miR-149 represses metastasis of hepatocellular carcinoma by targeting actin-regulatory proteins PPM1F

Abstract

// Gang Luo 1 , Ya-Ling Chao 1 , Bo Tang 1 , Bo-Sheng Li 1 , Yu-Feng Xiao 1 , Rui Xie 1 , Shu-Ming Wang 1 , Yu-Yun Wu 1 , Hui Dong 1, 3 , Xiang-De Liu 2 , Shi-Ming Yang 1 1 Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China 2 Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China 3 Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA Correspondence to: Shi-Ming Yang, e-mail: shimingyang@yahoo.com Xiang-De Liu, e-mail: liuxd@medmail.com.cn Keywords: hepatocellular carcinoma, miR-149, metastasis, PPM1F, microRNA Received: April 29, 2015      Accepted: October 02, 2015      Published: October 14, 2015 ABSTRACT microRNAs have been implicated in hepatocellular carcinoma (HCC) metastasis, which is predominant cause of high mortality in these patients. Although an increasing body of evidence indicates that miR-149 plays an important role in the growth and metastasis of multiple types of cancers, its role in the progression of HCC remains unknown. Here, we demonstrated that miR-149 was significantly down-regulated in HCC, which was correlated with distant metastasis and TNM stage with statistical significance. A survival analysis showed that decreased miR-149 expression was correlated with a poor prognosis of HCC as well. We found that over-expression of miR-149 suppressed migration and invasion of HCC cells in vitro . In addition, we identified PPM1F (protein phosphatase, Mg 2+ /Mn 2+ -dependent, 1F) as a direct target of miR-149 whose expression was negatively correlated with the expression of miR-149 in HCC tissues. The re-expression of PPM1F rescued the miR-149-mediated inhibition of cell migration and invasion. miR-149 regulated formation of stress fibers to inhibit migration, and re-expression of PPM1F reverted the miR-149-mediated loss of stress fibers. Moreover, we demonstrated that over-expression of miR-149 reduced pMLC2, a downstream effector of PPM1F, in MHCC-97H cells. In vivo studies confirm inhibition of HCC metastasis by miR-149. Taken together, our findings indicates that miR-149 is a potential prognostic biomarker of HCC and that the miR-149/PPM1F regulatory axis represents a novel therapeutic target for HCC treatment.