MiR-429 increases the metastatic capability of HCC via regulating classic Wnt pathway rather than epithelial-mesenchymal transition.
Epigenetic modification of miR-429 can manipulate liver T-ICs via targeting the RBBP4/E2F1/Oct4 axis, which might be crucial for hepatocarcinogenesis. However, whether miR-429 plays a role in regulating metastasis of hepatocellular carcinoma is still unclear. Using quantitative methylation analysis and real-time PCR, we have identified the hypomethylated status and upregulation of miR-429 in portal vein metastasis samples in comparison with their matched primary tumor. The ectopic expression of miR-429 dramatically induced the expression of MMP2/7/9 and enhanced HCC migration and invasion in vitro and in vivo in an EMT-independent manner. Both bioinformatics and functional studies elucidated the direct regulation of miR-429 on the 3'UTR of the PTEN gene, which leads to the activation of PI3K/AKT signaling and the nuclear translocation of β-catenin, eventually. Conversely, the knockdown of miR-429 efficiently recovered the expression of PTEN and attenuated PI3K/AKT/β-catenin-mediated cell metastasis. Clinically, the higher expression of miR-429 and nucleus relocation of β-catenin were identified as the adverse prognosis factors for recurrence-free survival (RFS) and overall survival (OS). In summary, our results here defined miR-429 as a key inducer for HCC pathogenesis and metastasis with potential utility for tumor intervention.
National Center for Liver Cancer, Shanghai, China; Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
Jing
J
Tang
National Center for Liver Cancer, Shanghai, China; Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
Liang
L
Li
National Center for Liver Cancer, Shanghai, China; Graduate School of Fujian Medical University, Fuzhou, Fujian Province 350108, China.
Wentao
W
Huang
Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
Chengjun
C
Sui
National Center for Liver Cancer, Shanghai, China.
Yingcheng
Y
Yang
National Center for Liver Cancer, Shanghai, China.
Ximeng
X
Lin
National Center for Liver Cancer, Shanghai, China.
Guojun
G
Hou
National Center for Liver Cancer, Shanghai, China.
Xin
X
Chen
National Center for Liver Cancer, Shanghai, China.
Jing
J
Fu
Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
Shengxian
S
Yuan
Bioinformatics Division, TNLIST/Department of Automation, Tsinghua University, Beijing 100084, China.
Shao
S
Li
National Center for Liver Cancer, Shanghai, China.
Wen
W
Wen
National Center for Liver Cancer, Shanghai, China.
Shanhua
S
Tang
National Center for Liver Cancer, Shanghai, China.
Dan
D
Cao
National Center for Liver Cancer, Shanghai, China; Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
Mengchao
M
Wu
National Center for Liver Cancer, Shanghai, China; Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China. Electronic address: hywangk@vip.sina.com.
Lei
L
Chen
National Center for Liver Cancer, Shanghai, China; Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China; National Laboratory for Oncogenes and Related Genes, Cancer Institute, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200441, China. Electronic address: chenlei@smmu.edu.cn.
Hongyang
H
Wang
D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D035683:MicroRNAs / Q000502:physiology*; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*
C546363:MIRN429 microRNA, human; D035683:MicroRNAs; D051153:Wnt Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
Hepatocellular carcinoma; Metastasis; PTEN; micoRNA-429