Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis
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
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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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 5

miR-148a suppresses cell proliferation, migration, and invasion through inhibition of HPIP expression.

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miR-148a suppresses cell proliferation, migration, and invasion through ...
(A and B) HepG2 cells expressing (A) miR-148a or miR-148a plus HPIP or (B) anti–miR-148a were cultured in regular medium. At specified times, cell numbers were determined by CCK-8 assay. The representative immunoblot (A, top panel) and real-time RT-PCR (B, top panel) show HPIP or miR-148a expression. (C) HepG2 cells expressing miR-148a or miR-148a plus HPIP were plated in soft agar and assayed for colony number after 3 weeks. Representative images show colonies in soft agar. Scale bar: 100 μM. (D and E) Cell invasion was evaluated in HepG2 cells expressing (D) miR-148a or miR-148a plus HPIP or (E) anti–miR-148a using a Matrigel invasion chamber. Invasive cells were fixed and stained with crystal violet (top panels). Scale bar: 100 mm. (F) MHCC97-H cells expressing miR-148a or miR-148a plus HPIP were analyzed as in A. (G) MHCC97-H cells expressing miR-148a or miR-148a plus HPIP were analyzed as in D. Scale bar: 100 mm. (H) Immunoblot analysis of MHCC97-H cells transfected with miR-148a or miR-148a plus HPIP. 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 < 0.05, **P < 0.01).