miR-22 targets YWHAZ to inhibit metastasis of hepatocellular carcinoma and its down-regulation predicts a poor survival.
Many miRNAs are associated with the carcinogenesis of hepatocellular carcinoma (HCC) and some exhibit potential prognostic value. In this study, to further confirm the prognostic value of miRNAs in HCC, we employed miRNA-sequencing data of tumor tissues of 372 HCC patients released by The Cancer Genome Atlas (TCGA) and identified 3 miRNAs including miR-22, miR-9-1 and miR-9-2 could be used as independent predictors for HCC prognostic evaluation. As a tumor-suppressive miRNA, miR-22 was down-regulated in HCC tissues. This down-regulation correlated with tumor vascular invasion, Edmondson-Steiner grade, TNM stage, and AFP level. Moreover, biofunctional investigations revealed that miR-22 significantly attenuated cellular proliferation, migration and invasion of HCC cells. Additionally, through gene expression profiles and bioinformatics analysis, YWHAZ was identified to be a direct target of miR-22 and its overexpression partially counteracted the inhibitory effects of miR-22 on HCC cells. Finally, molecular studies further confirmed that miR-22 promoted the accumulation of FOXO3a in nucleus and subsequently reversed invasive phenotype of HCC cells by repressing YWHAZ-mediated AKT phosphorylation. Taken together, these data demonstrate that miR-22 exhibits tumor-suppressive effects in HCC cells by regulating YWHAZ/AKT/FOXO3a signaling and might be used as an independent prognostic indicator for HCC patients.
Department of Blood Transfusion, Zhongnan Hospital of Wuhan University, Wuchang District, Wuhan 430071, P.R. China.
Ming
M
Chen
Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuchang District, Wuhan 430071, P.R. China.
Wei
W
Hu
Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuchang District, Wuhan 430071, P.R. China.
Chen-Ling
CL
Xiong
Guangdong Food and Drug Vocational College, Guangzhou 510520, P.R. China.
Zhen
Z
Qu
Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuchang District, Wuhan 430071, P.R. China.
Chang-Qing
CQ
Yin
Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuchang District, Wuhan 430071, P.R. China.
Yu-Hui
YH
Wang
Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuchang District, Wuhan 430071, P.R. China.
Chang-Liang
CL
Luo
Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuchang District, Wuhan 430071, P.R. China.
Qing
Q
Guan
Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuchang District, Wuhan 430071, P.R. China.
Chun-Hui
CH
Yuan
Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuchang District, Wuhan 430071, P.R. China.
Fu-Bing
FB
Wang
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D019295:Computational Biology; D030541:Databases, Genetic; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010766:Phosphorylation; D016016:Proportional Hazards Models; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
D048948:14-3-3 Proteins; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; C548375:MIRN22 microRNA, human; D035683:MicroRNAs; C572235:YWHAZ protein, human; D051057:Proto-Oncogene Proteins c-akt
FOXO3a; YWHAZ; hepatocellular carcinoma; miR-22; survival