray analysis and its function is strongly associated with mitosis (27). The revealed that ANXA3 protein expression is downregulated in proliferation index of Ki3 ‑ 4 is frequently used to estimate the RCC tissues compared with normal renal cortical tissues. malignant proliferation of tumour cells in the clinic setting (27). Increasing evidence suggest that generation of the 33 kDa Bcl2 i ‑ s an important indicator of the apoptotic signalling and 36 kDa isoforms of the ANXA3 protein has no association pathway, and is an antiapoptotic member of the Bcl2 ‑ protein with post‑translational modic fi ations, such as phosphorylation family (28). Upregulated ANXA3 expression causes alterations and N‑glycosylation (18). The mRNAs encoding ANXA3, in the expression levels of Ki‑34 and Bcl‑2, which signic fi antly which result from the alternative splicing of exon III, produce decreases the overall survival of patients with gastric cancer (26). two ANXA3 transcripts, including the 36 kDa isoform of the Upregulated ANXA3 expression was associated with a poor ANXA3 protein of a fulll ‑ ength protein and the 33 kDa isoform prognosis among 183 patients with gastric cancer (29). Inhibition of the ANXA3 protein, lacking the first 39 amino acid residues of ANXA3 suppresses tumorigenicity in vivo and suppresses of the N‑terminal region (18,21,23) (Fig. 1). The generation the proliferation, clone formation, migration and invasion of model of the two ANXA3 transcripts is similar to that of the gastric cancer cells (29). Taken together, these n fi dings suggest remaining members of the annexin family (2). that ANXA3 may serve as an independent marker of poor prognosis of gastric cancer. Recently, it has been demonstrated 2. ANXA3 and tumour that ANXA3 expression in the Ochratoxin A (OTA) induces the malignant transformation of human gastric epithelium cells ANXA3 and the development and progression of tumour. It (GES1 ‑ ) compared with normal GES1 c ‑ ells (30). The prolif ‑ has been reported that abnormal ANXA3 protein expression erative, migratory and invasive abilities of OTA‑GES1 ‑ T cells is closely associated with the development and progression of weaken following ANXA3 knockdown (30). Overexpression tumour. Overexpression of ANXA3 promotes the development of ANXA3 promotes the carcinogenesis of gastric cancer by and progression of tumours, such as upper tract urothelial cancer regulating the cell proliferation and apoptosis of gastric cancer. (UTUC), gastric carcinoma, hepatocellular carcinoma (HCC), However, further studies are required to determine the molec‑ breast cancer and osteosarcoma, whereas ANXA3 knockdown ular mechanisms underlying the contribution of ANXA3 to the suppresses the tumorigenesis of prostate carcinoma (24‑44) carcinogenesis of gastric cancer. (Table I). ANXA3 and the development and progression of HCC. ANXA3 ANXA3 and the development and progression of upper expression was detected in 20 pairs of HCC tumour tissues and tract urothelial cancer. Lu et al (24) investigated ANXA3 the corresponding normal tissues via immunohistochemical expression in urine samples and tissues, which were collected staining (31). The results demonstrated that ANXA3 expression from 13 patients with UTUC and 20 healthy individuals, was upregulated in 74% of HCC tumour tissues, suggesting that using non‑fixed volume stepwise weak anion exchange ANXA3 is strongly associated with the development of HCC. chromatography coupled with two‑dimensional electrophoresis This result was concordant with that of other groups (32,33). assay. The results revealed 55 differential expression proteins Western blot and quantitative PCR analyses were performed to ONCOLOGY LETTERS 22: 834, 2021 Table I. Role of Annexin A3 in the development and progression of cancer. Cancer Expression Role (Refs.) Upper tract urothelial cancer Upregulation in urine samples and tissues Strong association with tumorigenesis (24) Gastric cancer Upregulation in tumour tissues Promotes proliferation and (26) inhibits apoptosis of cells Hepatocellular carcinoma Upregulation in tumour tissues Enhances the proliferation, colony (31‑35) formation and migration of cells Prostate cancer Downregulation in tumour tissues Negatively associated with (38‑41) the pT stage and Gleason score Breast cancer Upregulation in tumour cells Promotes the proliferation (42,43) and colony formation of cells Osteosarcoma Upregulation in osteosarcoma cell lines Inhibits the apoptosis of cells (44) Figure 1. Diagram of the two isoforms of ANXA3. The 33 kDa and 36 kDa ANXA3 proteins. ANXA3 contains an N terminal, four annexin repeat domains (Ⅰ‑Ⅳ) and a C terminal. The 33 kDa isoform of ANXA3 lacks the first 39 amino acid residues of the N‑terminal region, unlike the 36 kDa isoform. ANXA3, Annexin