Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog

作者：Machida Keigo^*; Tsukamoto Hidekazu; Mkrtchyan Hasmik; Duan Lewei; Dynnyk Alla; Liu Helene Minyi; Asahina Kinji; Govindarajan Sugantha; Raye Ratna; Ou Jing hsiung James; Seki Ekihiro; Deshaies Raymond; Miyake Kensuke; Lai Michael M C

来源：Proceedings of the National Academy of Sciences, 2009, 106(5): 1548-1553.

DOI：10.1073/pnas.0807390106

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.

• 出版日期2009-2-3
• 单位河北医科大学