title: Squalene synthase induces tumor necrosis factor receptor 1 enrichment in lipid rafts to promote lung cancer metastasis.
abstract: BACKGROUND
  Metabolic alterations contribute to cancer development and progression. However, the molecular mechanisms relating metabolism to cancer metastasis remain largely unknown.
  
  
  OBJECTIVE
  To identify a key metabolic enzyme that is aberrantly overexpressed in invasive lung cancer cells and to investigate its functional role and prognostic value in lung cancer.
  
  
  METHODS
  The differential expression of metabolic enzymes in noninvasive CL1-0 cells and invasive CL1-5 cells was analyzed by a gene expression microarray. The expression of target genes in clinical specimens from patients with lung cancer was examined by immunohistochemistry. Pharmacologic and gene knockdown/overexpression approaches were used to investigate the function of the target gene during invasion and metastasis in vitro and in vivo. The association between the target gene expression and clinicopathologic parameters was further analyzed. Bioinformatic analyses were used to discover the signaling pathways involved in target gene-regulated invasion and migration.
  
  
  RESULTS
  Squalene synthase (SQS) was up-regulated in CL1-5 cells and in the tumor regions of the lung cancer specimens. Loss of function or knockdown of SQS significantly inhibited invasion/migration and metastasis in cell and animal models and vice versa. High expression of SQS was significantly associated with poor prognosis among patients with lung cancer. Mechanistically, SQS contributed to a lipid-raft-localized enrichment of tumor necrosis factor receptor 1 in a cholesterol-dependent manner, which resulted in the enhancement of nuclear factor-κB activation leading to matrix metallopeptidase 1 up-regulation.
  
  
  CONCLUSIONS
  Up-regulation of SQS promotes metastasis of lung cancer by enhancing tumor necrosis factor-α receptor 1 and nuclear factor-κB activation and matrix metallopeptidase 1 expression. Targeting SQS may have considerable potential as a novel therapeutic strategy to treat metastatic lung cancer.
authors.affiliation: 1 Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Fang
authors.initials: YF
authors.lastname: Yang
authors.forename: Yi-Hua
authors.initials: YH
authors.lastname: Jan
authors.forename: Yu-Peng
authors.initials: YP
authors.lastname: Liu
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Yang
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Su
authors.forename: Yu-Chan
authors.initials: YC
authors.lastname: Chang
authors.forename: Tsung-Ching
authors.initials: TC
authors.lastname: Lai
authors.forename: Jean
authors.initials: J
authors.lastname: Chiou
authors.forename: Hong-Yuan
authors.initials: HY
authors.lastname: Tsai
authors.forename: Jean
authors.initials: J
authors.lastname: Lu
authors.forename: Chia-Ning
authors.initials: CN
authors.lastname: Shen
authors.forename: Jin-Yuh
authors.initials: JY
authors.lastname: Shew
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Lu
authors.forename: Yuan-Feng
authors.initials: YF
authors.lastname: Lin
authors.forename: Ming-Shyan
authors.initials: MS
authors.lastname: Huang
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000096:biosynthesis; D004195:Disease Models, Animal; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000556:secondary*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D011379:Prognosis; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: TNFR1; cholesterol; lung cancer metastasis; squalene synthase