miRNA-487a Promotes Proliferation and Metastasis in Hepatocellular Carcinoma.
Purpose:Hepatocellular carcinoma (HCC) harbors highly metastatic properties, accounting for postoperative recurrence and metastasis. However, the mechanisms for metastasis and recurrence remain incompletely clear. This study aimed to investigate the role of hsa-miR-487a (miR-487a) in promoting the proliferation and metastasis of HCC and to elucidate the underlying molecular mechanisms.Experimental Design:198 HCC samples were analyzed for association between miR-487a expression and patient clinicopathological features and prognosis. The roles of miR-487a in proliferation and metastasis were validated bothin vivoandin vitroThe upstream regulator and downstream targets of miR-487a were determined using a dual luciferase reporter assay, chromatin immunoprecipitation and immunohistochemistry.Results:Our results demonstrate that upregulated miR-487a correlates with a poor prognosis for HCC patients. miR-487a enhances proliferation and metastasis of HCC cells by directly binding to sprouty-related EVH1 domain containing 2 (SPRED2) or phosphoinositide-3-Kinase regulatory subunit 1 (PIK3R1). Interestingly, miR-487a mainly promotes metastasis via SPRED2 induced mitogen activated protein kinase signaling and promotes proliferation via PIK3R1 mediated AKT signaling. Transcription of miR-487a was found to be activated by up-regulated heat shock factor 1, which we previously demonstrated to be an important metastasis-associated transcription factor in a previous study. Phosphorodiamidate morpholino oligomers effectively silenced miR-487a and inhibited HCC tumor progression in mouse models.Conclusions:Our findings show that miR-487a, mediated by heat shock factor 1, promotes proliferation and metastasis of HCC by PIK3R1 and SPRED2 binding, respectively. Our study provides a rationale for developing miR-487a as a potential prognostic marker or a potential therapeutic target against HCC.Clin Cancer Res; 23(10); 2593-604. ©2016 AACR.
Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Rui-Min
RM
Chang
Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Shuai
S
Xiao
Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Xiong
X
Lei
Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Hao
H
Yang
Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Feng
F
Fang
Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan, China. lianyueyang@hotmail.com.|Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Lian-Yue
LY
Yang
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D058543:Class Ia Phosphatidylinositol 3-Kinase; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic; D000076249:Heat Shock Transcription Factors / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction
D058543:Class Ia Phosphatidylinositol 3-Kinase; D000076249:Heat Shock Transcription Factors; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D012097:Repressor Proteins; C568526:MIRN487 microRNA, human; C500760:SPRED2 protein, human; C588001:PIK3R1 protein, human