Pancreatic Adenocarcinoma Up-Regulated Factor Promotes Epithelial–Mesenchymal Transition and Lung Metastasis in Hepatocellular Carcinoma

Pancreatic adenocarcinoma upregulated factor (PAUF), a novel secreted protein highly expressed in pancreatic ductal adenocarcinoma, also influences cell invasiveness, motility, and proliferation in several cancer types. Transforming growth factor-beta (TGF-β)-induced PAUF expression enhances cancer cell migration and invasion in pancreatic ductal adenocarcinoma through mitogen-activated protein kinase (MEK)–extracellular signal-regulated kinase (ERK) activation; however, the roles of PAUF in regulating epithelial–mesenchymal transition (EMT) and promoting lung metastasis in hepatocellular carcinoma (HCC) remain unclear. Thus, we investigated the regulatory mechanisms and functional roles of TGF-β-induced PAUF expression in the HCC cell lines HepG2 and Huh-7, which showed high and low expression of intact TGF-β type I and II receptors, respectively. We found that TGF-β-induced PAUF expression is mediated through the activation of the TGF-β type I/II receptor–Smads signaling pathway and that PAUF promotes EMT-associated migration and invasion by stimulating the MEK–ERK signaling cascade. In vivo studies further demonstrated that PAUF plays a critical role in lung metastatic potential, as PAUF knockdown HepG2 cells exhibited markedly reduced pulmonary metastasis, whereas PAUF-overexpressing Huh-7 cells showed substantially enhanced lung metastasis. This study identifies PAUF as a critical promoter of lung metastatic potential in HCC cells and a potential therapeutic target for HCC.