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Abstract
Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzy010/5253900 by DeepDyve user on 20 July 2022 BioscienceHorizons Volume 11 2018 10.1093/biohorizons/hzy010 ............................................................................................ ..................................................................... Review article Transcription factors controlling E-cadherin down- regulation in ovarian cancer 1, 2 Holly Russell and Md Zahidul Islam Pranjol University of Exeter Medical School, Exeter, Devon EX1 2LU, UK Current address: Centre for Translational Medicine & Therapeutics, The William Harvey research Institute, Queen Mary University of London Charterhouse Square, London EC1M 6BQ, UK *Corresponding author: University of Exeter Medical School, Exeter, Devon EX1 2LU, UK. Email: hvr204@exeter.ac.uk Supervisor: Md Zahidul Islam Pranjol, Postdoctoral Researcher, Centre for Translational Medicine & Therapeutics, The William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. ............................................................................................ ..................................................................... Transcription factors (TFs), such as Snail, Slug and Twist, control the down-regulation of cell–cell adhesion molecule E- cadherin in ovarian cancer. Low E-cadherin aids tumour cells in undergoing epithelial–mesenchymal transition (EMT) to motile morphology, disseminating to other organs. High TF levels have also correlated with chemoresistance and poor prog- nosis. This review aims to discern mechanisms of E-cadherin reduction by TFs and identifies hypoxia-inducible factor 1α (HIF1α) as an upstream regulator in hypoxic conditions. Association with chemoresistance is investigated, and whether its reversal is possible. Snail was found to bind more strongly to the E-cadherin promoter than Slug; it was suggested that Snail maintained EMT whilst Slug induced it. The use of differential zinc fingers by Snail and Slug to bind to the E-cadherin pro- moter supported this. HIF1α was shown to lie upstream of all three TFs and protein degradation or post-transcriptional regu- lation using miR-548c may regulate of Twist downstream. Further study into this is needed. High Snail expression correlated with cisplatin resistance, with knockdown of Snail reversing it. The same may be true for Twist and Slug, though some studies conflicted this. These findings show promising potential of TFs and HIF1α as therapeutic targets for EMT prevention and even chemoresistance reversal. Key words: E-cadherin, ovarian cancer, N-cadherin, twist, snail, slug, EMT, OSE, HIF-1α, miR-548c, chemoresistance Submitted on 12 July 2018; editorial decision on 23 October 2018 ............................................................................................ ..................................................................... reaching the omentum and peritoneum (Vergara et al., 2010). Introduction This dissemination results in high malignancy ~90% from Ovarian cancer is one of the largest causes of cancer death OSE (Cho and Shih, 2009). For dissemination to occur, cells among women (The American Cancer Society, 2017), with must detach from the ovary and become motile, transitioning the highest death rate of female reproductive cancers. It was from epithelial to mesenchymal, a fibroblast-like morphology estimated that around 22 440 women in the US would be (Vergara et al., 2016). This is epithelial–mesenchymal trans- newly diagnosed with ovarian cancer in 2017, with 14 080 ition (EMT). It occurs through down-regulation of cell–cell deaths as a result. The disease is particularly lethal due to its adhesion molecules—in particular E-cadherin. Several tran- vague symptoms and thus, lack of early diagnosis. Though scription factors controlling this expression have been identi- there are many histological types of ovarian tumours, most fied—Snail, Slug, Twist1/2, Zeb1/2 and Sip1 (Vergara et al., originate from the ovarian surface epithelium (OSE), and dis- 2016). Snail and Slug are zinc-finger proteins involved in seminate through the lymphatic system or peritoneal fluid, changing cell shape and morphology in migratory cells ............................................................................................... .................................................................. © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzy010/5253900 by DeepDyve user on 20 July 2022 Review article Bioscience Horizons � Volume 11 2018 ............................................................................................... .................................................................. (Dattoli et al., 2015). Twist is a basic helix-loop-helix supported this. This indicates Snail’s ability to stably regulate involved in embryonic development and cellular differenti- E-cadherin