期刊
JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
卷 27, 期 -, 页码 19-22出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1440-1746.2011.07010.x
关键词
alcohol; hepatocellular carcinoma; hepatitis C virus; obesity; tumor-initiating stem-like cells
资金
- NCATS NIH HHS [UL1 TR000124] Funding Source: Medline
- NCI NIH HHS [P01 CA123328-05, R01 CA108302, CA108302, CA123328, P30 CA014089, P01 CA123328] Funding Source: Medline
- NIAAA NIH HHS [R01 AA018857-04, RC2 AA019392, R01 AA018857, R24AA012885, 1R01AA018857-01, R24 AA012885, RC2AA019392-01, P50 AA011999, P50AA11999] Funding Source: Medline
- NIAID NIH HHS [AI83025U19, U19 AI083025-04, U19 AI083025] Funding Source: Medline
- NIDDK NIH HHS [P30 DK048522] Funding Source: Medline
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-beta 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.
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