MicroRNA-135a contributes to the development of portal vein tumor thrombus by promoting metastasis in hepatocellular carcinoma

Liu, Shupeng; Guo, Weixing; Shi, Jie; Li, Nan; Yu, Xiya; Xue, Jie; Fu, Xiaohui; Chu, Kaijian; Lu, Chongde; Zhao, Jiangsha; Xie, Dong; Wu, Mengchao; Cheng, Shuqun; Liu, Shanrong

doi:10.1016/j.jhep.2011.08.008

« Previous Next »Journal of Hepatology
Volume 56, Issue 2 , Pages 389-396, February 2012

MicroRNA-135a contributes to the development of portal vein tumor thrombus by promoting metastasis in hepatocellular carcinoma

Shupeng Liu
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
- Changhai Hospital, Second Military Medical University, Shanghai, China
- These authors contributed equally to this work.
Weixing Guo
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
- These authors contributed equally to this work.
Jie Shi
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
Nan Li
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
Xiya Yu
- Changhai Hospital, Second Military Medical University, Shanghai, China
Jie Xue
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
Xiaohui Fu
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
Kaijian Chu
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
Chongde Lu
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
Jiangsha Zhao
- Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China
Dong Xie
- Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China
Mengchao Wu
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
Shuqun Cheng
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
- Corresponding authors. Addresses: Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China. Tel.: +86 21 55221092; fax: +86 21 65562400 (S. Liu), Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, China. Tel.: +86 21 81875251; fax: +86 21 65562400 (S. Cheng).
Shanrong Liu
- Changhai Hospital, Second Military Medical University, Shanghai, China
- Corresponding authors. Addresses: Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China. Tel.: +86 21 55221092; fax: +86 21 65562400 (S. Liu), Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, China. Tel.: +86 21 81875251; fax: +86 21 65562400 (S. Cheng).

Received 10 January 2011; received in revised form 1 August 2011; accepted 14 August 2011. published online 02 September 2011.

Background & Aims

Portal vein tumor thrombus (PVTT) has previously been demonstrated to correlate with poor prognosis of hepatocellular carcinoma. Approximately 50–80% of HCC is accompanied by portal or hepatic vein invasion. The underlying mechanisms of PVTT development remain unclear. This study aimed to elucidate the role of miR-135a in PVTT tumorigenesis.

Methods

In the present study, we investigated the expression of microRNAs and mRNAs in PVTT tissues using advanced microRNA and cDNA microarray techniques. MicroRNA (miR)-135a was noted to be highly over-expressed in PVTT and the cell line CSQT-2 and was selected for further study. We characterized the function of miR-135a in vitro and in vivo. We also analyzed the clinical relevance of miR-135a in relation to the prognosis and survival of HCC patients with PVTT.

Results

Our analyses found that the miRNA and mRNA expression profiles of PVTT were distinct from the parenchyma tumor. Overexpression of miR-135a favors invasive and metastatic behavior in vitro. Furthermore, in a CSQT-2 orthotopic transplantation nude mouse model, blockade of miR-135a significantly reduced PVTT incidence. We also found that miR-135a was transcribed by forkhead box M1 (FOXM1), and metastasis suppressor 1 (MTSS1) was identified as the direct and functional target of miR-135a. Additionally, the cohort analysis revealed the relevance of miR-135a with respect to the prognosis and survival of HCC patients with PVTT.