title: IGFBP-6 plays a role as an oncosuppressor gene in NPC pathogenesis through regulating EGR-1 expression.
abstract: Nasopharyngeal carcinoma (NPC) is prevalent in south-eastern Asia, particularly southern China, Singapore and Taiwan. The aim of this study was to identify the pivotal genes that may be altered during NPC progression. Using cDNA microarray analysis, we compared the expression of 18 genes between NPC and normal nasomucosal cells. qRT-PCR analysis found the expression of IBFBP-6 in NPC cell lines and immunolocalization of IGFBP-6 in NPC to be very weak. To explore the effects of IGFBP-6 on NPC tumour growth, we constructed inducible plasmids containing full-length IGFBP-6 cDNA (pBIG2i-IGFBP-6) and established pBIG2i-IGFBP-6-transfected NPC stable cell lines (NPC-TW01-pBIG2i-IGFBP-6). We then performed functional analysis of the IGFBP-6 in cell lines in vitro and in vivo. Over-expression of IGFBP-6 significantly suppressed the proliferation, invasion and metastatic activity of NPC cells and increased their apoptosis. We found the EGR-1, caspase-1 and TSP-1 genes to be markedly up-regulated when NPC-pBIG2i-IGFBP-6 was treated with doxycycline. Knocking down EGR-1 with EGR-1 siRNA resulted in a decrease in expression of caspase-1, TSP-1 and EGR-1 but not the expression of IGFBP-6. However, in knockdown cells the unchanged expression of IGFBP-6 did not inhibit the migration of NPC cells. Chromatin immunoprecipitation and luciferase reporter assay experiments showed that IGFBP-6 bound the EGR-1 promoter regions and activated EGR-1 promoter. We conclude that IGFBP-6 can regulate the progression of NPC by regulating the expression of EGR-1. These results suggest that IGFBP-6 could be used as a new target in NPC therapy.
authors.affiliation: Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yuan-Sung
authors.initials: YS
authors.lastname: Kuo
authors.forename: Yueh-Bih
authors.initials: YB
authors.lastname: Tang
authors.forename: Tung-Ying
authors.initials: TY
authors.lastname: Lu
authors.forename: Han-Chung
authors.initials: HC
authors.lastname: Wu
authors.forename: Chin-Tarng
authors.initials: CT
authors.lastname: Lin
mesh_terms: D000818:Animals; D001706:Biopsy; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D016153:Genes, Suppressor; D006801:Humans; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D051766:Early Growth Response Protein 1; D018976:Insulin-Like Growth Factor Binding Protein 6; D009363:Neoplasm Proteins