Alcohol, TLR4-TGF-β antagonism, and liver cancer
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Alcohol abuse and obesity are two known risk factors for hepatocellular carcinoma (HCC) that also synergistically promote HBV/HCV-related carcinogenesis. TLR4, the receptor for endotoxin, participates in inflammatory processes such as M1 activation of hepatic macrophages in alcoholic liver disease. However, its role in liver carcinogenesis via ectopic expression and activation has only recently been revealed in alcohol/HCV-associated HCC models. Alcohol feeding to mice expressing the HCV Ns5a in a hepatocyte specific manner aggravates liver inflammation via activation of overexpressed TLR4 in the parenchymal cells. Long-term alcohol feeding produces liver tumors in these transgenic mice in a manner dependent on TLR4. From these mice, CD133+/CD49f+ tumor-initiating stem cell-like cells (TICs) have been isolated. These TICs exhibit self-renewal and tumorigenic activities driven by TLR4-dependent upregulation of the stem cell factor NANOG. A defective TGF-β tumor suppressor pathway is identified in the TICs and mediated by NANOG target genes Igf2bp3 and Yap1. This TGF-β pathway antagonism is responsible in part for the TICs’ tumorigenic activity and chemoresistance. Conversely, mice with an attenuated TGF-β pathway due to haploinsufficiency of β2-Spectrin, spontaneously develop liver tumors and alcohol feeding increases tumor incidence in a TLR4-dependent manner. This reciprocal antagonism between TLR4 and TGF-β pathways may serve as a novel therapeutic target for HCC.
KeywordsTLR4 Cancer stem cells NANOG TGF-β
The authors’ research described in this review was supported by NIH Grants 1R01AA018857, 5RC2AA019392, and P50AA011999, and Department of Veterans Affairs.
Compliance with ethical requirements and Conflict of interest
The studies were also conducted following full approval of IRB and IACUC protocols by respective institutions for appropriate involvement of human and animal subjects. Hidekazu Tsukamoto, Lopa Mishra, and Keigo Machida declare no conflict of interest.
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