Overexpression and activation of YAP-1 in HCC T cells can induce immunosuppression by promoting Treg differentiation via transcriptional enhancement of TGFBR2.
In contrast, epithelial deletion of Tgfbr2 promoted tumorigenesis and reduced survival of mice with concomitant hepatic deletion of Pten, accompanied by an increase in tumor number and a shift from hepatocellular carcinoma to cholangiocarcinoma.
In conclusion, reduced TGFBR2 expression was associated with aggressive features of HCC such as IM, and may represent an immunohistochemical biomarker to detect aggressive HCC.
Increased phosphorylated ERK1/2 expression was also present in the tumors from the TGFa;Tgfbr2(hepko) mice and correlated with downregulated Raf kinase inhibitor protein expression, which is a common molecular event in human HCC.
The differences in the expression level of TGFBR2 between LCC and non-LCC were consistent with the histopathologic classification of these tumors, suggesting that the defective TGFBR2 expression might contribute to the carcinogenesis and/or development of LCC.
Our data suggest that the down regulation of TGR2 in preneoplastic lesions and HCC tissues might contribute to resistance to the growth inhibitory effects of TGF-beta1, and to the roles of TGF-beta1 in the development and progression of preneoplastic lesions and HCC in a chemically induced rat hepatocarcinogensis model.
Interestingly, simultaneous down-regulation of c-met and TGF-beta-RII was observed in 23% of the hepatocellular carcinomas, 85% of which also showed nuclear p53 staining.