Oncogenic Role of miR-200c-3p in High-Grade Serous Ovarian Cancer Progression via Targeting the 3'-Untranslated Region of DLC1.

Sheril June Ankasha,Mohamad Nasir Shafiee,Norfilza Mohd Mokhtar,Norhazlina Abdul Wahab,Raja Affendi Raja Ali

doi:10.3390/ijerph18115741

Abstract

High-grade serous ovarian cancer (HGSC) is the most common ovarian cancer with highly metastatic properties. A small non-coding RNA, microRNA (miRNA) was discovered to be a major regulator in many types of cancers through binding at the 3′-untranslated region (3′UTR), leading to degradation of the mRNA. In this study, we sought to investigate the underlying mechanisms involved in the dysregulation of miR-200c-3p in HGSC progression and metastasis. We identified the upregulation of miR-200c-3p expression in different stages of HGSC clinical samples and the downregulation of the tumor suppressor gene, Deleted in Liver Cancer 1 (DLC1), expression. Over expression of miR-200c-3p in HGSC cell lines downregulated DLC1 but upregulated the epithelial marker, E-cadherin (CDH1). Based on in silico analysis, two putative binding sites were found within the 3′UTR of DLC1, and we confirmed the direct binding of miR-200c-3p to the target binding motif at position 1488–1495 bp of 3′UTR of DLC1 by luciferase reporter assay in a SKOV3 cell line co-transfected with vectors and miR-200c-3p mimic. These data showed that miR-200c-3p regulated the progression of HGSC by regulating DLC1 expression post-transcription and can be considered as a promising target for therapeutic purposes.

Highlights

Ovarian cancer is the fifth most common cancer in women, and is the leading cause of death for patients with gynecological cancer
Serous ovarian cancer (SOC) is classified into two categories, namely low-grade serous carcinoma (LGSC), which is a prototype for type I ovarian cancer and comprises less than five percent of epithelial ovarian cancer (EOC) cases, and high-grade serous carcinoma (HGSC), which is a prototype for type II ovarian cancer
All the tissues obtained were histologically validated using hematoxylin and eosin (H&E) staining by a pathologist to confirm that the normal ovary tissue samples were free from cancer or inflammatory cells and that the cancer tissues contained more than 80% malignant cells

Summary

Introduction

Ovarian cancer is the fifth most common cancer in women, and is the leading cause of death for patients with gynecological cancer. High levels of genetic and molecular heterogeneity are reported for epithelial ovarian cancer (EOC), and these epithelial cells can be transformed into different histological subtypes, either resembling the fallopian tube layer (serous, 52%), endometrium (endometrioid, 10%), endocervix glands (mucinous, 6%), or other vaginal cells (6%); the rest are rare histotypes [1,2]. Serous ovarian cancer (SOC) is classified into two categories, namely low-grade serous carcinoma (LGSC), which is a prototype for type I ovarian cancer and comprises less than five percent of EOC cases, and high-grade serous carcinoma (HGSC), which is a prototype for type II ovarian cancer. LGSC patients are often diagnosed at an early stage (stage I or II) with low mortality rates and tumor growth.

Methods

Results

Conclusion