A3; aa, amino acids. detect ANXA3 expression in 34 matched HCC tissues of and Nt‑ erminal kinase (JNK) signalling pathway (33). Recently, it adjacent normal liver tissues (32). The results demonstrated that has been reported that ANXA3 can promote tumorigenicity ANXA3 expression was notably higher in HCC tumour tissues in HCC by remodelling the immune microenvironment by compared with normal liver tissues, at both protein and mRNA regulating the infiltrated neutrophil‑lymphocyte ratio (iNLR) levels, which was further confirmed via immunohistochemistry and the release of chemokines, CXCL8 and CCL25 from HCC staining. ANXA3 expression was elevated in almost 58.1% cells (36). High ANXA3 expression is associated with high of 155 clinical primary HCC samples. Upregulated ANXA3 iNLR, and high risk of mortality in patients with HCC (36). expression was positively associated with tumour size of HCC, Taken together, these findings suggest that ANXA3 may be a advanced clinical stage and number of lesions, but was negatively potential diagnostic marker and therapeutic target for HCC (37). associated with the prognosis of HCC. Further functional inves‑ tigations demonstrated that upregulated ANXA3 expression ANXA3 and the development and progression of prostate enhanced cell proliferation, colony formation, cell migration cancer. A previous study identie fi d that ANXA3 is one of the and invasion of HCC. Conversely, downregulation of ANXA3 four proteins whose expression signic fi antly differs between significantly suppressed these cell behaviours. Collectively, 31 prostate cancer tissues and matched benign tissues on differ‑ these n fi dings suggest that ANXA3 may severe as an indepen ‑ ential radioactive quantic fi ation (38). Immunohistochemistry dent prognostic factor for patients with HCC. ANXA3 may play analysis further demonstrated that ANXA3 expression was an oncogenic role in promoting tumorigenesis of HCC, and thus lower in the cancer group compared with the benign group, and is considered a novel target for HCC therapy (32). A previous low ANXA3 expression was dependent on the Gleason pattern study demonstrated that ANXA3 expression is higher in 50.6% of prostate cancer with a negative correlation. Köllermann et al of primary HCC clinical samples compared with matched adja‑ and Jeun et al also provided powerful data regarding the asso‑ cent normal liver samples (33). ciation between ANXA3 and prostate cancer (39,40). These The cancer stem cell (CSC), which has the capacity for authors examined altered ANXA3 expression in prostate tumour initiation, self‑renewal and differentiation, has recently cancer, benign epithelium and highg ‑ rade prostatic intraepi ‑ been considered to contribute to the recurrence and metastasis of thelial neoplasia (PIN) tissues using immunohistochemistry HCC (34). CD133 is a molecular indicator of CSCs in HCC and is and tissue microarray. The results demonstrated that ANXA3 used to obtain HCC steml ‑ ike cells isolated from HCC cells (35). expression was notably downregulated in prostate cancer tissues Pan et al reported that compared with non‑CSCs, CSCs derived compared with benign epithelium and highg ‑ rade PIN tissues, from Huh7 cells highly expressed endogenous ANXA3 (32). and ~27.2% of prostatic cancer samples negatively expressed In addition, ANXA3 plays an essential role in conferring the ANXA3. Downregulated ANXA3 expression was negatively stemness of HCC by inhibiting the hypoxiai‑ nducible factor associated with the pT stage and Gleason score of prostate (HIF)‑1 α/NOTCH pathway (34). Tong et al demonstrated that cancer but positively associated with poor prognosis of prostate both endogenous and exogenous ANXA3 proteins can maintain cancer, suggesting that ANXA3 may be used as a marker for the the CSC characteristics of HCC cells and facilitate selfr ‑ enewal early diagnosis of prostate cancer. Other studies have reported and proliferation of HCC CSCs by downregulating the cJ ‑ UN the value of ANXA3 in diagnosing prostate cancer (40,41). LIU et al: ANNEXIN A3 AND CANCER Table II. Role of Annexin A3 in cancer resistance to drugs. Cancer Drugs Resistance (Refs.) Hepatocellular carcinoma Cisplatin, 5‑fluorouracil, staurosporine and sorafenib Increase (33,34,45) Ovarian carcinoma Platinum and cisplatin Increase (46‑48) Lung cancer Platinum, cisplatin and oxaliplatin Increase (49,50) Prostate cancer Cyclophosphamide Increase (51) Breast cancer Doxorubicin Increase (52) Colorectal cancer Oxaliplatin Increase (53) Western blot analysis was performed to detect ANXA3 protein ANXA3 and the drug resistance of tumours. Recently, it has expression in the urine samples of 590 patients, of whom been suggested that ANXA3 may exert an important inu fl ence 367 had prostate