Platelet derived growth factor receptor alpha (PDGFRalpha) signaling in liver biology: Promises and Perils.

摘要

Hepatocellular carcinoma (HCC) is amongst the top common cancers and the third cause of cancer related death worldwide. It is a disease of dismal prognosis. Much effort has been devoted to identifying the major players involved in HCC to facilitate the development of efficacious treatments. Due to the commonalities between development and cancer, our lab used developing livers to identify genes that might play a crucial role in HCC. We identified increased expression of Platelet Derived Growth Factor Receptor Alpha (PDGFRalpha), its ligands and activity in early developing mouse livers, which coincided with ongoing cell proliferation. Blockade of PDGFRalpha signaling using a mouse specific PDGFRalpha blocker in embryonic liver cultures led to significantly decreased cell proliferation and survival. PDGFRalpha overexpression was also evident in HCC with around 63% of the patients showing around 7-fold up-regulation. PDGFRalpha upregulation was also identified as the chief molecular basis of enhanced tumorigenesis in hepatocyte-specific beta-catenin knockout mice exposed to chemical carcinogen. In fact, blockade of PDGFRalpha in this model led to a significant abrogation of tumorigenesis.;Since most HCC develop in the background of cirrhosis where liver regeneration is ongoing and critical for maintenance of hepatic function, it is important to identify pathways that are dispensable for normal liver regeneration, but indispensable for tumor cell proliferation and viability. We sought to determine if PDGFRalpha, which is indispensable to HCC was important in liver regeneration using partial hepatectomy (PHx) model. We identified a dramatic increase in total PDGFRalpha at 24hrs after PH, which was accompanied by its tyrosine phosphorylation. However, hepatocyte-specific Pdgfra knockout mice (KO) that lacked any spontaneous phenotype, showed no difference in hepatocyte proliferation at 40hrs. Interestingly, we identified an increase in total and phosphorylated EGFR and MET expression in the KO at 24hrs, which eventually led to a modest increase in hepatocyte proliferation at 72hrs. Interestingly, PDGFRA knockdown in human hepatoma cells did not lead to EGFR or MET upregulation indicating that PDGFRalpha is redundant in liver regeneration but not in HCC.;Thus we have uncovered important roles of PDGFRalpha in liver development, regeneration, and cancer.