Transforming growth factor β (TGFβ) is a multifunctional cytokine which is importantly implicated in hepatocarcinogenesis. The current study provides novel evidence that TGFβ upregulates the expression of multiple receptor tyrosine kinases (RTKs), including EGFR, PDGFβR, FGFR1, IGF1R, and even a novel IGF1R splice variant in human hepatocellular carcinoma (HCC) cells. This, in turn, sensitizes HCC cells to individual cognate RTK ligands, leading to cell survival. Our data showed that the TGFβ-mediated increase in growth factor sensitivity led to evasion of apoptosis induced by the mutikinase inhibitor, sorafenib. Conversely, we observed that inhibition of the TGFβ signaling pathway by LY2157299, a TGFβRI kinase inhibitor, enhanced sorafenib-induced apoptosis, in vitro. Systematic computational analyses of TGFβ related genes in human patient datasets implicated this large family of ligands, receptors, and signaling molecules as potential contributors to HCC disease initiation and progression. Taken together, our findings disclose an important interplay between TGFβ and RTK signaling pathways, which is critical for hepatocellular cancer cell survival and resistance to therapy.