cancer and 223 had an unverie fi d adenocar ‑ on the drug resistance of different types of tumours, such as cinoma (41). The results demonstrated that the sensitivity and HCC, ovarian carcinoma, lung adenocarcinoma (LADC) and specificity of ANXA3 as a diagnostic marker for prostate prostatic carcinoma (Table II). cancer exceeded that of tPSA, since patients had negative n fi d ‑ ings on digital rectal examination and low prostate‑specic fi Role of ANXA3 in HCC drug resistance. To study the role of antigen concentration (21 ‑ 0 ng/ml). A recent study reported that ANXA3 in drug resistance, the expression of ANXA3 was ANXA3 expression in urine is clinically associated with the changed in different HCC cell lines by overexpressing ANXA3 actual tumour volume (40). Collectively, these n fi dings suggest or by targeting the ANXA3‑specific shRNA vectors (32). that the quantic fi ation of ANXA3 expression in urine samples Results of the in vitro drug sensitivity assay and in vivo tumour may be used as a specic fi marker for the early diagnosis of growth suppression assay indicated that overexpression of prostate cancer. ANXA3 notably enhanced the drug resistance of HCC cells to cisplatin and 5‑u fl orouracil (5‑FU), while ANXA3 knock ‑ ANXA3 and the development and progression of breast down significantly decreased the resistance to these drugs. cancer. ANXA3 expression is higher in breast cancer cell lines Thus, ANXA3 may play an important role in the occurrence (MDAM ‑ B 231, HCC‑69 and HCC1 ‑ 954) compared with other of drug resistance in patients with HCC, and may serve as cell types (42). ANXA3 knockdown inhibits the proliferation an innovative target for HCC treatment. Tong et al (33) and colony forming ability of MDAM ‑ B 231 cells in vitro (42). reported that increased ANXA3 expression resulted in the In another study, the inu fl ence of ANXA3 on the incidence of occurrence of drug resistance among patients with HCC to breast cancer was evaluated using a nude mouse model bearing cisplatin, 5‑FU and staurosporine both in vitro and in vivo. a subcutaneous tumour in vivo (43). The volume and weight of Another study investigated the role of ANXA3 in the tumours in the ANXA3 silencing group was smaller compared resistance of HCC cells to 5‑FU (32). They established the with the control group. Furthermore, the level of red blood Bel7302/5‑FU cell line, which is resistant to 5‑FU, and its vessels was relatively low in the ANXA3 silencing group. The parental Bel7302 cell line, which is sensitive to 5‑FU (32). proliferation rate was lower; however, the G /G cell ratio was Using the quantitative proteomic method bearing isobaric 0 1 higher in the transfection group compared with the control labelling combined with 2D LC‑MS /MS, ANXA3 expres‑ group (43). ANXA3 expression was associated with the size sion was identie fi d to be higher in Bel7302 /5‑FU compared of the tumour and diseasef ‑ ree survival in 30 patients with with Bel7302, which was further validated via western primary breast cancer (42). Taken together, these findings blot and quantitative PCR analyses. Furthermore, ANXA3 suggest that ANXA3 plays an important role in the initiation knockdown in 5‑FU‑resistant Bel7302 /5‑FU cells notably and progression of breast cancer, and thus may be used as a decreased the drug resistance of HCC cells to 5‑FU, cisplatin potential therapeutic target for breast cancer. and adriamycin. A recent study demonstrated that ANXA3 expression is higher in sorafenib‑resistant HCC cells, HepG2 ANXA3 and the development and progression of osteo‑ and Huh7, and sorafenib‑resistant patient‑derived HCC sarcoma. ANXA3 expression is higher in osteosarcoma xenografts (45). Patients with low ANXA3 expression had cell lines, HOS and U2OS, compared with osteoblasts (44). a better prognosis after receiving sorafenib treatment than To further examine the role of ANXA3 in osteosarcoma those with high ANXA3 expression. Furthermore, ANXA3 cells, ANXA3 siRNA was transfected into HOS, U2OS knockdown in the sorafenib‑resistant HCC cells, HepG2 and and osteoblasts. The mRNA and protein expression levels Huh7, suppressed the resistance of HCC cells to sorafenib (45). of ANXA3 were successfully inhibited following transfec‑ Further experiments demonstrated that antiA ‑ NXA3 therapy tion with siRNA. The results demonstrated that ANXA3 (antiA ‑ NXA3 monoclonal antibody) combined with sorafenib knockdown decreased the apoptotic rate of HOS and U2OS can increase the apoptotic rate compared with sorafenib alone cells by 3‑fold (44). These findings suggest that ANXA3 may in sorafenib‑resistant HCC cells (45). Taken together, these n fi d ‑ regulate the tumorigenicity by influencing the apoptosis of ings suggest that ANXA3 may be strongly associated