title: Hepatitis B virus mRNA-mediated miR-122 inhibition upregulates PTTG1-binding protein, which promotes hepatocellular carcinoma tumor growth and cell invasion.
abstract: As the most abundant liver-specific microRNA, miR-122 is involved in diverse aspects of hepatic function and neoplastic transformation. Our previous study showed that miR-122 levels are significantly decreased in hepatitis B virus (HBV)-infected patients, which may facilitate viral replication and persistence (S. Wang, L. Qiu, X. Yan, W. Jin, Y. Wang, L. Chen, E. Wu, X. Ye, G. F. Gao, F. Wang, Y. Chen, Z. Duan, and S. Meng, Hepatology 55:730-741, 2012). Loss of miR-122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G1-modulated P53 activity.). In this study, we provide evidence that all HBV mRNAs harboring an miR-122 complementary site act as sponges to bind and sequester endogenous miR-122, indicating that the highly redundant HBV transcripts are involved in HBV-mediated miR-122 suppression. We next identified pituitary tumor-transforming gene 1 (PTTG1) binding factor (PBF) as a target of miR-122 and demonstrated that HBV replication causes an obvious increase in PBF levels. Furthermore, we observed that the miR-122 levels were decreased and PBF was upregulated in chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC). Overexpression and knockdown studies both revealed that PBF enhances proliferation and invasion of HCC cells, and silencing PBF resulted in a dramatic reduction of HCC tumor growth in vivo. Mechanistic analysis demonstrated that PBF interacts with PTTG1 and facilitates PTTG1 nuclear translocation, subsequently increasing its transcriptional activities. Therefore, we identified a novel HBV mRNA-miR-122-PBF regulatory pathway that facilitates malignant hepatocyte growth and invasion in CHB which may contribute to CHB-induced HCC development and progression. Our work underscores the reciprocal interplay of host miRNA sequestration and depletion by viral mRNAs, which may contribute to chronic-infection-related cancer.
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
authors.forename: Changfei
authors.initials: C
authors.lastname: Li
authors.forename: Yanzhong
authors.initials: Y
authors.lastname: Wang
authors.forename: Saifeng
authors.initials: S
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Wu
authors.forename: Junli
authors.initials: J
authors.lastname: Hao
authors.forename: Hongxia
authors.initials: H
authors.lastname: Fan
authors.forename: Ying
authors.initials: Y
authors.lastname: Ju
authors.forename: Yuping
authors.initials: Y
authors.lastname: Ding
authors.forename: Lizhao
authors.initials: L
authors.lastname: Chen
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Chu
authors.forename: Wenjun
authors.initials: W
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Ye
authors.forename: Songdong
authors.initials: S
authors.lastname: Meng
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000821:virology*; D005260:Female; D006515:Hepatitis B virus / Q000472:pathogenicity*; D019694:Hepatitis B, Chronic / Q000821:virology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000821:virology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism*; D012367:RNA, Viral / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C531907:MIRN122 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C112633:PTTG1IP protein, human; D012333:RNA, Messenger; D012367:RNA, Viral