PNAS：阐明酗酒及丙肝引发肝癌机制

科学家弄清了把酗酒和丙型肝炎感染与肝细胞癌风险增加联系起来的复杂分子事件。肝细胞癌是一种肝癌，它是全世界第五常见的癌症。此前的研究表明大量饮酒可以极大地增加感染丙型肝炎病毒（HCV）的患者出现肝细胞癌的几率。
美国南加州大学Keigo Machida及其同事分析了一种称为NS5A的病毒蛋白质，此前的实验表明它可以诱导一种细菌内毒素受体的更高水平的表达。酒精摄入增加了细菌感染的风险，这组科学家认为，如果患者也感染了HCV，它会导致内毒素受体信号传导的过度激活。如果人体的自然抗癌应答减弱，过多的抗菌应答然后会导致肿瘤生长风险的增加。这组科学家证实了实验小鼠体内有高浓度的NS5A，并检查了来自感染HCV的人类患者的肝脏活检样本。在那些也酗酒的患者子集中，这组科学家发现了抗菌应答增加的迹象。这组科学家提出，有可能用药物针对性地应对内毒素受体信号传导，从而抵消患肝细胞癌的风险。（生物谷Bioon.com）
生物谷推荐原始出处：
PNAS Published online before print January 26, 2009, doi: 10.1073/pnas.0807390106
Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog Keigo Machidaab1, Hidekazu Tsukamotoacd, Hasmik Mkrtchyana, Lewei Duanb, Alla Dynnyka, Helene Minyi Liub, Kinji Asahinaa, Sugantha Govindarajanac, Ratna Raye, Jing-hsiung James Ouab, Ekihiro Sekif, Raymond Deshaiesg, Kensuke Miyakeh and Michael M.-C. Laibi
aSouthern California Research Center for Alcoholic, Liver, and Pancreatic Diseases and Cirrhosis, and Departments of bMolecular Microbiology and Immunology and cPathology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90033; dVA Greater Los Angeles Healthcare System, Los Angeles, CA 90033; eDepartment of Pathology, Saint Louis University, St. Louis, MO 63103; fUniversity of California at San Diego, La Jolla, CA 92093; gHoward Hughes Medical Institute and Division of Biology, California Institute of Technology, Pasadena, CA 91125; hInstitute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; and iDepartment of Microbiology and Immunology, National Cheng Kung University, Tainan 701, Taiwan
Alcohol synergistically enhances the progression of liver disease and the risk for liver cancer caused by hepatitis C virus (HCV). However, the molecular mechanism of this synergy remains unclear. Here, we provide the first evidence that Toll-like receptor 4 (TLR4) is induced by hepatocyte-specific transgenic (Tg) expression of the HCV nonstructural protein NS5A, and this induction mediates synergistic liver damage and tumor formation by alcohol-induced endotoxemia. We also identify Nanog, the stem/progenitor cell marker, as a novel downstream gene up-regulated by TLR4 activation and the presence of CD133/Nanog-positive cells in liver tumors of alcohol-fed NS5A Tg mice. Transplantation of p53-deficient hepatic progenitor cells transduced with TLR4 results in liver tumor development in mice following repetitive LPS injection, but concomitant transduction of Nanog short-hairpin RNA abrogates this outcome. Taken together, our study demonstrates a TLR4-dependent mechanism of synergistic liver disease by HCV and alcohol and an obligatory role for Nanog, a TLR4 downstream gene, in HCV-induced liver oncogenesis enhanced by alcohol.