科學(xué)家弄清了把酗酒和丙型肝炎感染與肝細(xì)胞癌風(fēng)險(xiǎn)增加聯(lián)系起來(lái)的復(fù)雜分子事件,。肝細(xì)胞癌是一種肝癌，它是全世界第五常見(jiàn)的癌癥,。此前的研究表明大量飲酒可以極大地增加感染丙型肝炎病毒（HCV）的患者出現(xiàn)肝細(xì)胞癌的幾率,。
美國(guó)南加州大學(xué)Keigo Machida及其同事分析了一種稱為NS5A的病毒蛋白質(zhì)，此前的實(shí)驗(yàn)表明它可以誘導(dǎo)一種細(xì)菌內(nèi)毒素受體的更高水平的表達(dá),。酒精攝入增加了細(xì)菌感染的風(fēng)險(xiǎn),，這組科學(xué)家認(rèn)為，如果患者也感染了HCV,，它會(huì)導(dǎo)致內(nèi)毒素受體信號(hào)傳導(dǎo)的過(guò)度激活,。如果人體的自然抗癌應(yīng)答減弱，過(guò)多的抗菌應(yīng)答然后會(huì)導(dǎo)致腫瘤生長(zhǎng)風(fēng)險(xiǎn)的增加,。這組科學(xué)家證實(shí)了實(shí)驗(yàn)小鼠體內(nèi)有高濃度的NS5A,，并檢查了來(lái)自感染HCV的人類(lèi)患者的肝臟活檢樣本。在那些也酗酒的患者子集中,，這組科學(xué)家發(fā)現(xiàn)了抗菌應(yīng)答增加的跡象,。這組科學(xué)家提出，有可能用藥物針對(duì)性地應(yīng)對(duì)內(nèi)毒素受體信號(hào)傳導(dǎo),，從而抵消患肝細(xì)胞癌的風(fēng)險(xiǎn),。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
