Hepatitis B virus X protein upregulates Lin28A/Lin28B through Sp-1/c-Myc to enhance the proliferation of hepatoma cells.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE

Publication: <2002->: Basingstoke : Nature Publishing Group
Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-

Carcinoma, Hepatocellular/*genetics ; DNA-Binding Proteins/*genetics ; Hepatitis B/*complications ; Liver Neoplasms/*genetics; Animals ; Blotting, Western ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/virology ; Cell Proliferation ; Chromatin Immunoprecipitation ; DNA-Binding Proteins/metabolism ; Electrophoretic Mobility Shift Assay ; Female ; Hep G2 Cells ; Hepatitis B/genetics ; Hepatitis B/metabolism ; Heterografts ; Humans ; Immunohistochemistry ; Immunoprecipitation ; Liver Neoplasms/pathology ; Liver Neoplasms/virology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mice, Transgenic ; Middle Aged ; Promoter Regions, Genetic ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; RNA-Binding Proteins ; Reverse Transcriptase Polymerase Chain Reaction ; Sp1 Transcription Factor/genetics ; Sp1 Transcription Factor/metabolism ; Tissue Array Analysis ; Trans-Activators ; Up-Regulation ; Viral Regulatory and Accessory Proteins

Hepatitis B virus X protein (HBx) plays critical roles in the pathogenesis of hepatocellular carcinoma (HCC). Here, we were interested in knowing whether the oncogene Lin28A and its homolog Lin28B are involved in the hepatocarcinogenesis mediated by HBx. We showed that the expression levels of Lin28A and Lin28B were increased in clinical HCC tissues, HepG2.2.15 cell line and liver tissues of p21-HBx transgenic mice. Interestingly, the expression levels of HBx were positively associated with those of Lin28A/Lin28B in clinical HCC tissues. Moreover, the overexpression of HBx resulted in the upregulation of Lin28A/Lin28B in hepatoma HepG2/H7402 cell lines by transient transfection, suggesting that HBx was able to upregulate Lin28A and Lin28B. Then, we examined the mechanism by which HBx upregulated Lin28A and Lin28B. We identified that the promoter region of Lin28A regulated by HBx was located at nt -235/-66 that contained Sp-1 binding element. Co-immunoprecipitation showed that HBx was able to interact with Sp-1 in HepG2-X cells. Moreover, chromatin immunoprecipitation (ChIP) demonstrated that HBx could bind to the promoter of Lin28A, which failed to work when Sp-1 was silenced. Electrophoretic mobility shift assay (EMSA) further identified that HBx was able to interact with Sp-1 element in Lin28A promoter via transcription factor Sp-1. In addition, we found that c-Myc was involved in the activation of Lin28B mediated by HBx. In function, Lin28A/Lin28B played important roles in HBx-enhanced proliferation of hepatoma cells in vitro and in vivo. In conclusion, HBx activates Lin28A/Lin28B through Sp-1/c-Myc in hepatoma cells. Lin28A/Lin28B serves as key driver genes in HBx-induced hepatocarcinogenesis.

0 (DNA-Binding Proteins)
0 (LIN28B protein, human)
0 (MYC protein, human)
0 (Proto-Oncogene Proteins c-myc)
0 (RNA-Binding Proteins)
0 (Sp1 Transcription Factor)
0 (Trans-Activators)
0 (Viral Regulatory and Accessory Proteins)
0 (hepatitis B virus X protein)

Date Created: 20130116 Date Completed: 20140311 Latest Revision: 20201209

20231215

10.1038/onc.2012.618

23318446