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Hepatitis B virus X protein downregulates expression of the miR-16 family in malignant hepatocytes in vitro.
Br J Cancer. 2011 Jun 28; 105(1):146-53.BJ

Abstract

BACKGROUND

Hepatitis B virus X protein (HBx) is involved in the initiation and progression of hepatocellular carcinoma (HCC) by regulating the host protein-coding genes. In this study, we showed that HBx altered the expression of microRNAs (miRNAs) to promote proliferation and transformation in malignant hepatocytes in vitro.

METHODS

miRNA microarray and quantitative reverse-transcription polymerase chain reactions (qRT-PCRs) were performed to identify miRNAs that were differentially regulated by HBx in HCC cells. Protein, mRNA, and miRNA expression analyses; cell cycle and apoptosis analyses; loss/gain-of-function analysis; and luciferase reporter assays were performed to delineate the consequences of miR-16 family repression in HepG2 cells.

RESULTS

Hepatitis B virus X protein induced widespread deregulation of miRNAs in HepG2 cells, and the downregulation of the miR-16 family was reproducible in HepG2, SK-HEP-1, and Huh7 cells. CCND1, a target of the miR-16 family, was derepressed by HBx in HepG2 cells. c-Myc mediated the HBx-induced repression of miR-15a/16 in HepG2 cells. Ectopically expressed miR-15a/16 suppressed the proliferation, clonogenicity, and anchorage-independent growth of HBx-expressing HepG2 cells by arresting them in the G1 phase and inducing apoptosis, whereas reduced expression of miR-16 accelerated the growth and cell-cycle progression of HepG2 cells.

CONCLUSIONS

Hepatitis B virus X protein altered the in vitro expression of miRNAs in host malignant hepatocytes, particularly downregulating the miR-16 family. Repression of miR-15a/16 is c-Myc mediated and is required for the HBx-induced transformation of HepG2 cells in vitro. Therefore, miR-16 family may serve as a therapeutic target for hepatitis B virus (HBV)-associated HCC.

Authors+Show Affiliations

Department of Hepatobiliary Surgery, Sun-Yat-Sen Memorial Hospital, Sun-Yat-Sen University, 107 Yanjiang West Road, Guangzhou 510120, People's Republic of China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21629246

Citation

Wu, G, et al. "Hepatitis B Virus X Protein Downregulates Expression of the miR-16 Family in Malignant Hepatocytes in Vitro." British Journal of Cancer, vol. 105, no. 1, 2011, pp. 146-53.
Wu G, Yu F, Xiao Z, et al. Hepatitis B virus X protein downregulates expression of the miR-16 family in malignant hepatocytes in vitro. Br J Cancer. 2011;105(1):146-53.
Wu, G., Yu, F., Xiao, Z., Xu, K., Xu, J., Tang, W., Wang, J., & Song, E. (2011). Hepatitis B virus X protein downregulates expression of the miR-16 family in malignant hepatocytes in vitro. British Journal of Cancer, 105(1), 146-53. https://doi.org/10.1038/bjc.2011.190
Wu G, et al. Hepatitis B Virus X Protein Downregulates Expression of the miR-16 Family in Malignant Hepatocytes in Vitro. Br J Cancer. 2011 Jun 28;105(1):146-53. PubMed PMID: 21629246.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatitis B virus X protein downregulates expression of the miR-16 family in malignant hepatocytes in vitro. AU - Wu,G, AU - Yu,F, AU - Xiao,Z, AU - Xu,K, AU - Xu,J, AU - Tang,W, AU - Wang,J, AU - Song,E, Y1 - 2011/05/31/ PY - 2011/6/2/entrez PY - 2011/6/2/pubmed PY - 2011/9/23/medline SP - 146 EP - 53 JF - British journal of cancer JO - Br. J. Cancer VL - 105 IS - 1 N2 - BACKGROUND: Hepatitis B virus X protein (HBx) is involved in the initiation and progression of hepatocellular carcinoma (HCC) by regulating the host protein-coding genes. In this study, we showed that HBx altered the expression of microRNAs (miRNAs) to promote proliferation and transformation in malignant hepatocytes in vitro. METHODS: miRNA microarray and quantitative reverse-transcription polymerase chain reactions (qRT-PCRs) were performed to identify miRNAs that were differentially regulated by HBx in HCC cells. Protein, mRNA, and miRNA expression analyses; cell cycle and apoptosis analyses; loss/gain-of-function analysis; and luciferase reporter assays were performed to delineate the consequences of miR-16 family repression in HepG2 cells. RESULTS: Hepatitis B virus X protein induced widespread deregulation of miRNAs in HepG2 cells, and the downregulation of the miR-16 family was reproducible in HepG2, SK-HEP-1, and Huh7 cells. CCND1, a target of the miR-16 family, was derepressed by HBx in HepG2 cells. c-Myc mediated the HBx-induced repression of miR-15a/16 in HepG2 cells. Ectopically expressed miR-15a/16 suppressed the proliferation, clonogenicity, and anchorage-independent growth of HBx-expressing HepG2 cells by arresting them in the G1 phase and inducing apoptosis, whereas reduced expression of miR-16 accelerated the growth and cell-cycle progression of HepG2 cells. CONCLUSIONS: Hepatitis B virus X protein altered the in vitro expression of miRNAs in host malignant hepatocytes, particularly downregulating the miR-16 family. Repression of miR-15a/16 is c-Myc mediated and is required for the HBx-induced transformation of HepG2 cells in vitro. Therefore, miR-16 family may serve as a therapeutic target for hepatitis B virus (HBV)-associated HCC. SN - 1532-1827 UR - https://www.unboundmedicine.com/medline/citation/21629246/Hepatitis_B_virus_X_protein_downregulates_expression_of_the_miR_16_family_in_malignant_hepatocytes_in_vitro_ L2 - http://dx.doi.org/10.1038/bjc.2011.190 DB - PRIME DP - Unbound Medicine ER -