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C-terminal-truncated hepatitis B virus (HBV) X (HBx) (ctHBX) is frequently detected in hepatocellular carcinoma (HCC) through HBV integration into the host genome. However, the molecular mechanisms underlying ctHBx-associated oncogenic signaling have not yet been clarified. To elucidate the biological role of ctHBx in hepato-oncogenesis, we functionally analyzed ctHBx-mediated regulation of the activin membrane-bound inhibitor bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) through transforming growth factor-β (TGF-β) or β-catenin (CTNNB1) in HCC cells and in an animal model, and we compared its role to that of the full-length HBx protein. Ectopic ctHBx expression generated more colonies in anchorage-dependent and -independent growth assays than did HBx expression alone. ctHBx downregulated BAMBI to a greater degree than did HBx in HCC cells. HBx activated the Wnt/β-catenin pathway, which positively regulated the BAMBI expression through T-cell factor 1 signaling, whereas ctHBx negatively regulated the Wnt/β-catenin pathway. BAMBI downregulated the β-catenin and TGF-β1 signaling pathways. TGF-β1 positively regulated BAMBI expression thorough Smad3 signaling.
Furthermore, knockdown of BAMBI was more tumorigenic in HCC cells. Therefore, downregulation of both β-catenin and TGF-β1 signaling by BAMBI might contribute to tumor suppression in mice xenotransplanted with HepG2 or SH-J1 cells. Taken together, ctHBx may have a more oncogenic role than HBx through its inhibition of tumor-suppressive β-catenin/BAMBI signaling.
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참고문헌 (24)
참고문헌 신청
[학
Bo-Ra Yun / 2010 / Enhancement of parthenolide-induced apoptosis by a PKC-alpha inhibition through heme oxygenase-1 blockage in cholangiocarcinoma cells / Experimental and M
Brechot C / 1980 / Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma / Nature 286 (5772) : 533 ~ 535
Diatchenko L / 1996 / Suppression subtractive hybridization : a method for generating differentially regulated or tissue-specific cDNA probes and libraries / Proc Natl Acad
El-Serag HB / 2004 / Hepatocellular carcinoma: recent trends in the United States / Gastroenterology 127 : 27 ~ 34
Bo-Ra Yun / 2010 / Enhancement of parthenolide-induced apoptosis by a PKC-alpha inhibition through heme oxygenase-1 blockage in cholangiocarcinoma cells / Experimental and M
Brechot C / 1980 / Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma / Nature 286 (5772) : 533 ~ 535
Diatchenko L / 1996 / Suppression subtractive hybridization : a method for generating differentially regulated or tissue-specific cDNA probes and libraries / Proc Natl Acad
El-Serag HB / 2004 / Hepatocellular carcinoma: recent trends in the United States / Gastroenterology 127 : 27 ~ 34
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