國家衛生研究院 NHRI:Item 3990099045/10154
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    題名: Hepatocarcinogenesis in transgenic mice carrying hepatitis B virus pre-S/S gene with the sW172* mutation
    作者: Lai, MW;Liang, KH;Lin, WR;Huang, YH;Huang, SF;Chen, TC;Yeh, CT
    貢獻者: Institute of Molecular and Genomic Medicine
    摘要: Hepatitis B virus (HBV) carrying the rtA181T/sW172* mutation conferred cross-resistance to adefovir and lamivudine. Cell-based and clinical studies indicated that HBV carrying this mutation had an increased oncogenic potential. Herein, we created transgenic mouse models to study the oncogenicity of the HBV pre-S/S gene containing this mutation. Transgenic mice were generated by transfer of the HBV pre-S/S gene together with its own promoter into C57B6 mice. Four lines of mice were created. Two of them carried wild-type gene and produced high and low levels of HBV surface antigen (HBsAg) (TgWT-H and L). The other two carried the sW172* mutation with high and low intrahepatic expression levels (TgSW172*-H and L). When sacrificed 18 months after birth, none of the TgWT mice developed hepatocellular carcinoma (HCC), whereas 6/26 (23.1%) TgSW172*-H and 2/24 (8.3%) TgSW172*-L mice developed HCC (TgWT vs TgSW172*; P=0.0021). Molecular analysis of liver tissues revealed significantly increased expression of glucose-regulated protein 78 and phosphorylated extracellular signal-regulated kinases 1 in TgSW172* mice, and decreased expression of B-cell lymphoma-extra large in TgSW172*-H mice. Higher proportion of apoptotic cells was found in TgSW172*-H mice, accompanied by increased cyclin E levels, suggesting increased hepatocyte turnover. Combined analysis of complimentary DNA microarray and microRNA array identified microRNA-873-mediated reduced expression of the CUB and Sushi multiple domains 3 (CSMD3) protein, a putative tumor suppressor, in TgSW172* mice. Our transgenic mice experiments confirmed that HBV pre-S/S gene carrying the sW172* mutation had an increased oncogenic potential. Increased endoplasmic reticulum stress response, more rapid hepatocyte turnover and decreased CSMD3 expression contributed to the hepatocarcinogenesis.
    日期: 2016-12-05
    關聯: Oncogenesis. 2016 Dec 05;5(12):Article number e273.
    Link to: http://dx.doi.org/10.1038/oncsis.2016.77
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2157-9024&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000391949000001
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85002263407
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