Differential Expression Pattern of Epithelial Mesenchymal Transition Gens: AXL, GAS6, Claudin-1, and Cofilin-1, in Different Stages of Epithelial Ovarian Cancer

  • Elham HASSANI Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
  • Mahmood SHEKARI KHANIANI Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
  • Mojtaba SAFFARI Cancer Biology Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
  • Amirnader EMAMI RAZAVI Iran National Tumor Bank, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
  • Reza SHIRKOOHI Cancer Biology Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
  • Sima MANSOORI DERAKHSHAN 1. Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran 2. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
Keywords: QRT-PCR; AXL; GAS6; Claudin-1; Cofilin-1

Abstract

Abstract Background: Epithelial ovarian cancer (EOC), is the fatal form of gynecological cancer. Almost 70% of ovarian cancer patients are detected at an advanced stage (III-IV) with metastases. Epithelial‑mesenchymal transition (EMT) is a critical process associated with metastasis. This study investigated the expression levels of AXL, GAS6, Claudin-1, and Cofilin-1, as genes involved in EMT in relation to clinicopathologic features in ovarian cancer patients. Methods: In this descriptive study, 78 ovarian epithelial cancer patients were enrolled. Samples were provided by the Iran National Tumor Bank, founded by the Cancer Institute of Tehran University of Medical Sciences in 2017. The expression levels of AXL, GAS6, Claudin-1, and Cofilin-1 genes were investigated in a fresh, frozen tumor sample and normal adjacent tissue by real-time PCR (RT-PCR). Results: Findings showed a significant relationship between the overexpression of AXL and TNM staging (P=0.03). The expression level of GAS6 decreased in more advanced stages (P=0.01). There is a negative relationship between Cofilin-1 expression level and TNM staging (P=0.002). Claudin-1 expression level was higher in low stages compared with that in high stages (P=0.01). There was no relationship between gene expression levels of target genes with size and grade of the tumor. Conclusion: Given the importance of these genes in EMT, alteration in their expression pattern can contribute to the progression of the disease and distant metastasis of cancer cells. Additionally, knowing the alteration pattern of these genes expression can help to better understanding and prediction of the prognosis of EOC.  

