Alcohol, TLR4-TGF-β antagonism, and liver cancer

Abstract

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.

Keywords: Cancer stem cells; NANOG; TGF-β; TLR4.

Figure 1

This schematic diagram depicts that alcohol and HCV interact to render synergistic effects on the evolution of alcoholic liver disease that is governed by gene-environment interactions (dotted arrows and solid black lines). TLR4 mediates promotion of liver inflammation and cancer as depicted by red arrows and alcohol and HCV facilitate these TLR4-dependent mechanisms as shown by blue arrows.

Figure 2

Reciprocal antagonism by TLR4 oncogenic and TGF-β tumor suppressor pathways. TLR4 is ectopically upregulated in hepatocytes by HCV NS5A and activated by endotoxemia caused by alcohol intake or obesity. Activated TLR4 induces the pluripotency factor NANOG to generate tumor-initiating stem cell-like cells (TICs) partly via compromised TGF-β pathway by IGF2BP3 and YAP1 induced by NANOG. Conversely, defective TGF-β pathway upregulates TLR4 and causes liver tumorigenesis.