Regulation of hnRNPA1 by microRNAs controls the miR-18a–K-RAS axis in chemotherapy-resistant ovarian cancer

Cristian Rodriguez-Aguayo,Paloma Del C Monroig,Roxana S Redis,Emine Bayraktar,Maria I Almeida,Cristina Ivan,Enrique Fuentes-Mattei,Mohammed H Rashed,Arturo Chavez-Reyes,Bulent Ozpolat,Rahul Mitra,Anil K Sood,George A Calin,Gabriel Lopez-Berestein

doi:10.1038/celldisc.2017.29

Abstract

The regulation of microRNA (miRNA) biogenesis, function and degradation involves a range of mechanisms, including interactions with RNA-binding proteins. The potential contribution of regulatory miRNAs to the expression of these RNA interactor proteins that could control other miRNAs expression is still unclear. Here we demonstrate a regulatory circuit involving oncogenic and tumor-suppressor miRNAs and an RNA-binding protein in a chemotherapy-resistant ovarian cancer model. We identified and characterized miR-15a-5p and miR-25-3p as negative regulators of hnRNPA1 expression, which is required for the processing of miR-18a-3p, an inhibitor of the K-RAS oncogene. The inhibition of miR-25-3p and miR-15a-5p decreased the proliferation, motility, invasiveness and angiogenic potential and increased apoptosis when combined with docetaxel. Alteration of this regulatory circuit causes poor overall survival outcome in ovarian cancer patients. These results highlight miR-15a-5p and miR-25-3p as key regulators of miR-18a-3p expression and its downstream target K-RAS, through direct modulation of hnRNPA1 expression. Our results demonstrate the therapeutic potential of inhibiting miR-25-3p and miR-15a-5p and the use of miR-18a-3p/KRAS ratio as a prominent outcome prognostic factor.

Highlights

Regulation of the hnRNPA1 RNA-binding protein by either miR-15a-5p or miR-25-3p leads to increased tumor growth by inhibiting the biogenesis of miR-18a-3p, an inhibitor of the K-RAS oncogene
Results hnRNPA1 expression is decreased in chemoresistant ovarian cancer cells
To analyze the physiological relevance of hnRNPA1 expression in chemoresistant ovarian cancer, we performed a screen for protein expression in three chemotherapy-sensitive and resistant pairs of ovarian cancer cell lines (Figure 1a)

Summary

Introduction

Regulation of the hnRNPA1 RNA-binding protein by either miR-15a-5p or miR-25-3p leads to increased tumor growth by inhibiting the biogenesis of miR-18a-3p, an inhibitor of the K-RAS oncogene. Regulation of the hnRNPA1 RNA-binding protein by either miR-15a-5p or miR-25-3p leads to increased tumor growth by inhibiting the biogenesis of miR-18a-. This work identifies miR-15a-5p/miR-25-3p/miR-18a-3p/K-RAS pathway as a potential target for overcoming resistance to chemotherapy in cancer cells and improving patient outcomes. MicroRNAs (miRNAs) are small non-coding RNAs that repress gene expression [1]; they target most protein-coding transcripts and are involved in most developmental and pathological processes in animals [2]. Several studies have reported that RNAbinding proteins are key components in the determination of miRNA function [11, 12], as they control different stages of miRNA biogenesis and their localization, degradation and activity [13]. Alteration of RNA-binding protein function can lead to impairment in any of the crucial steps of the miRNA pathway [14]

Methods

Results

Conclusion