15 It was originally proposed that liver stem cells, or oval cells, have the capacity to regenerate the liver during these times of chronic liver injury.37, 38 Recently, Amin and Mishra20 proposed a refinement of this oval cell model, where activated liver stem cells acquire resistance to TGFβ-induced cell growth inhibition and differentiation, and thus are able to escape the normal cell cycle control and undergo malignant transformation. During chronic liver diseases, TGFβ is secreted by nonparenchymal cells such as hepatic stellate cells and acts as a stimulator of extracellular matrix production, resulting in fibrosis and
cirrhosis.17 Nearly 95% of HCC is developed in a cirrhotic liver in chronic hepatitis C infection and almost 60% during chronic hepatitis B.17 As a profibrotic growth
factor in liver, TGFβ acts as an inhibitor of hepatocyte proliferation; however, the exact role of TGFβ in HCC selleck antibody inhibitor initiation and progression remains controversial. It is believed that TGFβ inhibits carcinogenesis at the early stage and acts as a promoter of cancer progression at the later stage disease.39 Increased hepatocarcinogenesis from stem cells through disruption of TGFβ and IL-6 signaling provided additional evidence of the association between TGFβ and HCC.32 Some studies revealed that cellular stress, hypoxia, for example, and the mTOR signal pathway, are able to induce CD133 expression in cancer cells.27, 40 This finding indicated that CD133 expression in liver cells Chlormezanone may be in response to microenvironmental alterations. For example, in a cirrhotic liver the cells are exposed to a microenvironment abundant in TGFβ. Therefore, we postulated BMS-777607 datasheet that elevated TGFβ might be able to trigger CD133 transcription. In our current findings we demonstrated that TGFβ1 was capable of inducing CD133 expression in CD133− Huh7 cells. Although TGFβ1-induced CD133+ Huh7 cells were less tumorigenic than that of native CD133+ Huh7 cells, the induced CD133+ cells were characterized as significantly more
tumorigenic than native CD133− cells in vivo. These findings might serve as an additional link between TGFβ and malignant transformation in chronic liver injury. A previous publication demonstrated that CD133 expression is controlled by five alternative promoters, with promoter-1 and -2 active in liver tissue.26 CD133 promoter-1 and -2 are located in a CpG island, indicating that CD133 transcription in the liver may be regulated by epigenetic modification through promoter methylation status. Promoter methylation is an important mechanism that leads to gene transcriptional silencing. CpG hypermethylation in promoter regions of tumor suppressors has been linked to tumorigenesis.21, 22 For example, Ras and downstream Ras effectors were activated due to epigenetic silencing of inhibitors of the Ras pathway in HCC.41 In terms of CD133, recent reports indicate that expression is inversely correlated with promoter methylation.
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