title: Hepatitis B virus induces cell proliferation via HBx-induced microRNA-21 in hepatocellular carcinoma by targeting programmed cell death protein4 (PDCD4) and phosphatase and tensin homologue (PTEN).
abstract: Hepatitis B viral infection-induced hepatocellular carcinoma is one of the major problems in the developing countries. One of the HBV proteins, HBx, modulates the host cell machinery via several mechanisms. In this study we hypothesized that HBV enhances cell proliferation via HBx-induced microRNA-21 in hepatocellular carcinoma. HBx gene was over-expressed, and miRNA-21 expression and cell proliferation were measured in Huh 7 and Hep G2 cells. miRNA-21 was over-expressed in these cells, cell proliferation and the target proteins were analyzed. To confirm the role of miRNA-21 in HBx-induced proliferation, Hep G 2.2.1.5 cells (a cell line that expresses HBV stably) were used for miRNA-21 inhibition studies. HBx over-expression enhanced proliferation (3.7- and 4.5-fold increase; n = 3; p<0.01) and miRNA-21 expression (24- and 36-fold increase, normalized with 5S rRNA; p<0.001) in Huh 7 and Hep G2 cells respectively. HBx also resulted in the inhibition of miRNA-21 target proteins, PDCD4 and PTEN. miRNA-21 resulted in a significant increase in proliferation (2- and 2.3-fold increase over control cells; p<0.05 in Huh 7 and Hep G2 cells respectively) and decreased target proteins, PDCD4 and PTEN expression. Anti-miR-21 resulted in a significant decrease in proliferation (p<0.05) and increased miRNA-21 target protein expression. We conclude that HBV infection enhances cell proliferation, at least in part, via HBx-induced miRNA-21 expression during hepatocellular carcinoma progression.
authors.affiliation: Institute of Liver and Biliary Sciences, New Delhi, India.
authors.forename: Preeti
authors.initials: P
authors.lastname: Damania
authors.affiliation: Institute of Liver and Biliary Sciences, New Delhi, India.
authors.forename: Bijoya
authors.initials: B
authors.lastname: Sen
authors.affiliation: Institute of Liver and Biliary Sciences, New Delhi, India.
authors.forename: Sadaf Bashir
authors.initials: SB
authors.lastname: Dar
authors.affiliation: South Asian University, New Delhi, India.
authors.forename: Satendra
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Institute of Liver and Biliary Sciences, New Delhi, India.
authors.forename: Anupama
authors.initials: A
authors.lastname: Kumari
authors.affiliation: Institute of Liver and Biliary Sciences, New Delhi, India.
authors.forename: Ekta
authors.initials: E
authors.lastname: Gupta
authors.affiliation: Institute of Liver and Biliary Sciences, New Delhi, India.
authors.forename: Shiv Kumar
authors.initials: SK
authors.lastname: Sarin
authors.affiliation: South Asian University, New Delhi, India.
authors.forename: Senthil Kumar
authors.initials: SK
authors.lastname: Venugopal
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015870:Gene Expression; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D051059:PTEN Phosphohydrolase