Twist-related protein 1 enhances oral tongue squamous cell carcinoma cell invasion through β-catenin signalling

Abstract

Accumulating evidence suggests that β-catenin signaling may be involved in oral tongue squamous cell carcinoma (OTSCC) cell invasion. Abnormal activation of twist-related protein 1 (TWIST1 or TWIST) has been identified in several types of human cancer. A recent study showed that overexpression of TWIST is associated with a poor prognosis in patients with OTSCC and may enhance OTSCC cell invasion. This study investigated the effect of TWIST on β-catenin signaling in OTSCC cells and its impact on OSTCC cell invasion. Stable overexpression of TWIST, with or without knockdown of β-catenin, and stable knockdown of TWIST were performed in SCC-4 and TCA8113 human OTSCC cells. Overexpression of TWIST in SCC-4 and TCA8113 cells increased β-catenin signaling luciferase reporter activity, mRNA levels of the β -catenin signaling target genes, c-Myc and c-Jun levels, soluble β-catenin level, the phosphorylation status of glycogen synthase kinase-3β (GSK-3β) at serine 9, matrix metalloproteinase-2 (MMP-2) expression and cell invasion. Knockdown of TWIST had the opposite effect. All of these changes, with the exception of phosphorylation of GSK-3β, were eliminated by stable knockdown of β-catenin. In addition, the phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002 abrogated the enhancing effects of TWIST on mRNA levels of c-Myc and c-Jun, soluble β-catenin levels, MMP-2 expression, cell invasion and GSK-3β phosphorylation. In conclusion, the present study demonstrated that TWIST enhances cell invasion and MMP-2 expression in OTSCC cells through β -catenin signaling, probably via a PI3K-dependent mechanism. This study provides novel insights into the molecular mechanisms underlying OTSCC progression.