期刊
FRONTIERS IN ONCOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2022.836517
关键词
hepatitis B virus; mutation; hepatocarcinogenesis; PAI1; CDC20; inflammation
类别
资金
- National Key Basic Research Program of China [2015CB554006]
- National Natural Science Foundation of China [91529305, 81520108021, 81673250, 81521091, 82003538, 81502882]
- Shanghai Yangfan Program [20YF1458800]
- program of Shanghai Municipal Health Commission (GC) [GWV-10.1XK17]
The study aimed to explore the mechanism by which hepatitis B virus X mutations increase the occurrence of hepatocellular carcinoma (HCC) and identify potential therapeutic targets. The results showed that M3-HBx and Ct-HBx mutants had a higher HCC incidence compared to wild-type HBx. M3-HBx had a stronger capacity to upregulate inflammatory cytokines and promote cell proliferation in HepG2 and HeLa cells. Plasminogen activator inhibitor-1 (PAI1) and cell division cycle 20 (CDC20) were identified as novel effectors, and their expression was significantly upregulated by M3-HBx and Ct-HBx in both cells and mouse livers. Silencing PAI1 attenuated the effects of M3-HBx and Ct-HBx on cell growth. PAI1 could be a promising prognostic biomarker and therapeutic target in HBV-related HCC.
We aimed to elucidate the mechanism by which hepatitis B virus X (HBx) mutations increase the occurrence of hepatocellular carcinoma (HCC) and identify novel putative therapeutic targets. Wild-type HBx (WT-HBx) and four HBx mutants (M1, A1762T/G1764A; M2, T1674G+T1753C+A1762T/G1764A; M3, C1653T+T1674G+A1762T/G1764A; and Ct-HBx, carboxylic acid-terminal truncated HBx) were delivered into Sleeping Beauty (SB) mouse models. The HCC incidence was higher in the M3-HBx- and Ct-HBx-injected SB mice. M3-HBx had a stronger capacity of upregulating inflammatory cytokines than other HBx variants. Ectopic expression of M3-HBx and Ct-HBx significantly increased proliferation and S phase proportion of HepG2 and HeLa cells, compared to WT-HBx. Plasminogen activator inhibitor-1 (PAI1) and cell division cycle 20 (CDC20) were identified as novel effectors by cDNA microarray analysis. M3-HBx and Ct-HBx significantly upregulated the expression of PAI1 and CDC20 in HepG2 and HeLa cells as well as the livers of SB mice. Silencing PAI1 attenuated the effects of M3-HBx and Ct-HBx on the growth of HepG2 and HeLa cells. PAI1, an important player bridging the HBx mutants and HCC, should be a promising candidate as a prognostic biomarker and therapeutic target in HBV-related HCC.
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