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Hepatocellular carcinoma (HCC) is a worldwide threat to public health, especially in China, where chronic hepatitis B virus (HBV) infection is found in 80–90% of all HCCs. The HBV-encoded X antigen (HBx) is a trans-regulatory protein involved in virus-induced hepatocarcinogenesis. Although the carboxyl-terminus-truncated HBx, rather than the full-length counterpart, is frequently overexpressed in human HCCs, its functional mechanisms are not fully defined. We investigated the molecular function of a naturally occurring HBx variant which has 35 amino acids deleted at the C-terminus (HBxΔ35). Genome-wide scanning analysis and PCR validation identified growth arrest-specific 2 (GAS2) as a direct target of HBxΔ35 at transcriptional level in human immortalized liver cells. HBxΔ35 was found to bind the promoter region of GAS2 and attenuate its expression to promote hepatocellular proliferation and tumourigenicity. Further functional assays demonstrated that GAS2 induces p53-dependent apoptosis and senescence to counteract HBxΔ35-mediated tumourigenesis. Notably, GAS2 expression was significantly down-regulated in HCCs compared with the corresponding normal tissues. In conclusion, our integrated study uncovered a novel viral mechanism in hepatocarcinogenesis, wherein HBxΔ35 deregulates cell growth via direct silencing of GAS2 and thereby provides a survival advantage for pre-neoplastic hepatocytes to facilitate cancer development. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Hepatocellular carcinoma (HCC) is a worldwide threat to public health, especially in China, where chronic hepatitis B virus (HBV) infection is found in 80-90% of all HCCs. The HBV-encoded X antigen (HBx) is a trans-regulatory protein involved in virus-induced hepatocarcinogenesis. Although the carboxyl-terminus-truncated HBx, rather than the full-length counterpart, is frequently overexpressed in human HCCs, its functional mechanisms are not fully defined. We investigated the molecular function of a naturally occurring HBx variant which has 35 amino acids deleted at the C-terminus (HBxΔ35). Genome-wide scanning analysis and PCR validation identified growth arrest-specific 2 (GAS2) as a direct target of HBxΔ35 at transcriptional level in human immortalized liver cells. HBxΔ35 was found to bind the promoter region of GAS2 and attenuate its expression to promote hepatocellular proliferation and tumourigenicity. Further functional assays demonstrated that GAS2 induces p53-dependent apoptosis and senescence to counteract HBxΔ35-mediated tumourigenesis. Notably, GAS2 expression was significantly down-regulated in HCCs compared with the corresponding normal tissues. In conclusion, our integrated study uncovered a novel viral mechanism in hepatocarcinogenesis, wherein HBxΔ35 deregulates cell growth via direct silencing of GAS2 and thereby provides a survival advantage for pre-neoplastic hepatocytes to facilitate cancer development.

Hepatocellular carcinoma (HCC) is a worldwide threat to public health, especially in China where chronic hepatitis B virus (HBV) infection is found in 80-90% of all HCCs. The HBV encoded X antigen (HBx) is a trans-regulatory protein involved in the virus-induced hepatocarcinogenesis. Although the carboxyl-terminus truncated HBx, rather than the full-length counterpart, is frequently overexpressed in human HCCs, its functional mechanisms have yet been fully defined. In this study, we investigated the molecular pathogenesis of a naturally-occurring HBx variant which has 35 amino acids deleted at C-terminus (HBxΔ35). By performing genome-wide scanning analysis and PCR validation, we identified growth arrest-specific 2 (GAS2) as a direct target of HBxΔ35 at transcriptional level in human immortalized liver cells. HBxΔ35 was found to bind the promoter region of GAS2 and suppress its expression to promote hepatocellular proliferation and tumorigenicity. Further functional assays showed that overexpression of GAS2 inhibited tumor growth both in vitro and in vivo by inducing p53-dependent apoptosis. Conversely, siRNA-mediated knockdown of GAS2 in hepatocytes attenuated apoptotic response and reduced cell susceptibility to etoposide-induced apoptosis. Notably, GAS2 expression was significantly down-regulated in truncated HBx-expressing HCCs compared with the corresponding normal tissues. In conclusion, our integrated study uncovered a novel viral mechanism in hepatocarcinogenesis, wherein HBxΔ35 ablates p53-driven apoptosis via direct silencing of GAS2, and thereby provides survival advantage for pre-neoplastic hepatocytes to facilitate cancer development. Citation Format: Alfred S. L. Cheng, Ranxu Zhu, Myth T.S. Mok, Wai Kang, Ka-Fai To, Joseph J.Y. Sung, Henry L.Y. Chan. Truncated HBx-dependent silencing of growth arrest-specific 2 promotes hepatocarcinogenesis through inhibition of p53-mediated apoptosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 814. doi:10.1158/1538-7445.AM2015-814

G A A b st ra ct s disease. TLR2-/-MyD88+/+MDR1A-/macrophages hyperresponded to LPS stimulation with increased production of IL-1β proteinwhich was not evident in TLR2+/+MyD88+/+MDR1A-/macrophages. Conclusions: Exacerbation of UC-like pancolitis in TLR2/MDR1A double deficiency requires IL-1R/MyD88 signalling. Aberrant LPS-induced IL-1β signalling via IL1R/MyD88 may represent a critical inducer of severe pathology and a novel therapeutic target in a subgroup of UC patients.

3, 7 (9.2%): Ki67 negative, 33 (43.4%); positive, 43 (56.6%). The staining intensity of Skp2 and Cks1 showed significant linear correlation (Pearson's R 0.427, p < 0.01). Each staining intensity of Skp2 and Cks1 also showed significant linear correlations with the staining intensity of p27kip1, respectively (Pearson's R 0.314, p < 0.01 for Skp2 and p27kip1, Pearson's R 0.403, p < 0.01 for Cks1 and p27kip1). The positive immunostaining group for Ki67 showed significantly stronger immunostaining intensity for Skp2 (p < 0.01), Cks1 (p < 0.01) and cytoplasmic p27kip1 (p = 0.033). By Kaplan-Meier analyses, the higher IS (p = 0.018) and stronger immunostaining intensity (p < 0.01) of Skp2 and Cks1 were significantly associated with shorter survival for patients with extrahepatic cholangiocarcinoma. Conclusions: Overexpression of Skp2/Cks1 and aberrant localization of p27kip1 into cytoplasm might be useful predictors of prognosis in patients with extrahepatic bile duct cancer.