expression compared to Slug. ation (Nuti et al., 2014). All three bind to E-boxes in the E- Though this evidence is fairly conclusive, it should be cadherin promoter and have been associated with its down- remarked that reliability of the studies above is questionable. regulation and resulting EMT (Vergara et al., 2016). Stable transfection of Snail and Slug into SKOV3 cells in the Furthermore, these transcription factors have been associated study by Kurrey et al. (2005) was only successful in two and with chemoresistance (Kurrey et al., 2009; Nuti et al., 2014). one clones respectively. Without repeat stable samples to A few upstream regulators of Snail, Slug and Twist, for check, E-cadherin repression could be concluded to be a result instance hypoxia-inducible factor 1α (HIF1α), have been of random mutation. Furthermore, a study by Bolós et al. identified (Thiery et al., 2009). These are potential therapeutic (2003) using pcDNA3-Slug and Snail transfection separately targets for the repression of transcription factors and subse- into ovarian cancer cells showed the ability of Slug to induce quent reversal of chemoresistance, but the mechanisms EMT independently of Snail. This contradicts the hypothesis through which these transcription factors act must first be of Snail and Slug work synergistically in this process. understood. This review will focus on the mechanisms of Nonetheless, this study uses MDCK cells rather than ovarian Snail, Slug and Twist in down-regulation of E-cadherin and cancer cells. Snail and Slug may interact differently in these differences between them. Focus will be placed on HIF1α as two tissues. Future studies are required, using ovarian cancer an upstream regulator of these factors. Their association with cells and investigating E-cadherin levels over a longer time cisplatin resistance will also be investigated. Cisplatin is a period. It may have been that Snail expression would have standard chemotherapeutic agent, commonly used to treat increased in MDCK cells, given time. ovarian carcinoma (The American Cancer Society, 2017). Resistance of the tumour to cisplatin is a major hindrance to Interestingly, the study by Kurrey et al. (2005) showed the effectiveness of treatment (Miow et al., 2014). Should Slug upregulation as a result of hypoxia, suggesting the Snail, Slug or Twist be associated with this resistance, their involvement of HIF1α upstream. Hypoxia induced expression inhibition might aid in cisplatin resistance reversal. of Snail, HIF1α and Slug. E-cadherin also decreased, most likely as a result. It is possible, therefore, that Slug may induce E-cadherin repression under adverse conditions such as hyp- Differences between Snail and Slug oxia. Snail may then act later to maintain EMT. HIF1α may transcription factors therefore be a target for therapeutic knockout. Studies should be undergone to investigate the effect of this. It may be that in Snail and Slug have been shown to correlate with reduced level the absence of sufficient oxygen, HIF1α is released to cause of E-cadherin expression (Batlle et al.,2000; Bolós et al., dissemination through Slug, Snail and Twist upregulation. 2003). However, there is evidence that the two act in differen- CRISPR/cas9 could be used to knockout HIF1α to test this tial ways. Immunoblotting of SKOV3 OSE carcinoma cell lines theory. The effect of differing oxygen levels on tumour dis- (Kurrey et al.,2005) showing ectopic expression of mSnail and semination might also be a valid area of study. mSlug individually resulted in EMT. It was found that Snail overexpression repressed E-cadherin, β-catenin, occludin and Zo1—adherens and tight junction components. Interestingly, Twist repression of E-cadherin and Slug overexpression also resulted in the repression of desmo- HIF1α involvement somal junction components. This is indicative of the two’sdif- ferential roles in EMT induction. Correspondingly, mutation More recently, Twist was identified as a transcriptional of zinc fingers of Snail and Slug in mice HEK293T and OSE repressor of E-cadherin. Examination of Twist and E- carcinoma cells (Villarejo et al.,2014) showed the use of differ- cadherin expression in ovarian cancer tissues by PCR testing ent zinc fingers in repression of E-cadherin. Mutation of ZF1 (Wang et al., 2013) showed high Twist expression and low E- and ZF2 simultaneously in Snail mice leads to complete the cadherin compared to normal ovarian tissue. Use of RNAi to loss of E-cadherin repression. Contrastingly, repression of ZF3 knockout expression resulted in significant increase in E- or ZF4 individually in Slug mice was required for the same cadherin, as well as β-catenin. This corroborates results found effect. This further supports the idea that the two act differently by Kim et al. (2014) in a similar study using immunohisto- on E-cadherin, using different zinc fingers. It is plausible that chemistry to examine expression