Oncotarget

Research Papers:

MicroRNA-451: epithelial-mesenchymal transition inhibitor and prognostic biomarker of hepatocelluar carcinoma

Jia-Yuan Huang, Kai Zhang, Dong-Qin Chen, Jing Chen, Bing Feng, Haizhu Song, Yitian Chen, Ziman Zhu, Lei Lu, Wei De, Rui Wang and Long-Bang Chen _

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Oncotarget. 2015; 6:18613-18630. https://doi.org/10.18632/oncotarget.4317

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Abstract

Jia-Yuan Huang1,*, Kai Zhang1,*, Dong-Qin Chen1,*, Jing Chen1, Bing Feng1, Haizhu Song1, Yitian Chen1, Ziman Zhu2, Lei Lu3, Wei De4, Rui Wang1 and Long-Bang Chen1

1 Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China

2 Department of Hepatobiliary Surgery, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, China

3 Liver Disease Center of PLA, The 81th Hospital of PLA, Nanjing, Jiangsu, China

4 Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China

* These authors have contributed equally to this work

Correspondence to:

Rui Wang, email:

Long-Bang Chen, email:

Keywords: hepatocellular carcinoma, miR-451, c-Myc, epithelial-mesenchymal transition, invasion

Received: December 12, 2014 Accepted: May 12, 2015 Published: May 27, 2015

Abstract

Increasing evidence indicates that dysregulation of microRNAs (miRNAs) plays critical roles in malignant transformation and tumor progression. Previously, we have shown that microRNA-451 (miR-451) inhibits growth, increases chemo- or radiosensitivity and reverses epithelial to mesenchymal transition (EMT) in lung cancer. However, the roles of miR-451 in hepatocelluar carcinoma (HCC) progression and metastasis are still largely unknown. Reduced miR-451 in HCC tissues was observed to be significantly correlated with advanced clinical stage, metastasis and worse disease-free or overall survival. Through gain- and loss-of function experiments, we demonstrated that miR-451 inhibited cell growth, induced G0/G1 arrest and promoted apoptosis in HCC cells. Importantly, miR-451 could inhibit the migration and invasion in vitro, as well as in vivo metastasis of HCC cells through regulating EMT process. Moreover, the oncogene c-Myc was identified as a direct and functional target of miR-451 in HCC cells. Knockdown of c-Myc phenocopied the effects of miR-451 on EMT and metastasis of HCC cells, whereas overexpression of c-Myc partially attenuated the functions of miR-451 restoration. Furthermore, miR-451 downregulation-induced c-Myc overexpression leads to the activation of Erk1/2 signaling, which induces acquisition of EMT phenotype through regulation of GSK-3β/snail/E-cadherin and the increased expression of MMPs family members in HCC cells. Collectively, these data demonstrated that miR-451 is a novel prognostic biomarker for HCC patients and that function as a potential metastasis inhibitor in HCC cells through activation of the Erk1/2 signaling, at least partially by targeting c-Myc. Thus, targeting miR-451/c-Myc/Erk1/2 axis may be a potential strategy for the treatment of metastatic HCC.


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