Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis
Xiaojie Xu, … , Nan Du, Qinong Ye
Xiaojie Xu, … , Nan Du, Qinong Ye
Published January 16, 2013
Citation Information: J Clin Invest. 2013;123(2):630-645. https://doi.org/10.1172/JCI64265.
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Research Article Oncology

Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis

Abstract

MicroRNAs (miRNAs) have been shown to be dysregulated in virus-related cancers; however, miRNA regulation of virus-related cancer development and progression remains poorly understood. Here, we report that miR-148a is repressed by hepatitis B virus (HBV) X protein (HBx) to promote cancer growth and metastasis in a mouse model of hepatocellular carcinoma (HCC). Hematopoietic pre–B cell leukemia transcription factor–interacting protein (HPIP) is an important regulator of cancer cell growth. We used miRNA target prediction programs to identify miR-148a as a regulator of HPIP. Expression of miR-148a in hepatoma cells reduced HPIP expression, leading to repression of AKT and ERK and subsequent inhibition of mTOR through the AKT/ERK/FOXO4/ATF5 pathway. HBx has been shown to play a critical role in the molecular pathogenesis of HBV-related HCC. We found that HBx suppressed p53-mediated activation of miR-148a. Moreover, expression of miR-148a was downregulated in patients with HBV-related liver cancer and negatively correlated with HPIP, which was upregulated in patients with liver cancer. In cultured cells and a mouse xenograft model, miR-148a reduced the growth, epithelial-to-mesenchymal transition, invasion, and metastasis of HBx-expressing hepatocarcinoma cells through inhibition of HPIP-mediated mTOR signaling. Thus, miR-148a activation or HPIP inhibition may be a useful strategy for cancer treatment.

Authors

Xiaojie Xu, Zhongyi Fan, Lei Kang, Juqiang Han, Chengying Jiang, Xiaofei Zheng, Ziman Zhu, Huabo Jiao, Jing Lin, Kai Jiang, Lihua Ding, Hao Zhang, Long Cheng, Hanjiang Fu, Yi Song, Ying Jiang, Jiahong Liu, Rongfu Wang, Nan Du, Qinong Ye

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Figure 4

HBx inhibits p53-mediated activation of miR-148a and activates HPIP through repression of miR-148a.

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HBx inhibits p53-mediated activation of miR-148a and activates HPIP thro...
(A) HBx suppresses miR-148a expression and increases HPIP expression. LO2 cells were transfected with increasing doses of Myc-tagged HBx or Myc-tagged HBx(1–110) or L-HDAg and analyzed for miR-148a expression by real-time RT-PCR and for HPIP expression by immunoblot. (B) LO2 cells were transfected with FLAG-tagged p53, p53(R249S), or p53 (R273H) and analyzed as in A. (C) LO2 cells were transfected with Myc-tagged HBx and p53 siRNAs or control siRNA and analyzed as in A. (D) Luciferase activity of different promoter constructs in LO2 cells transfected with p53 or empty vector. The arrow indicates the position of the transcriptional start site. Filled circles show the position of the p53-binding site, and the “X” shows the mutated p53-binding site. (E) ChIP analysis of p53 occupancy on the miR-148a promoter in LO2 cells transfected with Myc-tagged HBx or HBx(1–110). (F) LO2 cells were transfected with HBx or HBx plus miR-148a and analyzed as in A. All values shown are mean ± SD of triplicate measurements and have been repeated 3 times with similar results (*P < 0.05, **P < 0.01).