Transglutaminase 2 Maintains Hepatocyte Growth Factor Signaling to Enhance the Cancer Cell Phenotype

Transglutaminase 2 (TG2) is a key epidermal squamous cell carcinoma cancer cell survival protein. However, how TG2 maintains the aggressive cancer phenotype is not well understood. The present studies show that TG2, which is highly expressed in epidermal cancer stem-like cells (ECS cells), maintains hepatocyte growth factor (HGF) signaling to drive an aggressive ECS cell cancer phenotype. Inhibiting TG2 reduces MET tyrosine kinase receptor expression and activity and attenuates the cancer cell phenotype. Moreover, inhibition of TG2 or HGF/MET function reduces downstream MEK1/2 and ERK1/2 activity, and this is associated with reduced cancer cell spheroid formation, invasion, and migration, and reduced stem and EMT marker expression. Treatment of TG2 knockdown cells with HGF partially restores the aggressive cancer phenotype, confirming that MET signaling is downstream of TG2. MET knockout reduces ERK1/2 signaling, doubles the time to initial tumor appearance, and reduces overall tumor growth. These findings suggest that TG2 maintains HGF/MET and MAPK (MEK1/2 and ERK1/2) signaling to drive the aggressive ECS cell cancer phenotype and tumor formation, and that TG2-dependent MET signaling may be a useful anti-cancer target. IMPLICATIONS: TG2 is an important epidermal squamous cell carcinoma stem cell survival protein. We show that TG2 activates an HGF/MET, MEK1/2 ERK1/2 signaling cascade that maintains the aggressive cancer phenotype.