in 123 ovarian cancer cases. Snail is required to maintain EMT, whilst Slug aids in its induc- Twist expression correlated to reduced E-cadherin expres- tion. The study by Kurrey et al. (2005) using hypoxic condi- sion, as well as overall survival. Both studies indicate the dir- tions showed initial increased Slug mRNA levels, which then ect repression of E-cadherin by Twist and its further reduced to the basal level after 12 h. Snail, however, was only association with poor prognosis. detected after 60 h. This supports the theory that Snail stabi- lises rather than induces EMT, being triggered at a later stage. Interestingly, the study by Kim et al. also showed increased Indeed, Snail was found to have a stronger binding affinity for HIF1α expression corresponding to Twist. This relationship the E-cadherin promoter than Slug. Band shift studies of was noted in other studies, perhaps indicating the role of a MDCK (lung cancer) cells in another study (Bolós et al.,2003) HIF1α/TWIST/E-cadherin pathway in EMT. Microarray ............................................................................................... .................................................................. 2 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzy010/5253900 by DeepDyve user on 20 July 2022 Bioscience Horizons � Volume 11 2018 Review article ............................................................................................... .................................................................. evaluation of expression in normal vs carcinoma endometrial Sun et al. (Sun et al.,2016) showed Twist to be a target of samples (Feng et al., 2013) showed a significant (p < 0.01) miR-548c. miR-548c is a microRNA involved in translational increase in HIF1α and Twist along with decreased E- repression or degradation of RNA. This contests the former cadherin. HIF1α overexpression correlated with increased study (Yin et al.,2013) and suggests that Twist is regulated Twist. This further supports the hypothesis that HIF1α lies through the repression degradation of RNA rather than pro- directly upstream of Twist. However, though significant (p < teasomal degradation. It is of note, however, that it is possible 0.01), the correlation found using a Spearman’s rank test was for both mechanisms of Twist regulation to occur (Fig. 1). weak (r = 0.249). This suggests either a coincidental relation- Further study of upstream regulatory factors of Twist is ship between the two, or that other factors may be required to required, not only to prove or disprove these mechanisms, but interact with HIF1α to induce Twist. This would explain why also to identify potential targets for treatment. If miR-548c upregulation of HIF1α resulted in increased Twist expression does indeed repress Twist, it has potential for future thera- in some, but not all cases. Furthermore, a larger sample size peutic treatment. of endometrial carcinoma patients than normal endometrial samples was used. This might influence the rise in significance of the results. Further research is necessary to prove this Negative regulation of Snail and mechanism of E-cadherin repression, perhaps by using Slug transcription factors via Twist CRISPR/Cas9 to knockout HIF1α. Not only is Twist negatively regulated, but burgeoning evi- Another explanation for the weak correlation between dence suggests that it may regulate Snail and Slug expression. HIF1α and Twist is the activity of post-transcriptional or trans- In a study by Forghanifard et al. (2017) ectopic expression of lational repression. In one study (Yin et al.,2013), Twist was Twist via transfection into KYSE-30 cells drastically reduced transfected into epithelial ovarian cancer stem cells using plas- Snail expression, with a 7-fold reduction in Snail mRNA. mids containing the full-length gene. As expected, this resulted Furthermore, both TWIST and Snail are induced downstream in a significant increase in Twist mRNA expression. However, of nuclear factor kappa B (NF-κB)—a signalling pathway protein expression did not increase alongside. This implies the heavily involved in inflammation (Šošic´ et al., 2003). This involvement of factors repressing the protein after transcrip- upregulation appears to act as a negative feedback loop, with tion. This could occur through the use of microRNAs, or deg- Twist inhibiting further NF-κB activation. Whether Snail may radation of the protein. The use of MG132 to block also aid in this negative regulation is yet to be uncovered. It proteasome activity restored expression of Twist protein along- may be that, as well as inhibiting NF-κB, Twist mediates Snail side its mRNA, suggesting regulation to be through protein expression in EMT. Chip immunoprecipitation by Lander degradation. In contrast, the use of luciferase reporter assay by et al. (2013) revealed binding of Snail and Slug to E-box sequences via zinc-finger interaction with