Cancer stem cells generated by alcohol, diabetes, and hepatitis C virus.
Cancer stem cells (tumor-initiating stem-like cells: TISCs) are resistant to chemotherapy and are associated with metastatic hepatocellular carcinoma (HCC), which is commonly observed in hepatitis C virus (HCV)-infected patients with obesity or alcohol abuse. However, it is unknown whether the TLR4-NANOG pathway serves as a universal oncogenic signaling in the genesis of TISCs and HCC. We aimed to determine whether Tlr4 is a putative proto-oncogene for TISCs in liver oncogenesis due to different etiologies and how Tlr4 is regulated at the transcriptional and epigenetic levels. CD133+/CD49f+ TISCs were isolated using FACS from HCC developed in HCV Core Tg mice fed alcohol, diethylnitrosamine-treated mice, and alcoholic patients with or without HCV infection. CD133+/CD49f+ cells isolated from the animal models and patients are tumorigenic both in vitro and in a xenograft model, and Tlr4 or Nanog silencing with shRNA attenuates their tumor initiating property. Functional oncogene screening of a cDNA library identified the organ size control pathway targets Yap1 and AKT activator Igf2bp3 as NANOG-dependent genes that inhibit transforming growth factor-β signaling in TISCs. Tlr4 expression is higher in TISCs compared with CD133-/CD49f+ cells. Taken together, Tlr4 may be a universal proto-oncogene responsible for the genesis of TLR4-NANOG dependent TISCs, and this pathway serves as a novel therapeutic target for HCC.
Southern California Research Center for ALPD and Cirrhosis, Los Angeles, California, USA. kmachida@usc.edu
Keigo
K
Machida
Chia-Lin
CL
Chen
Jian-Chang
JC
Liu
Claudine
C
Kashiwabara
Douglas
D
Feldman
Samuel W
SW
French
Linda
L
Sher
Jeong Joseph
JJ
Hyeongnam
Hidekazu
H
Tsukamoto
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D002472:Cell Transformation, Viral; D048909:Diabetes Complications / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006526:Hepatitis C / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D000090063:Proto-Oncogene Mas; D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D018398:Homeodomain Proteins; C000715470:MAS1 protein, human; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D000090063:Proto-Oncogene Mas; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4