Distinct functions of transforming growth factor-β signaling in c-MYC driven hepatocellular carcinoma initiation and progression
Haichuan Wang, Pan Wang, Meng Xu, Xinhua Song, Hong Wu, Matthias Evert, Diego F. Calvisi, Yong Zeng, Xin Chen
Abstract
Dysregulation of transforming growth factor-beta (TGFβ) signaling has been implicated in liver carcinogenesis with both tumor promoting and inhibiting activities. Activation of the c-MYC protooncogene is another critical genetic event in hepatocellular carcinoma (HCC). However, the precise functional crosstalk between c-MYC and TGFβ signaling pathways remains unclear. In the present investigation, we investigated the expression of TGFβ signaling in c-MYC amplified human HCC samples as well as the mechanisms whereby TGFβ modulates c-Myc driven hepatocarcinogenesis during initiation and progression. We found that several TGFβ target genes are overexpressed in human HCCs with c-MYC amplification. In vivo, activation of TGFβ1 impaired c-Myc murine HCC initiation, whereas inhibition of TGFβ pathway accelerated this process. In contrast, overexpression of TGFβ1 enhanced c-Myc HCC progression by promoting tumor cell metastasis. Mechanistically, activation of TGFβ promoted tumor microenvironment reprogramming rather than inducing epithelial-to-mesenchymal transition during HCC progression. Moreover, we identified PMEPA1 as a potential TGFβ1 target. Altogether, our data underline the divergent roles of TGFβ signaling during c-MYC induced HCC initiation and progression.