the Twist C- terminal. Indeed, deletion of the C-terminal WR domain abol- ished Twist association with Snail, as well its inhibition of Slug chromatin recruitment. Furthermore, co-expression of Snail with Twist stabilised the protein. This stabilisation was hypothesised to occur via Snail interference with other Twist- binding proteins (Lander et al., 2013). Interestingly, inhib- ition of Twist phosphorylation by GSK-3β led to decreased Twist/Slug interaction. These findings outline a complex, hier- archical method of Snail, Slug and Twist regulation, with each factor mediating the other. While Snail and Slug control early stage EMT, Twist may act later to downregulate Snail and Slug, thus regulating late stage EMT. The discovery of GSK-3β interaction with Twist via phos- phorylation adds further complexity. It is plausible that Twist association with Snail and Slug is regulated by GSK-3β, ensur- ing its occurrence only in late stage EMT. Despite the conceiv- ability of this idea, it is notable that study into this interaction Figure 1. Summary of HIF1α induced activation of Snail, Slug and Twist and subsequent EMT. HIF1α binds DNA, resulting in TF by Lander et al. (2013) was performed in the context of transcription. miR-548c may bind and degrade Twist RNA. Proteasome Xenopus neural crest development. Thus, extrapolation of activity could also regulate Twist protein levels. Translated TFs bind these findings to ovarian tumours is a stretch. It is advised, DNA inducing several expression alterations, including E-cadherin therefore, that further studies of Twist, Snail and Slug inter- repression. Evidence indicates Slug induces EMT whilst Snail binds action be performed specifically in OSE tissue. Nonetheless, later to stabilise and maintain repression of adhesion molecules. these studies present an intriguing model of EMT regulation Repression of said molecules aids in transition to mesenchymal to be corroborated by study in other tissues. morphology in EMT. ............................................................................................... .................................................................. 3 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzy010/5253900 by DeepDyve user on 20 July 2022 Review article Bioscience Horizons � Volume 11 2018 ............................................................................................... .................................................................. found E-cadherin expression was confined to OSE in inclu- Transcription factors and cisplatin sion cysts and deep clefts. Immunochemical staining revealed resistance no expression on the ovary surface. This is corroborated by multiple studies investigating E-cadherin in OSE (Maines- Evidence that EMT may be related to cisplatin resistance was Bandiera and Auersperg, 1997). Maines-Bandiera and noted in recent studies, with Snail’s contribution largely evi- Auersperg suggested that the mesenchymal-like morphology denced. A study on A459 lung carcinoma cell lines (Wang of OSE cells allows rapid progression to EMT in monolayer et al., 2014) showed increased Snail levels when treated with culture. However, investigation of metaplastic OSE cells by cisplatin to develop resistance. Knockout of Snail using Maines-Bandeira and Auersperg (1997) found an abundance siRNA led to a decrease in cell viability under cisplatin treat- of E-cadherin expression. Furthermore, prominence of E- ment. In another study (Kaufhold and Bonavida, 2014), tran- cadherin increased in columnar and cuboidal OSE compared scriptome microarrays between ovarian tumour A2780 cells to flat. This suggests that, though absent in flat OSE, E- and their cisplatin-resistant daughter A2780cis cells also cadherin plays a role in specific intercellular adhesion in showed Snail overexpression. Again, use of SiRNA to knock- cuboidal and columnar OSE, for instance, in epithelial inclu- out Snail transcripts resulted in EMT reversion and increased sion cysts. Furthermore, its expression in OSE may indicate cisplatin sensitivity. This reveals promising potential for progression to metaplasia (Maines-Bandiera and Auersperg, future methods of treatment of cisplatin-resistant tumours, 1997). Interestingly, morphology and E-cadherin expression though further study, perhaps on live animals may be of metaplastic OSE resembles oviductal, endometrial and required. Furthermore, siRNA is prone to mistakes (Latifi endocervical epithelium (Auersperg et al., 1999). This may be et al., 2011), so studies using more accurate methods of gen- a result of OSE differentiation towards these related tissue ome editing such as CRISPR/cas9 could be performed. types during metaplastic progression. Indeed, transfection of E-cadherin cDNA into mouse OSE resulted in initiation of a Interestingly, the study by Kaufhold and Bonavida (2014) metaplastic, epithelialized phenotype resembling neoplastic also revealed