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

Keigo Machida | Zendy; Hidekazu Tsukamoto | Zendy; Hasmik Mkrtchyan | Zendy; Lewei Duan | Zendy; Alla Dynnyk | Zendy; Helene Minyi Liu | Zendy; Kinji Asahina | Zendy; Sugantha Govindarajan | Zendy; Ratna B. Ray | Zendy; Jinghsiung James Ou | Zendy; Ekihiro Seki | Zendy; Raymond J. Deshaies | Zendy; Kensuke Miyake | Zendy; Michael M. C. Lai | Zendy

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

Author(s) -

Keigo Machida,

Hidekazu Tsukamoto,

Hasmik Mkrtchyan,

Lewei Duan,

Alla Dynnyk,

Helene Minyi Liu,

Kinji Asahina,

Sugantha Govindarajan,

Ratna B. Ray,

Jinghsiung James Ou,

Ekihiro Seki,

Raymond J. Deshaies,

Kensuke Miyake,

Michael M. C. Lai

Publication year - 2009

Publication title -

proceedings of the national academy of sciences

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.011

H-Index - 771

eISSN - 1091-6490

pISSN - 0027-8424

DOI - 10.1073/pnas.0807390106

Subject(s) - homeobox protein nanog , cancer research , biology , stem cell , cancer stem cell , carcinogenesis , liver disease , transactivation , progenitor cell , nanog homeobox protein , microbiology and biotechnology , induced pluripotent stem cell , embryonic stem cell , cancer , gene expression , biochemistry , gene , genetics

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.

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