Squalene synthase promotes the invasion of lung cancer cells via the osteopontin/ERK pathway

Cholesterol is the major component of lipid rafts. Squalene synthase (SQS) is a cholesterol biosynthase that functions in cholesterol biosynthesis, modulates the formation of lipids rafts and promotes lung cancer metastasis. In this study, we investigated the lipid raft-associated pathway of SQS in lung cancer. Gene expression microarray data revealed the upregulation of secreted phosphoprotein 1 (SPP1; also known as osteopontin, OPN) in CL1-0/SQS-overexpressing cells. Knockdown of OPN in SQS-overexpressing cells inhibits their migration and invasion, whereas an OPN treatment rescues the migration and invasion of SQS knockdown cells. High OPN expression is associated with lymph node status, advanced stage and poor prognosis in patients with lung cancer. Moreover, patients with high SQS expression and high OPN expression show poor survival compared with patients with low SQS expression and low OPN expression. SQS induces the phosphorylation of Src and ERK1/2 via OPN, resulting in increased expression of MMP1 and subsequent metastasis of lung cancer cells. Based on our findings, SQS expression increases the expression of OPN and phosphorylation of Src through cholesterol synthesis to modulate the formation of lipid rafts. SQS may represent a therapeutic strategy for lung cancer.