with the osteosarcoma cells. multi‑drug resistance (MDR) in HCC. The association between ONCOLOGY LETTERS 22: 834, 2021 ANXA3 and drug resistance in HCC provides novel and impor‑ Role of ANXA3 in prostate cancer drug resistance. tant clues to further investigate MDR in other types of tumours. Thoenes et al (51) established an SCID mice model, developed a prostate cancer phenotype that is resistant to metronomic cyclo‑ Role of ANXA3 in ovarian carcinoma drug resistance. In phosphamide (CPA) and obtained samples of prostate cancer human ovarian cancer cell lines, which are resistant to platinum, PC3D ‑ 3 and PC4D ‑ 4 cell lines that are resistant to CPA and ANXA3 expression was reported to be higher than that in human parental prostate cancer PC3D ‑ 3 cell lines. The results demon ‑ epithelial ovarian cancer cell lines. ANXA3 expression notably strated that ANXA3 expression in prostate cancer PC3D ‑ 3 and increased in tumour tissues obtained from platinumr ‑ esistant PC4D ‑ 4 cell lines that are tolerant to CPA was higher than that patients with ovarian cancer than those obtained from plat‑ in parental prostate cancer PC3‑D3 cell lines. Furthermore, inum‑sensitive patients (46‑48). Yan et al (47) demonstrated ANXA3 expression was notably higher in xenografts treated that upregulated ANXA3 expression notably decreases the with CPA compared with groups without CPA treatment. These amount of cisplatin uptake and p53 expression induced by results indicate that high ANXA3 expression may enhance cisplatin, and ANXA3 knockdown significantly increases the drug resistance of prostate cancer to CPA, and can serve intracellular cisplatin concentrations in ovarian cancer cells. as a novel biomarker for predicting chemoresistance in prostate These results suggest that the upregulation of ANXA3 expres‑ cancer. sion may be the specic fi mechanism responsible for the increase in ovarian cancer chemoresistance to cisplatin; however, the Role of ANXA3 in breast cancer drug resistance. Doxorubicin precise mechanism of ANXA3 leading to cisplatin resistance (Dox) is widely used for the treatment of breast cancer. To in ovarian cancer requires further investigation. Another study further investigate the role of ANXA3 in the resistance of breast indicated that ANXA3 was detected in the ovarian cancer cancer to Dox, ANXA3 expression was inhibited in the human cell culture medium (48). The amount of secreted ANXA3 is breast cancer cell line, MDAM ‑ B2 ‑ 31 and mouse mammary dependent on the expression level of ANXA3 in ovarian cancer cancer cell line, 4T1, and ANXA3 silencing cells were treated and the degree of ovarian cancer chemoresistance to cisplatin. with Dox (52). Flow cytometric analysis demonstrated that there The research demonstrated that there were more elliptical was increased Dox accumulation in ANXA3 silencing cells vesicles containing different concentrations of drugs in the compared with normal cells (52). To further investigate the role cytoplasm of platinumr ‑ esistant ovarian cancer cell lines than in of ANXA3 in the resistance of breast cancer to Dox in vivo, platinums ‑ ensitive parental ovarian cancer cell lines (48). Part ANXA3 silencing and normal MDA‑MB2 ‑ 31 and 4T1 cells of the elliptical vesicles can fuse with the cell membrane, which were transplanted into the BALB/c mice. When the tumour size suggests that ANXA3 expression may be owing to exocytosis reached to 23 ‑ mm, the mice were treated with Dox. The results and the release of exosomes. These results demonstrate that demonstrated that ANXA3 silencing enhanced the sensitivity ANXA3 increases the chemoresistance of ovarian cancer of Dox to breast cancer (52). Thus, ANXA3 may inu fl ence the to platinum by increasing the aggregation of vesicles and the resistance of breast cancer to Dox by regulating the cellular exocytosis of vesicles containing drugs. Thus, ANXA3 may be accumulation of Dox. a valuable target for the chemical therapy of ovarian cancer. Role of ANXA3 in colorectal cancer drug resistance. Ox is Role of ANXA3 in lung cancer drug resistance. A previous used as a chemotherapy drug for colorectal cancer (CRC) (53). study investigated ANXA3 expression in lung cancer A549 To determine the role of ANXA3 on Ox resistance in CRC, cells, with and without platinum resistance, and LADC two CRC cell lines, HCT116 and SW480, were treated tissues (49). The results demonstrated that ANXA3 expression with Ox and exhibited resistance to Ox (HCT116/Ox and in platinum‑resistant lung cancer A549 cells was signic fi antly SW480/Ox) (53). The halfm ‑ aximum inhibitory concentration higher than that in the nonr ‑ esistant groups, at both the protein values of Ox in HCT116/Ox and SW480/Ox cells were higher and mRNA levels. In addition, ANXA3 expression