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Cancer stem cells generated by alcohol, diabetes, and hepatitis C virus.

Journal of gastroenterology and hepatology | February 09, 2012 |

Machida, Keigo | Chen, Chia-Lin | Liu, Jian-Chang | Kashiwabara, Claudine | Feldman, Douglas | French, Samuel W | Sher, Linda | Hyeongnam, Jeong Joseph | Tsukamoto, Hidekazu
Machida, Chen, et al. "Cancer stem cells generated by alcohol, diabetes, and hepatitis C virus." Journal of gastroenterology and hepatology 27 Suppl 2. (2012): 19-22. Web.

Abstract

Cancer stem cells (tumor-initiating stem-like cells: TISCs) are resistant to chemotherapy and are associated with metastatic hepatocellular carcinoma ( ... e a universal proto-oncogene responsible for the genesis of TLR4-NANOG dependent TISCs, and this pathway serves as a novel therapeutic target for HCC.

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.

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Fig 1. Machida, Chen, et al. "Cancer stem cells generated by alcohol, diabetes, and hepatitis C virus." Journal of gastroenterology and hepatology 27 Suppl 2. (2012): 19-22. Web.
Nihms340266f1
Fig 1. Machida, Chen, et al. "Cancer stem cells generated by alcohol, diabetes, and hepatitis C virus." Journal of gastroenterology and hepatology 27 Suppl 2. (2012): 19-22. Web.

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