title: 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: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, People’s Republic of China.
authors: Xiaojie
authors: X
authors: Xu
authors: Zhongyi
authors: Z
authors: Fan
authors: Lei
authors: L
authors: Kang
authors: Juqiang
authors: J
authors: Han
authors: Chengying
authors: C
authors: Jiang
authors: Xiaofei
authors: X
authors: Zheng
authors: Ziman
authors: Z
authors: Zhu
authors: Huabo
authors: H
authors: Jiao
authors: Jing
authors: J
authors: Lin
authors: Kai
authors: K
authors: Jiang
authors: Lihua
authors: L
authors: Ding
authors: Hao
authors: H
authors: Zhang
authors: Long
authors: L
authors: Cheng
authors: Hanjiang
authors: H
authors: Fu
authors: Yi
authors: Y
authors: Song
authors: Ying
authors: Y
authors: Jiang
authors: Jiahong
authors: J
authors: Liu
authors: Rongfu
authors: R
authors: Wang
authors: Nan
authors: N
authors: Du
authors: Qinong
authors: Q
authors: Ye
mesh_terms: D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D056970:Co-Repressor Proteins; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000472:pathogenicity; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics*; D009361:Neoplasm Invasiveness; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D056970:Co-Repressor Proteins; C550570:MIRN148 microRNA, human; D035683:MicroRNAs; C554644:Mirn148 microRNA, mouse; C413449:PBXIP1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D058570:TOR Serine-Threonine Kinases