was also than that in their parental cells, suggesting that HCT116/Ox detected in platinum‑resistant LADC tissues, suggesting and SW480/Ox were resistant to Ox. Furthermore, ANXA3 that ANXA3 may play an important role in the resistance of expression in HCT116/Ox and SW480/Ox was higher LADC to cisplatin. Platinumr ‑ esistant lung cancer A549 cells compared with HCT116 and SW480 cells, suggesting that were further treated with a molecular compound that can ANXA3 is associated with Ox resistance in CRC cells. Further bind with ANXA3. Analysis demonstrated that cell viability experiments demonstrated that ANXA3 silencing suppressed of cisplatin‑resistant LADC signica fi ntly reduced, suggesting Ox resistance in CRC via the mitogena ‑ ctivated protein kinase that the compound targeting ANXA3 can induce cell death in signalling pathway (53). Collectively, these results suggest that platinumr ‑ esistant lung cancer A549 cells. Thus, ANXA3 may ANXA3 plays an important role in CRC resistance to Ox. be a novel therapeutic target to circumvent cisplatin resistance Thus, clinical studies are required to determine the role of in patients with LADC (49). A recent study demonstrated that ANXA3 in CRC resistance to Ox. ANXA3 expression is higher in oxaliplatin (Ox)r ‑ esistant A549 lung cancer cells (A549/Ox) compared with normal A549 cells, Role of ANXA3 in tumour metastasis. Recent studies have which suggests that ANXA3 may be associated with lung demonstrated that altered ANXA3 expression is closely associ‑ cancer cell resistance to Ox (50). Further experiments demon‑ ated with the metastasis of different types of cancer (Table III). strated that ANXA3 knockdown in A549/Ox cells can enhance ANXA3 expression is higher in different types of cancer tissues the effect of Ox on lung cancer cells (50). Collectively, these compared with controls, such as breast, lung, gallbladder and findings suggest that ANXA3 knockdown can suppress the colon cancer tissues. Overexpression of ANXA3 promotes resistance of lung cancer cells to Ox. cancer metastasis. ANXA3 expression is downregulated in LIU et al: ANNEXIN A3 AND CANCER Table III. Role of Annexin A3 in the metastasis of cancer. Cancer Expression Role (Refs.) Breast cancer Upregulation in patients with May promote metastasis (54‑57) lymph node metastasis Lung cancer Upregulation in patients with metastasis May promote lymph node metastasis (58,59) Papillary thyroid carcinoma Downregulation in patients with metastasis Significantly associated with metastasis (60) Gallbladder carcinoma Upregulation in patients with metastasis May promote metastasis (61,62) Colon cancer Upregulation in patients with cancer May promote metastasis (63‑68) via the HIF‑1 α pathway Pancreatic cancer Upregulation in patients with Promotes epithelial‑to‑mesenchymal (69) pancreatic cancer transition and lymph node metastasis HIF, hypoxia‑inducible factor. papillary thyroid carcinoma compared with normal tissues, cancer cells (59). These results suggest that ANXA3 expression which promotes cancer metastasis (54‑69). may promote lymph node metastasis of lung cancer. Thus, ANXA3 may be used as a novel biomarker for predicting the Role of ANXA3 in breast cancer metastasis. Previous studies metastasis and prognosis of lung cancer. have reported that ANXA3 is expressed in several human breast cancer cell lines and 60 breast cancer tissues (42,54). Western Role of ANXA3 in papillary thyroid carcinoma metastasis. blot and immunohistochemistry analyses demonstrated that Jung et al (60) analysed the differential protein expression of ANXA3 is highly expressed in MCF7 a ‑ nd MDA‑MB‑435 25 pairs of papillary thyroid carcinomas and corresponding cells, and breast cancer tissues (54). Other studies have reported normal tissues by performing two‑dimensional electrophoresis, the high ANXA3 expression in breast cancer cells, and ANXA3 mass spectrometry, western blot, northern blot and immunohis‑ silencing signic fi antly suppresses the migration and invasion of tochemical analyses, and found that ANXA3 expression was breast cancer cells (42,55). ANXA3 was positively expressed in lower in papillary thyroid carcinoma compared with the controls, 27/35 patients with lymph node metastasis, and only positively at both mRNA and protein levels. Immunohistochemistry expressed in 12/25 patients without lymph node metastasis (54). analysis demonstrated that ANXA3 expression in papillary Further analysis demonstrated that the diseasef ‑ ree survival and thyroid carcinoma with lymph node metastasis decreased, but overall survival times of patients with ANXA3p ‑ ositive breast the differences were not signic fi ant. However, ANXA3 expres ‑ cancer were signic fi antly shorter compared with patients with sion was signic fi antly