Distinct functions of transforming growth factor-β signaling in c-MYC driven hepatocellular carcinoma initiation and progression

Dysregulation of transforming growth factor-beta (TGF beta) 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 TGF beta signaling pathways remains unclear. In the present investigation, we investigated the expression of TGF beta signaling in c-MYC amplified human HCC samples as well as the mechanisms whereby TGF beta modulates c-Myc driven hepatocarcinogenesis during initiation and progression. We found that several TGF beta target genes are overexpressed in human HCCs with c-MYC amplification. In vivo, activation of TGF beta 1 impaired c-Myc murine HCC initiation, whereas inhibition of TGF beta pathway accelerated this process. In contrast, overexpression of TGF beta 1 enhanced c-Myc HCC progression by promoting tumor cell metastasis. Mechanistically, activation of TGF beta promoted tumor microenvironment reprogramming rather than inducing epithelial-to-mesenchymal transition during HCC progression. Moreover, we identified PMEPA1 as a potential TGF beta 1 target. Altogether, our data underline the divergent roles of TGF beta signaling during c-MYC induced HCC initiation and progression.

Automated summary

The dysregulation of TGF beta signaling has been implicated in both tumor promoting and inhibiting activities in liver carcinogenesis. Activation of c-MYC is critical in hepatocellular carcinoma (HCC). The interactions between c-MYC and TGF beta signaling pathways are complex and play divergent roles in HCC initiation and progression.