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

Yi-Fang Yang,Yi-Hua Jan,Yu-Chan Chang,Michael Hsiao,Chih-Jen Yang,Ming-Shyan Huang

doi:10.1038/s41389-020-00262-2

Abstract

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.

Highlights

Lung cancer is one of the most common malignancies both in Taiwan and in many other countries
Squalene synthase (SQS) expression is correlated with poor survival rates in lung cancer patients In our study, we aimed to identify a key metabolic pathway that is aberrantly overexpressed in invasive lung cancer cell and investigate its role
The cholesterol biosynthesis pathway has eight enzymes that were upregulated in CL1-5 cells, including (1) hydroxymethylglutaryl-CoA synthase 1 (HMGCS1), (2) farnesyl-diphosphate synthase (FDPS), (3) farnesyldiphosphate farnesyltransferase (FDFT1, known as squalene synthase, SQS), (4) squalene epoxidase (SQLE); (5) methylsterol monooxygenase 1 (MSMO1), (6) cytochrome P450, family 51, subfamily A (CYP51A1); (7) 7dehydrocholesterol reductase (DHCR7), and (8) 24dehydrocholesterol reductase (DHCR24) (Fig. S1)[7]

Summary

Introduction

Lung cancer is one of the most common malignancies both in Taiwan and in many other countries. It remains the leading cause of cancer-related death, with more than 1.3 million people dying of the disease annually[1]. Lung cancer is classified according to the histological type into small cell carcinoma and non-small cell lung carcinoma (NSCLC); NSCLC accounts for approximately 80% of all lung cancer cases[2,3]. The high mortality rate of NSCLC is attributed to its high rate modulates raft composition and promotes metastasis in lung cancer by inducing clustering of rafts in the cell membrane, leading to an enrichment of the TNF-α receptor in rafts[7]

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