lower in papillary thyroid carcinoma with ANXA3n ‑ egative breast cancer. However, ANXA3 expression lymph node metastasis. Papillary thyroid carcinoma tissues is not associated with age, hormone receptor, tumour grade and without lymph node metastasis had a staining score of >3, while histology (54). Further studies also confirmed that ANXA3 those with lymph node metastasis had a staining score of ≤3. expression is positively associated with the diseasef ‑ ree survival Further analysis revealed that ANXA3 expression was high in and overall survival of lymph node metastasis in patients with 61.1% of papillary microcarcinoma tissues without lymph node breast cancer (42,56). ANXA3 expression is higher in patients metastasis; however, the expression of ANXA3 was low in with triple‑negative breast cancer, which frequently metasta ‑ 67.2% of papillary thyroid carcinoma tissues with lymph node sises compared with other types of cancer (56,57). These results metastasis. These results suggest that low ANXA3 expression is suggest that high ANXA3 expression may promote the metas‑ signic fi antly associated with the metastasis of papillary thyroid tasis of breast cancer. ANXA3 is an independent factor of poor carcinoma; thus, it may be used as one of the negative predictive prognosis in breast cancer, and thus may be a novel potential indexes of papillary thyroid carcinoma. therapeutic target for predicting breast cancer metastasis (56,57). Role of ANXA3 in gallbladder carcinoma metastasis. Role of ANXA3 in lung cancer metastasis. The differential Tan et al (61) performed two‑dimensional electrophoresis and protein expression between LADC tissues with and without mass spectrometry to evaluate the differential protein expres‑ lymph node metastasis were identified using fluorescence sion of ANXA3 between six pairs of gallbladder carcinoma differential gel electrophoresis and mass spectrometry and benign gallbladder tissues. Immunohistochemical analysis analysis (58). Western blot and immunohistochemistry analyses demonstrated that high ANXA3 expression was closely associ‑ demonstrated that the expression of ANXA3 was higher in ated with tumour grade, lymph node metastasis and postoperative the metastasis group compared with the nonm ‑ etastasis group. survival of gallbladder carcinoma. Similarly, Wang et al (62) Further analysis indicated that high ANXA3 expression performed western blot and reverse transcription‑quantitative increased the postoperative recurrence rate and decreased the PCR analyses, and reported that ANXA3 expression was average and overall survival rate of patients with LADC, which signic fi antly higher in GBC‑SD18H cells, with high metastatic was not associated with sex, age, tumour size and differentiation. potential, compared with GBC‑SD18L cells, with low metastatic In addition, ANXA3 silencing inhibits the invasion of lung potential (62). Collectively, these results suggest that ANXA3 ONCOLOGY LETTERS 22: 834, 2021 may promote gallbladder carcinoma metastasis. Thus, ANXA3 with ANXA3 shRNA and LY294002, ANXA3 expression may be used as a therapeutic target for gallbladder carcinoma. decreased, but the PI3K/Akt pathway was not activated (71). This suggests that ANXA3 may regulate cellular behaviour in Role of ANXA3 in colon cancer metastasis. The mRNA levels individuals with AMI via the PI3K/Akt pathway. Thus, ANXA3 of ANXA3 in the blood of patients with colon cancer was may play an important role in the development of cancer via the signic fi antly higher compared with healthy controls (63,64). PI3K/Akt pathway. Another study reported that ANXA3 expression was upregu‑ lated in colon cancer tissues, suggesting that ANXA3 may be NF‑ κB signalling pathway. ANXA3 expression is upregu‑ closely associated with colon cancer (65). Xie et al analysed lated in breast cancer tissues compared with paracancerous ANXA3 and HIF‑ α expression and their association with the tissues (52). High ANXA3 expression is associated with poor clinicopathological characteristics and prognosis of 60 patients overall survival, suggesting that ANXA3 may play an impor‑ with colon cancer (65,66). The results demonstrated that tant role in the development of breast cancer (52). To further 65 and 47% of patients with colon cancer had high ANXA3 evaluate its role in breast cancer, shRNA‑targeted ANXA3 and HIF‑ α expression, respectively, and ANXA3 was closely was transfected in vivo and vitro. The results demonstrated that associated with tumour size and Dukes' staging. HIF‑ α is as ANXA3 silencing inhibited cell invasion, whilst promoting key regulator of tumour angiogenesis (67,68). It can stimulate cell proliferation (52). This result remains controversial, as it is vascular endothelial growth factor (VEGF) expression in difc