overexpression of Slug, Twist2 and Zeb2 in OSE (Auersperg et al., 1999). This suggests that though E- cisplatin-resistant cells, whereas analysis of A459 lung carcin- cadherin may act as a tumour suppressor in late stage carcin- oma cell lines by Wang et al. (2014) did not demonstrate such omas, its upregulation in OSE aids progression to metaplasia observations. A point of note in this study, however, is that and early neoplasia. actual resistance of the cell after exposure to cisplatin seems to have been assumed, not tested. Conclusions as to Snail, Slug This fluctuation in E-cadherin levels indicates a complex and Twist’s effect on these cells cannot therefore be fully asso- and combinatorial regulation which is yet to be fully under- ciated with its effect on cisplatin resistance. Furthermore, this stood. Although Snail Slug and Twist have been shown to study used lung carcinoma cell lines, whereas Kaufhold and decrease E-cadherin expression in the transference from nor- Bonavida (Kaufhold and Bonavida, 2014) investigated ovarian mal to malignant tissue, their presence in benign tumours carcinoma lines. Thus, results from this are deemed more reli- may not have the same effect. Indeed, though levels of these able. Nonetheless, both studies indicate a crucial role of Snail in TFs were significantly higher in benign tumours (Yi et al., cisplatin resistance homologous in both ovarian and lung can- 2014), E-cadherin expression was present in 40.4% more cers. One study (Latifi et al., 2011) on ovarian cancer cells benign tumour samples than normal or malignant tissue. This showed increased mRNA levels of Snail, Slug and Twist in prompts the consideration that yet another transcription fac- response to cisplatin. This may have been the tumour acquiring tor or miRNA may inhibit Snail Slug and Twist in benign tis- resistance through transcription factor upregulation. This fur- sue, thus negating subsequent E-cadherin down-regulation. ther suggests the involvement of Slug and Twist in cisplatin Identifying this factor might give an insight into the mechan- resistance. Further studies into Twist and Slug’sinvolvement isms of malignancy formation and targets for its reversal. should be undergone by using CRISPR/cas9 to reduce their Furthermore, the increase of E-cadherin in benign tumours expression and observe the effects. More physiological methods suggests a direct upregulation via not only inhibition of Snail, of transcription factor repression could also be used, perhaps Slug and Twist, but another transcription factor. Should this by utilising an inhibitor such as oligonucleotide-Co(III) Schiff factor or mechanism of E-cadherin upregulation be identified, base conjugate, which inhibits Snail, Slug and Sip1 (Harney its use in vivo to prevent EMT (and malignancy) might be et al.,2009) by preventing binding to DNA. Other transcription considered. Interestingly, in the same study, borderline ovar- factors are not inhibited. This may therefore have potential for ian tumours showed a 50% presence of E-cadherin after west- development as a less error prone cancer therapeutic. ern blotting (Yi et al., 2014). Though high, this level of expression is 7% lower than in benign samples. This lower expression may be a result of conversion from benign to E-cadherin in normal ovarian malignant phenotype. Thus, examination of transcription fac- tor expression between benign and borderline ovarian epithelium tumours would be a prudent area of study. Inspection of dif- ferentially expressed genes in these tissues might identify fac- Interestingly, E-cadherin presence in normal OSE is limited tors responsible for benign to malignant transition. Such compared to other epithelial tissues. Sundfeldt et al. (1997) ............................................................................................... .................................................................. 4 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzy010/5253900 by DeepDyve user on 20 July 2022 Bioscience Horizons � Volume 11 2018 Review article ............................................................................................... .................................................................. Batlle, E., Sancho, E., Francí, C. et al. (2000) The transcription factor snail factors would be promising targets for gene therapy. Though is a repressor of E-cadherin gene expression in epithelial tumour E-cadherin plays a role in cancer progression, the specifics cells, Nature Cell Biology,2, 84–89. doi:10.1038/35000034. remain unclear. Davidson (2001) suggested E-cadherin expression occurs intermittently during expression. This idea Bolós, V., Peinado, H., Pérez-Moreno, M. A. et al. (2003) The transcription is supported by the differential E-cadherin expression depend- factor Slug represses E-cadherin expression and induces epithelial ing on the stage of tumour (Yi et al., 2014). However, the