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 8

Expression of miR-148a and HPIP and their correlation in patients with liver cancer.

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Expression of miR-148a and HPIP and their correlation in patients with l...
(A) miR-148a expression in human cancerous liver tissues and adjacent normal liver tissues was plotted using real-time RT-PCR. The Mann-Whitney U test was used for comparison of cancer tissues with normal tissues (n = 52). (B) Comparison of expression levels of miR-148a in patients with HCC with and without HBV infection (independent t test). (C) Representative immunohistochemical staining of HPIP in cancerous (C) liver tissues and adjacent normal (N) liver tissues. The boxed areas in the left images are magnified in the middle and right images. Scale bar: 250 μm (left), 50 μm (middle and right). HPIP expression scores were plotted and compared (Mann-Whitney U test). (D) Comparison of HPIP scores in patients with HCC with and without HBV infection (independent t test). (E) The relationship between miR-148a and HPIP expression was detected by Spearman rank correlation analysis in liver samples. Symbols represent individual samples. (F) Proposed model for the HBx/miR-148a/HPIP/mTOR pathway that regulates cell growth, EMT, migration, invasion, and metastasis of HCC. In box-and-whisker plots, horizontal bars indicate the medians, boxes indicate 25th to 75th percentiles, and whiskers indicate 10th and 90th percentiles.