References

1. Tiwari A, Hadley JA, Hendricks GL et al (2013). Characterization of ascites-derived ovarian tumor cells from spontaneously occurring ovarian tumors of the chicken: evidence for E-cadherin upregulation. PLoS One, 8:e57582.
2. Lau MT, So WK, Leung PC (2013). Fibroblast growth factor 2 induces E-cadherin down-regulation via PI3K/Akt/mTOR and MAPK/ERK signaling in ovarian cancer cells. PLoS One, 8:e59083.
3. Arab M, Khayamzadeh M, Tehranian A et al (2010). Incidence rate of ovarian cancer in Iran in comparison with developed countries. Indian J Cancer, 47:322-7.
4. Lynch HT, Casey MJ, Snyder CL et al (2009). Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management. Mol Oncol, 3:97-137.
5. Shih Ie M, Davidson B (2009). Pathogenesis of ovarian cancer: clues from selected overexpressed genes. Future Oncol, 5:1641-57.
6. Jiang L, Wang H, Li J et al (2014). Up-regulated FASN expression promotes transcoelomic metastasis of ovarian cancer cell through epithelial-mesenchymal transition. Int J Mol Sci, 15:11539-54.
7. Mishra A, Wang J, Shiozawa Y et al (2012). Hypoxia stabilizes GAS6/Axl signaling in metastatic prostate cancer. Mol Cancer Res, 10:703-12.
8. Rizvi I, Gurkan UA, Tasoglu S et al (2013). Flow induces epithelial-mesenchymal transition, cellular heterogeneity and biomarker modulation in 3D ovarian cancer nodules. Proc Natl Acad Sci U S A, 110:E1974-83.
9. Sun BO, Fang Y, Li Z et al (2015). Role of cellular cytoskeleton in epithelial-mesenchymal transition process during cancer progression. Biomed Rep, 3:603-610.
10. Shirkoohi R (2013). Epithelial mesenchymal transition from a natural gestational orchestration to a bizarre cancer disturbance. Cancer Sci, 104:28-35.
11. Lamouille S, Xu J, Derynck R (2014). Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol, 15:178-96.
12. Rankin EB, Fuh KC, Taylor TE et al (2010). AXL is an essential factor and therapeutic target for metastatic ovarian cancer. Cancer Res, 70:7570-9.
13. Hewitt KJ, Agarwal R, Morin PJ (2006). The claudin gene family: expression in normal and neoplastic tissues. BMC Cancer, 6:186.
14. Boylan KL, Misemer B, De Rycke MS et al (2011). Claudin 4 Is differentially expressed between ovarian cancer subtypes and plays a role in spheroid formation. Int J Mol Sci, 12:1334-58.
15. Litkouhi B, Kwong J, Lo CM et al (2007). Claudin-4 overexpression in epithelial ovarian cancer is associated with hypomethylation and is a potential target for modulation of tight junction barrier function using a C-terminal fragment of Clostridium perfringens enterotoxin. Neoplasia, 9:304-14.
16. Bhat AA, Sharma A, Pope J et al (2012). Caudal homeobox protein Cdx-2 cooperates with Wnt pathway to regulate claudin-1 expression in colon cancer cells. PLoS One, 7:e37174.
17. Zhou B, Moodie A, Blanchard AA et al (2015). Claudin 1 in Breast Cancer: New Insights. J Clin Med, 4:1960-76.
18. Zhou J, Wang Y, Fei J, Zhang W (2012). Expression of cofilin 1 is positively correlated with the differentiation of human epithelial ovarian cancer. Oncol Lett, 4:1187-1190.
19. Collazo J, Zhu B, Larkin S et al (2014). Cofilin drives cell-invasive and metastatic responses to TGF-β in prostate cancer. Cancer Res, 74:2362-2373.
20. Nagai S, Moreno O, Smith CA et al (2011). Role of the cofilin activity cycle in astrocytoma migration and invasion. Genes Cancer, 2:859-69.
21. Wu X, Liu X, Koul S et al (2014). AXL kinase as a novel target for cancer therapy. Oncotarget, 5:9546-63.
22. Zhu Y (2007). Tight Junction in Ovarian Surface Epithelium and Epithelial Ovarian Tumors. https://pdfs.semanticscholar.org/ed94/7256440f0f34c4e674d343222524d5e3f956.pdf?_ga=2.168720993.1552669655.1563114027-624890370.1563114027
23. Sharifian A, Pourhoseingholi MA, Norouzinia M, Vahedi M (2014). Ovarian cancer in Iranian women, a trend analysis of mortality and incidence. Asian Pac J Cancer Prev, 15:10787-90.
24. Alliance Ocn. OVARIAN CANCER Statistics 2014-2015. www.ovariancancer.org
25. Buehler M, Tse B, Leboucq A et al (2013). Meta-analysis of microarray data identifies GAS6 expression as an independent predictor of poor survival in ovarian cancer. Biomed Res Int, 2013:238284.
26. Gonzalez DM, Medici D (2014). Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal, 7:re8.
27. Becker M, De Bastiani MA, Muller CB et al (2014). High cofilin-1 levels correlate with cisplatin resistance in lung adenocarcinomas. Tumour Biol, 35:1233-8.
28. Zhang Y, Tong X (2010). Expression of the actin-binding proteins indicates that cofilin and fascin are related to breast tumour size. J Int Med Res, 38:1042-8.
29. English DP, Santin AD (2013). Claudins overexpression in ovarian cancer: potential targets for Clostridium Perfringens Enterotoxin (CPE) based diagnosis and therapy. Int J Mol Sci, 14:10412-37.
30. Kwon MJ (2013). Emerging roles of claudins in human cancer. Int J Mol Sci, 14:18148-80.
31. Sappayatosok K, Phattarataratip E (2015). Overexpression of Claudin-1 is Associated with Advanced Clinical Stage and Invasive Pathologic Characteristics of Oral Squamous Cell Carcinoma. Head Neck Pathol, 9:173-80.
32. Rankin EB, Giaccia AJ (2016). The Receptor Tyrosine Kinase AXL in Cancer Progression. Cancers (Basel), 8(11): E103.
Published
2019-09-03
How to Cite
1.
HASSANI E, SHEKARI KHANIANI M, SAFFARI M, EMAMI RAZAVI A, SHIRKOOHI R, MANSOORI DERAKHSHAN S. Differential Expression Pattern of Epithelial Mesenchymal Transition Gens: AXL, GAS6, Claudin-1, and Cofilin-1, in Different Stages of Epithelial Ovarian Cancer. Iran J Public Health. 48(9):1723-1731.
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Original Article(s)