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Regulation of HSulf-1 expression by variant hepatic nuclear factor 1 in ovarian cancer
- Source :
- Cancer research. 69(11)
- Publication Year :
- 2009
-
Abstract
- We recently identified HSulf-1 as a down-regulated gene in ovarian carcinomas. Our previous analysis indicated that HSulf-1 inactivation in ovarian cancers is partly mediated by loss of heterozygosity and epigenetic silencing. Here, we show that variant hepatic nuclear factor 1 (vHNF1), encoded by transcription factor 2 gene (TCF2, HNF1β), negatively regulates HSulf-1 expression in ovarian cancer. Immunoblot assay revealed that vHNF1 is highly expressed in HSulf-1–deficient OV207, SKOV3, and TOV-21G cell lines but not in HSulf-1–expressing OSE, OV167, and OV202 cells. By short hairpin RNA–mediated down-regulation of vHNF1 in TOV-21G cells and transient enhanced vHNF1 expression in OV202 cells, we showed that vHNF1 suppresses HSulf-1 expression in ovarian cancer cell lines. Reporter assay and chromatin immunoprecipitation experiments showed that vHNF1 is specifically recruited to HSulf-1 promoter at two different vHNF1-responsive elements in OV207 and TOV-21G cells. Additionally, down-regulation of vHNF1 expression in OV207 and TOV-21G cells increased cisplatin- or paclitaxel-mediated cytotoxicity as determined by both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and clonogenic assays and this effect was reversed by down-regulation of HSulf-1. Moreover, nude mice bearing TOV-21G cell xenografts with stably down-regulated vHNF1 were more sensitive to cisplatin- or paclitaxel-induced cytotoxicity compared with xenografts of TOV-21G clonal lines with nontargeted control short hairpin RNA. Finally, immunohistochemical analysis of 501 ovarian tumors including 140 clear-cell tumors on tissue microarrays showed that vHNF1 inversely correlates to HSulf-1 expression. Collectively, these results indicate that vHNF1 acts as a repressor of HSulf-1 expression and might be a molecular target for ovarian cancer therapy. [Cancer Res 2009;69(11):4843–50]
- Subjects :
- Cancer Research
Mice, Nude
Biology
Response Elements
Transfection
Article
Small hairpin RNA
Mice
Cell Line, Tumor
Gene expression
medicine
Animals
Humans
RNA, Small Interfering
Clonogenic assay
Hepatocyte Nuclear Factor 1-beta
Oligonucleotide Array Sequence Analysis
Ovarian Neoplasms
Reporter gene
Gene Expression Profiling
Carcinoma
Cancer
medicine.disease
Molecular biology
Xenograft Model Antitumor Assays
Gene expression profiling
Gene Expression Regulation, Neoplastic
Oncology
Female
Sulfotransferases
Ovarian cancer
Protein Binding
Subjects
Details
- ISSN :
- 15387445
- Volume :
- 69
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Cancer research
- Accession number :
- edsair.doi.dedup.....48ed5389dcb8e087171882e55d15cbc0