fi ult to determine whether the protein is ‘good’ or ‘bad’ for tumours (67,68). The expression patterns of ANXA3 and HIF‑ α the development of breast cancer. Further experiments indicated were similar, and their expression was closely associated. These that ANXA3 knockdown inhibited the NF‑ κB pathway by results suggest that high ANXA3 expression promotes the increasing IκBα expression, which is a cellular protein (52,72). development and metastasis of colon cancer, which may induce NF‑ κB plays an important role in the EMT process in a breast angiogenesis via the HIF‑ α signalling pathway. cancer model (73). ANXA3 silencing regulates the EMT process via the NF‑ κB pathway. Blockade of the IκBα pathway can alle‑ Role of ANXA3 in pancreatic cancer metastasis. Quantitative viate the EMT process induced by ANXA3 knockdown (73). PCR and western blot analyses demonstrated that ANXA3 These results suggest that ANXA3 may play roles in the devel‑ was highly expressed in 115 patients with pancreatic cancer opment of other types of cancer via the NF‑ κB pathway, which (PC) (69). ANXA3 silencing inhibits epithelialt ‑ om ‑ esenchymal should be validated by further studies. transition (EMT) and lymph node metastasis (69). In addition, ANXA3 knockdown suppresses the migratory and invasive JNK signalling pathway. ANXA3 is closely associated with abilities of PC cells in vitro (69). The suppression of lymph HCC. ANXA3 expression in the sera of patients with HCC is node metastasis by ANXA3 silencing has also been confirmed associated with their clinical features (8). Excessive ANXA3 in tumour xenografts in vivo (69). Taken together, these results expression plays an important role in promoting cancer and suggest that ANXA3 silencing can inhibit the metastasis of PC. inducing stem cell features in live CD133 liver CSCs (33). Thus, ANXA3 may be a potential therapeutic target for PC ANXA3 exerts its role by enhancing the JNK signalling metastasis. pathway, thus increasing JNK kinase activity and its expres‑ In conclusion, ANXA3 plays an important role in the devel‑ sion (33). Blockade of ANXA3 with a monoclonal antibody can opment, metastasis and drug resistance of different types of reduce tumour growth and selfr ‑ enewal in vitro and in vivo (33). cancer. However, the pathways by which ANXA3 exerts its role Cancer‑related fibroblasts (CAFs), which are found within remain unclear. cancer cells, have a signic fi ant effect on the proliferation, metas ‑ tasis, chemoresistance and invasion of cancer cells (74). ANXA3 3. Pathways by which ANXA3 exerts its role expression is higher in CAFs in tumour tissues compared with normal b fi roblasts (74). The CAF‑conditioned medium Phosphatidylinositol3 k ‑ inase (PI3K) /Akt signalling pathway. can increase ANXA3 expression in lung cancer cells, which The PI3K/Akt signalling pathway plays an important role in cell increases cisplatin resistance. Conversely, ANXA3 knockdown proliferation, metabolism and migration (70). AMI is a conse‑ in lung cancer increases cisplatin sensitivity. ANXA3 plays an quence of coronary atherosclerotic heart disease, which can lead important role in the chemoresistance of lung cancer by regu‑ to the reduction of myocardial cells (71). An AMI rat model was lating JNK activity. Using the specic fi JNK activity inhibitor constructed (71). ANXA3 shRNA was transfected into different can retard the effect of ANXA3 on cisplatin resistance. Thus, groups of rats to inhibit ANXA3 expression. The results ANXA3 expression promotes HCC and lung cancer via the demonstrated that ANXA3 silencing alleviated the inflam‑ JNK signalling pathway (74). Another study reported that mation reaction by reducing the expression of ina fl mmatory ANXA3 silencing ameliorates the intracranial aneurysm by markers, such as interleukin (IL)‑6, tumour necrosis factor α inhibiting the JNK signalling pathway (75). Thus, ANXA3 may (TNF‑ α) and nitric oxide (NO). Furthermore, transfection with exert its role in different types of cancer and diseases via the ANXA3 shRNA increased the mRNA and protein expression JNK signalling pathway. levels of Bcl2 ‑ , bFGF and VEGF, and phosphorylation of Akt. These findings suggest that ANXA3 silencing may regulate cell Extracellular signal‑regulated kinase (ERK) signalling behaviour via the PI3K/Akt signalling pathway. LY294002, an pathway. Quantitative proteomics analysis demonstrated that inhibitor of the PI3K/Akt signalling pathway, can activate the ANXA3 expression is higher in LADC tissues (76). Furthermore, PI3K/Akt signalling pathway and alleviate ina fl mmation, which ANXA3 knockdown inhibits the proliferation, invasion, migra‑ is caused by ANXA3 silencing (71). In animals transfected tion and metastases of LADC cells in vivo and in vitro (76). LIU