PDGFRα: A major escape pathway following β‐catenin suppression.

β‐Catenin signaling is implicated in 30% of hepatocellular cancers (HCC) and is a plausible therapeutic target. Several proof‐of‐principal studies employing siRNA, antisense or small molecule inhibitors to β‐catenin have effectively demonstrated negative impact on hepatoma growth. Recently, we utilized hepatocyte‐specific β‐catenin conditional knockout (KO) mice to study hepatocarcinogenesis in response to diethylnitrosamine (DEN). Paradoxically, a higher incidence of HCC was found in KO mice after DEN. We identified increased PDGFRα/PI3‐kinase activity as a mechanism of HCC. Here, we identify PDGFRα upregulation in response to β‐catenin knockdown as a more global phenomenon. PDGFRα expression was significantly greater in KO livers than controls at the baseline. Following partial hepatectomy (Phx) in the KO mice, elevated levels of PDGFRα were detected at all time‐points except 72hrs, which is the time of peak hepatocyte proliferation in KO. In light of PDGFRα ligands being released by hepatocytes after PH, it is conceivable that PDGFRα activation and internalization at 72hrs may be regulating cell proliferation in the absence of β‐catenin. We address this by transfecting hepatoma cells with β‐catenin siRNA or antisense. β‐Catenin suppression always led to increase in PDGFRα. When hepatoma cells were treated with PDGF‐CC, a PDGFRα ligand, a significant increase in thymidine incorporation, a marker of cell proliferation, was detected only in cultures transfected with β‐catenin siRNA. Thus, PDGFRα upregulation is observed when β‐catenin is suppressed and thus represents an important redundant mechanism of cell proliferation after β‐catenin inhibition and will be of essence in regeneration and cancer.