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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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 7

HPIP increases hepatoma cell proliferation, migration, and invasion through regulation of mTOR signaling.

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HPIP increases hepatoma cell proliferation, migration, and invasion thro...
(A) Cell proliferation assay for HepG2 cells transfected with HPIP or empty vector. Cells were treated with 20 nM or 200 nM rapamycin (Rap low or Rap high, respectively) for 24 hours. After 24 hours, the culture medium was changed to fresh drug-free medium, and cells were grown for the indicated times. (B) Western blot analysis of HepG2 cells from A. (C) Wound healing and (D) invasion assays for HepG2 cells transfected with HPIP or empty vector and treated with rapamycin for 24 hours or the indicated times. Scale bar: 100 μm. (E) Immunoblot analysis of HepG2 cells transfected with HPIP or empty vector and treated with rapamycin for 24 hours. Morphologic changes are shown in the photographs. Scale bar: 100 μm. All values shown are mean ± SD of triplicate measurements and have been repeated 3 times with similar results (*P < 0.01).