et al: ANNEXIN A3 AND CANCER Figure 2. Signal transduction pathways by which ANXA3 exerts its role. ANXA3 exerts its role by regulating cell proliferation, migration and apoptosis by downregulating the PI3K/Akt signalling pathway and upregulating the NF‑ κB, JNK, ERK and HIF1 s ‑ ignalling pathways. ANXA3, Annexin A3; PI3K, phosphatidylinositol3 ‑ kinase; NF‑ κB, nuclear factor‑ κB; JNK, cJ ‑ UN N‑terminal kinase; ERK, extracellular signal‑regulated kinase; HIF, hypoxiai ‑ nducible factor. However, the molecular mechanism by which ANXA3 knock‑ as prostate cancer, upper tract urothelial carcinoma, gastric down affects LADC cells remains unclear. It has been reported cancer, hepatocellular cancer, ovarian cancer, lung cancer, that ANXA3 silencing can reduce the phosphorylation of MEK breast cancer and gallbladder cancer. Its altered expression is and ERK (76). Thus, ANXA3 may exert its role via the ERK a potential biomarker for tumour staging, grading, metastasis signalling pathway. In addition, ANXA3 expression is higher in and prognosis of patients. Thus, it may be used as a novel two CRC cell lines, HCT116/Ox and SW480/Ox, which develop target for the treatment and diagnosis of tumour. ANXA3 Ox resistance. ANXA3 silencing can reduce the proliferation, exerts its role via the PI3K/Akt, NF‑ κB, JNK, ERK and migration, invasion, migration and metastases of CRC cells, HIF1 s ‑ ignalling pathways (Fig. 2). In addition, ANXA3 has but promote cell apoptosis. Furthermore, ANXA3 knockdown two isoforms (33 kDa and 36 kDa ANXA3 proteins), and the can reduce the phosphorylation of ERK and JNK. The ERK expression patterns of these two isoforms vary in different inhibitor can reverse the changes caused by ANXA3 knock‑ types of cells. Further studies are required to verify the func‑ down (53). Taken together, these n fi dings suggest that ANXA3 tion of ANXA3 and its two isoforms in tumours and their may exert its role via the ERK signalling pathway in lung cancer mechanisms. and CRC. Acknowledgements HIF1 s ‑ ignalling pathway. ANXA3 expression is higher in the sera of patients with melanoma compared with healthy Not applicable. controls (77). In addition, ANXA3 expression has a close association with the overall survival of patients with Funding melanoma, suggesting that ANXA3 may play an important role in melanoma. Overexpression of ANXA3 can promote No funding was received. the proliferation and migration of human melanoma WM1 ‑ 15 cells. Conversely, ANXA3 knockdown inhibits cell Availability of data and materials proliferation and migration (77). Furthermore, ANXA3 exerts its role by activating HIF1 ‑ α (77). Another study reported that Not applicable. ANXA3 increases the migration and tube formation of human umbilical vein endothelial cells (9). Furthermore, ANXA3 can Authors' contributions induce VEGF production via the HIF1 p ‑ athway (9). Thus, ANXA3 may play certain roles in cancer and the angiogenesis CL and NL performed the literature review and drafted the process via the HIF1 p ‑ athway. It also plays an important role initial manuscript. GL and XF critically revised the manu‑ in the maintenance of cancer steml‑ ike cells /canceri ‑ nitiating script for important intellectual content. Data authentication cells via the HIF pathway (78). is not applicable. All authors have read and approved the manuscript. 4. Conclusion and prospects Ethics approval and consent to participate ANXA3 is closely associated with the development, drug resis‑ tance, metastasis and prognosis of several malignancies, such Not applicable. ONCOLOGY LETTERS 22: 834, 2021 21. HamelinP ‑ eyron C, Vlaeminck‑Guillem V, Haïdous H, Schwall GP, Patient consent for publication Poznanović S, Gorius‑Gallet E, Michel S, Larue A, Guillotte M, Rufo fi n A, et al: Prostate cancer biomarker annexin A3 detected Not applicable. in urines obtained following digital rectal examination presents antigenic variability. Clin Biochem 47: 9019 ‑ 08, 2014. 22. Zamora DO, Riviere M, Choi D, Pan Y, Planck SR, Rosenbaum JT, Competing interests David LL and Smith JR: Proteomic profiling of human retinal and choroidal endothelial cells reveals molecular heterogeneity related to tissue of origin. Mol Vis 13: 20582 ‑ 065, 2007. The authors declare that they have no competing interests. 23. 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Tan Y, Meng HP, Wu Q, Wang FQ and Wu HR: Proteomic study International (CC BY-NC-ND 4.0) License. of gallbladder cancer, with special reference on the expression and signic fi ance of annexin A3. Zhonghua Bing Li Xue Za Zhi 39: 3823 ‑ 86, 2010 (In Chinese).

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Oncology Letters – Pubmed Central

Published: Oct 14, 2021

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