rea- to mesenchymal transitions: a comparison with Snail and E47 soning for this discontinuous expression requires further repressors, Journal of Cell Science, 116, 499–511. investigation. Until this fluctuation can be fully explained, manipulation of E-cadherin expression in cancer therapy may Cho, K. R. and Shih, I. M. (2009) Ovarian cancer, Annual Review of not be a viable treatment. Understanding this complex expres- Pathology,4,287–313. doi:10.1146/annurev.pathol.4.110807.092246. sion is vital to determining both E-cadherin’s role in EMT Dattoli, A. A., Hink, M. A., DuBuc, T. Q. et al. (2015) Domain analysis of and its potential as a therapeutic target. the Nematostella vectensis SNAIL ortholog reveals unique nucle- olar localization that depends on the zinc-finger domains, Scientific Reports, 5, 12147. doi:10.1038/srep12147. Conclusion Davidson, B. (2001) Ovarian carcinoma and serous effusions. Changing In conclusion, all three transcription factors reduce E-cadherin views regarding tumor progression and review of current literature 1. expression and the mechanisms of this process are beginning to Analytical Cellular Pathology, 23, 107–128. doi:10.1155/2001/418547. be understood in more detail. Understanding this could allow methods of knockdown of Snail, Slug and Twist in vivo to be Feng, Z., Gan, H., Cai, Z. et al. (2013) Aberrant expression of hypoxia- developed. Evidence that Snail and Slug work cooperatively inducible factor 1α, TWIST and E-cadherin is associated with aggressive must be taken into account, as one might compensate for the tumor phenotypes in endometrioid endometrial carcinoma, Japanese other’s loss. Twist, too, may play a role in this hierarchical Journal of Clinical Oncology, 43, 396–403. doi:10.1093/jjco/hys237. regulation. HIF1α has been found to be an upstream regulator Forghanifard, M. M., Ardalan Khales, S., Farshchian, M. et al. (2017) Negative of Twist and perhaps Snail and Slug. It may be that post- regulatory role of TWIST on SNAIL gene expression, Pathology translational or transcriptional regulation is involved, and if Oncology Research, 23, 85. https://doi.org/10.1007/s12253-016-0093-2. correct, this regulatory method could be augmented in vivo to regulate Snail, Slug or Twist expression. Though interesting, Harney, A. S., Lee, J., Manus, L. M. et al. (2009) Targeted inhibition of this requires far more research, as well as confirmation of Snail family zinc finger transcription factors by oligonucleotide-Co HIF1α’s involvement. Its involvement would indicate hypoxic (III) Schiff base conjugate, Proceedings of the National Academy of conditions to be stimulator of metastasis. In addition, Snail has Sciences of the United States of America, 106, 13667–13672. doi:10. been shown to correlate with cisplatin resistance. The involve- 1073/pnas.0906423106. ment of other transcription factors remains largely unknown Kaufhold, S. and Bonavida, B. (2014) Central role of Snail1 in the regula- and requires more detailed research. Nonetheless, the discovery tion of EMT and resistance in cancer: a target for therapeutic inter- of Snail’s connection could hold therapeutic values. If drugs vention, Journal of Experimental & Clinical Cancer Research : CR, 33, can be developed to remove or reduce Snail in patient tumours, 62. doi:10.1186/s13046-014-0062-0. reversal of cisplatin resistance might be possible. It is also plausible that reduction of other transcription factors as well as Kim, K., Park, E. Y., Yoon, M. S. et al. (2014) The role of TWIST in ovarian Snail might aid to prevent EMT, which may prevent metastasis epithelial cancers, The Korean Journal of Pathology, 48, 283–291. of the primary tumour. Despite these promising discoveries, E- doi:10.4132/KoreanJPathol.2014.48.4.283. cadherin regulation in ovarian carcinoma remains a complex Kurrey, N. K., Jalgaonkar, S. P., Joglekar, A. V. et al. (2009) Snail and slug process. E-cadherin fluctuation between normal, benign and mediate radioresistance and chemoresistance by antagonizing p53- malignant tissue has yet to be explained. Though the role of mediated apoptosis and acquiring a stem-like phenotype in ovarian Twist, Snail and Slug in this intermittent expression is becom- cancer cells, Stem Cells, 27, 2059–2068. doi:10.1002/stem.154. ing more defined, much work is yet required before therapies can be developed. Nonetheless, frequent investigation into this Kurrey, N. K., K, A. and Bapat, S. A. (2005) Snail and Slug are major deter- process is beginning to fill in the blanks. Once this picture is minants of ovarian cancer invasiveness at the transcription level, complete, therapeutic treatment of ovarian cancer may become Gynecologic Oncology, 97, 155–165. doi:10.1016/j.ygyno.2004.12.043. far more plausible. Lander, R., Nasr, T., Ochoa, S. D. et al. 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Journal
BioScience Horizons – Oxford University Press
Published: Jan 1, 2018