Role of miR-30a-3p Regulation of Oncogenic Targets in Pancreatic Ductal Adenocarcinoma Pathogenesis.

Hiroki Shimomura,Shogo Moriya,Tetsuya Idichi,Takako Tanaka,Masumi Wada,Hiroshi Kurahara,Yoshiaki Kita,Naohiko Seki,Takao Ohtsuka,Reona Okada,Yuto Hozaka

doi:10.3390/ijms21186459

Abstract

Our recent studies have implicated some passenger strands of miRNAs in the molecular pathogenesis of human cancers. Analysis of the microRNA (miRNA) expression signature in pancreatic ductal adenocarcinoma (PDAC) has shown that levels of miR-30a-3p, the passenger strand derived from pre-mir-30a, are significantly downregulated in PDAC tissues. This study aimed to identify the oncogenes closely involved in PDAC molecular pathogenesis under the regulation of miR-30a-3p. Ectopic expression assays showed that miR-30a-3p expression inhibited the aggressiveness of the PDAC cells, suggesting that miR-30a-3p acts as a tumor-suppressive miRNA in PDAC cells. We further identified 102 putative targets of miR-30a-3p regulation in PDAC cells by combining in silico analysis with gene expression data. Of these, ten genes (EPS8, HMGA2, ENDOD1, SLC39A10, TGM2, MGLL, SERPINE1, ITGA2, DTL, and UACA) were independent prognostic factors in multivariate analysis of survival of patients with PDAC (p < 0.01). We also investigated the oncogenic function of the integrin ITGA2 in PDAC cell lines. The integrin family comprises cell adhesion molecules expressed as heterodimeric, transmembrane proteins on the surface of various cells. Overexpression of ITGA2/ITGB1 (an ITGA2 binding partner) was detected in the PDAC clinical specimens. The knockdown of ITGA2 expression attenuated the malignant phenotypes of the PDAC cells. Together, results from these microRNA-based approaches can accelerate our understanding of PDAC molecular pathogenesis.

Highlights

Ductal carcinoma of the pancreas (PDAC) is derived from exocrine cells of the pancreatic duct and accounts for 90% of pancreatic cancer cases [1,2,3]
We focused on miR-30a-3p, the passenger strand derived from pre-mir-30a, based on our analysis of the signature that revealed significantly reduced levels of miR-30a-3p in pancreatic ductal adenocarcinoma (PDAC) tissues
Our data from the present study showed that the expression of miR-30a-3p inhibited the aggressive phenotype of cancer cells, suggesting that it may act as a tumor-suppressive miRNA in PDAC cells

Summary

Introduction

Ductal carcinoma of the pancreas (PDAC) is derived from exocrine cells of the pancreatic duct and accounts for 90% of pancreatic cancer cases [1,2,3]. Since many patients with PDAC are asymptomatic, most cases have reached an advanced stage at the time of diagnosis. Gemcitabine is an essential drug for the treatment of PDAC. FOLFIRINOX (folinic acid, 5-FU, irinotecan, and oxaliplatin), as well as gemcitabine and nab-paclitaxel regimens, are given as first-line treatments for advanced PDAC with distant metastases. These treatment regimens typically offer insufficient therapeutic effects [6].

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