ABSTRACT
Nasopharyngeal carcinoma (NPC) is prevalent in south-eastern Asia, and its tumourigenesis is rather complex. The purpose of this research was to identify the pivotal genes that may be altered during the early stage of NPC progression. Eleven genes were selected by comparative microarray analysis of NPC versus normal nasomucosal cells. The expression of SPARC (secreted protein, acidic, cysteine-rich) was statistically significantly down-regulated in NPC cells. In exploring the mechanism underlying the decreased transcription of SPARC in NPC cells, we found that the transcription factor SRY (sex-determining region Y)-box 5 (SOX-5) is up-regulated in NPC cells. RNA interference of SOX-5 by short hairpin RNA (shRNA) in NPC cells caused a dramatic increase in SPARC and chromosome immunoprecipitation assay showed that SOX-5 can bind directly to the SPARC promoter, suggesting that SOX-5 acts as a key transcriptional repressor of SPARC. We further demonstrated that shRNA knockdown of SOX-5 suppressed the proliferation of NPC cells, as well as their migratory ability, which was also observed when SPARC was over-expressed in NPC cells. Alternatively, blocking SPARC with an antagonistic antibody reversed the effects of SOX-5 knockdown. In 66 NPC patients, over-expression of SOX-5 in tumour cells correlated clinically with poor survival. Our study suggests that SOX-5 transcriptionally down-regulates SPARC expression and plays an important role in the regulation of NPC progression. SOX-5 is a potential tumour marker for poor NPC prognosis.
Subject(s)
DNA-Binding Proteins/physiology , Gene Expression Regulation, Neoplastic , Nasopharyngeal Neoplasms/metabolism , Nuclear Proteins/physiology , Osteonectin/biosynthesis , Transcription Factors/physiology , Animals , Binding Sites , Biomarkers, Tumor/biosynthesis , Disease Progression , Down-Regulation , Follow-Up Studies , Humans , Mice , Mice, SCID , Nasopharyngeal Neoplasms/genetics , Nasopharyngeal Neoplasms/pathology , Neoplasm Proteins/physiology , Neoplasm Transplantation , Oligonucleotide Array Sequence Analysis/methods , Osteonectin/genetics , Prognosis , Promoter Regions, Genetic , Protein Isoforms/biosynthesis , Protein Isoforms/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Reverse Transcriptase Polymerase Chain Reaction/methods , SOXD Transcription Factors , Survival Analysis , Transcription Factors/metabolism , Transplantation, Heterologous , Tumor Cells, CulturedABSTRACT
Metastasis and invasion occur in the majority of epithelial ovarian carcinoma at diagnosis. To delineate the molecular signature in ovarian cancer invasion, we established and characterized a human ovarian endometrioid carcinoma (EC) cell line OVTW59-P0 and its invasion-related sublines (P1-P4, in the order of increasing invasive activity). P4 showed faster migration and larger xenograft formation with metastasis than P0. By microarray analysis of different gene expression among P0-P4 sublines, one group of gene was found negatively correlated with cancer invasion. Among these genes, IGFBP-3 was identified as one of the most remarkably suppressed gene that showed lower gene expression in P4 than P0. Re-expression of IGFBP-3 in P4 effectively inhibited cell migration, invasion and metastasis, but did not affect cell proliferation. In 35 patients with EC tumors, low IGFBP-3 expression correlated clinically with higher tumor grade, advanced stage and poor survival. Our results provide evidence and indicate that IGFBP-3 plays an important role as an invasion-metastasis suppressor in ovarian EC.
