Oncotarget

Research Papers:

MicroRNA-452 promotes stem-like cells of hepatocellular carcinoma by inhibiting Sox7 involving Wnt/β-catenin signaling pathway

Zhiyun Zheng, Jimin Liu, Zhe Yang, Limin Wu, Haiyang Xie, Chaozhe Jiang, Binyi Lin, Tianchi Chen, Chunyang Xing, Zhikun Liu, Penghong Song, Shengyong Yin, Shusen Zheng and Lin Zhou _

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Oncotarget. 2016; 7:28000-28012. https://doi.org/10.18632/oncotarget.8584

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Abstract

Zhiyun Zheng1, Jimin Liu1,2, Zhe Yang1, Limin Wu1, Haiyang Xie1, Chaozhe Jiang1, Binyi Lin1, Tianchi Chen1, Chunyang Xing1, Zhikun Liu1, Penghong Song1, Shengyong Yin1, Shusen Zheng1,3, Lin Zhou1

1Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

2Department of Pathology and Molecular Medicine, Faculty of Health Science, McMaster University, Hamilton, Ontario, Canada

3Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China

Correspondence to:

Shusen Zheng, email: [email protected]

Lin Zhou, email: [email protected]

Keywords: miRNAs, liver cancer, CSCs, β-catenin, ATRA

Received: November 13, 2015     Accepted: February 15, 2016     Published: April 05, 2016

ABSTRACT

The decrease of microRNA-452 (miR-452) in gliomas promoted stem-like features and tumorigenesis. However, the role of miR-452, especially in regulating cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) remains ambiguous. We enriched stem-like HCC cells by serial passages of hepatospheres with chemotherapeutic agents. Stem-like characteristics including the capabilities of chemo-resistance, stemness-related gene expression profiling, self-renewal, tumorigenicity and metastasis formation were detected. MiR-452 was markedly increased in the chemo-resistant hepatospheres and human HCC tissues. and the overexpression of miR-452 in HCC patients predicted poor overall survival. MiR-452 significantly promoted stem-like characteristics in vitro and in vivo. Further, Sox7 was identified as the direct target of miR-452, which could physically bind with β-catenin and TCF4 in the nucleus and then inhibit the activity of Wnt/β-catenin signaling pathway. Finally, the combined chemotherapy of doxorubicin and all-trans retinoic acid (ATRA) showed dramatically efficiency in suppressing HCC metastasis. These data suggested that miR-452 promoted stem-like traits of HCC, which might be a potential therapeutic target for HCC. The combination of doxorubicin and ATRA might be a promising therapy in HCC management.


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