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Abstract
To develop effective therapies for advanced high grade serous ovarian cancer (HGSOC), understanding mechanisms of recurrence and metastasis is necessary. In this study, we define the epithelial/mesenchymal status of cell lines that accurately model HGSOC, and evaluate the therapeutic potential of targeting Snai1 (Snail), a master regulator of the epithelial/mesenchymal transition (EMT) in vitro and in vivo. The ratio of Snail to E-cadherin (S/E index) at RNA and protein levels was correlated with mesenchymal morphology in four cell lines. The cell lines with high S/E index (OVCAR8 and COV318) showed more CSC-like, motile, and chemoresistant phenotypes than those with low S/E index (OVSAHO and Kuramochi). We tested the role of Snail in regulation of malignant phenotypes including stemness, cell motility, and chemotherapy resistance: shRNA-mediated knockdown of Snail reversed these malignant phenotypes. Interestingly, the expression of let-7 tumour suppressor miRNA was upregulated in Snail knockdown cells. Furthermore, knockdown of Snail decreased tumour burden in an orthotopic xenograft mouse model. We conclude that Snail is important in controlling HGSOC malignant phenotypes and suggest that the Snail/Let-7 axis may be an attractive target for HGSOC treatment.
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1 Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA
2 Department of Molecular Biology, Chonbuk National University, Jeollabuk-do, Republic of Korea
3 University of California, Riverside - School of Medicine, Riverside, CA, USA
4 Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA; Center for Health Disparities and Molecular Medicine, Loma Linda University, Loma Linda, CA, USA
5 Beckman Research Institute, City of Hope, Duarte, CA, USA
6 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Loma Linda University Medical Center, Loma Linda, CA, USA