Abstract
Guanine nucleotide exchange factor T (GEFT), which is frequently overexpressed in cancers, is closely related to tumorigenicity and metastasis. Up to now, little is known about the relationship between GEFT and cholangiocarcinoma (CCA). The work explored the expression and function of GEFT in CCA and revealed the underlying mechanisms. Both CCA clinical tissues and cell lines expressed higher levels of GEFT than normal controls. High GEFT levels were correlated with a low overall survival rate in CCA patients. A decrease in GEFT by RNA interference caused remarkable anticancer effects in CCA cells, including retarded proliferation, delayed cell cycle progression, subdued metastatic potential and enhanced chemosensitivity. Mechanistically, GEFT mediated the Wnt-GSK-3β-β-catenin cascade associated with the regulation of Rac1/Cdc42. The inhibition of Rac1/Cdc42 markedly diminished the enhancing effect of GEFT on the Wnt-GSK-3β-β-catenin and reversed GEFT-mediated cancer-promoting effects in CCA. Moreover, the reactivation of β-catenin diminished GEFT-reduction-induced anticancer effects. Critically, CCA cells with decreasing GEFT had a weakened ability to form xenografts in mouse models. Collectively, this work illustrates that GEFT-mediated Wnt-GSK-3β-β-catenin cascade represents a novel mechanism underlying CCA progression and propose a decrease in GEFT as a potential path for treatment in CCA patients.