MiRNA-96 Suppresses KRAS and Functions as a Tumor Suppressor Gene in Pancreatic Cancer

Shuangni Yu,Jie Chen,Zhaohui Lu,Yihui Ma,Jia Yu,Jianping Liu,Changzheng Liu,Wugan Zhao,Yunxiao Meng

doi:10.1158/0008-5472.can-09-4531

Abstract

Therapeutic applications of microRNA (miRNA) in KRAS-driven pancreatic cancers might be valuable, but few studies have explored this area. Here, we report that miR-96 directly targets the KRAS oncogene and functions as a tumor-suppressing miRNA in pancreatic cancer cells. Ectopic expression of miR-96 through a synthetic miRNA precursor inhibited KRAS, dampened Akt signaling, and triggered apoptosis in cells. In human clinical specimens, miR-96 was downregulated or deleted where an association with KRAS elevations was observed. In vitro and in vivo assays established that miR-96 decreased cancer cell invasion and migration and slowed tumor growth in a manner associated with KRAS downregulation. Our findings identify miR-96 as a potent regulator of KRAS, which may provide a novel therapeutic strategy for treatment of pancreatic cancer and other KRAS-driven cancers.

Highlights

MicroRNAs have drawn more attention than the other classes of noncoding RNAs in the past several years, especially for their essential roles in cancer
More than 50% of the known miRNAs have been shown to participate in human tumorigenesis and/or metastasis by directly targeting oncogenes or tumor suppressor genes [1, 2]
The pancreatic cancer cell lines MIA PaCa-2, PANC-1, and BxPC-3 and the cervical adenocarcinoma cell line HeLa were obtained from the American Type Culture Collection in 1999 and cultured in DMEM (Sigma) supplemented with 10% fetal bovine serum (FBS; Hyclone) at 37°C with 5% CO2

Summary

Introduction

MicroRNAs (miRNA) have drawn more attention than the other classes of noncoding RNAs in the past several years, especially for their essential roles in cancer. Analysis of miR-96 expression in three pancreatic cancer cell lines (MIA PaCa-2, PANC1, and BxPC-3), revealed that miR-96 was downregulated in tumor cell lines as well (Fig. 1B). The most straightforward prediction from our luciferase reporter assays would be that ectopic expression of miR-96 should reduce KRAS protein levels in MIA PaCa2 and PANC-1 cells.

Results

Conclusion