title: Contribution of transcription factor, SP1, to the promotion of HB-EGF expression in defense mechanism against the treatment of irinotecan in ovarian clear cell carcinoma.
abstract: Ovarian clear cell carcinoma (OCCC) is a worst histological subtype than other ovarian malignant tumor. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a promising target for ovarian cancer therapy. The aims of this study were to validate the efficacy of HB-EGF-targeted therapy for OCCC and to identify the transcription factor that contributed to the induction of HB-EGF by SN38 treatment in OCCC cells. HB-EGF was highly expressed in OCCC cells, and an increase of HB-EGF was induced by SN38 which had only antitumor effect among conventional anticancer agents on OCCC. A specific inhibitor of HB-EGF, a cross-reacting material 197 (CRM197), led to a synergistic increase in the number of apoptotic OCCC cells with the treatment of SN38. The luciferase assay with 5'-deletion promoter constructs identified a GC-rich element between -125 and -178 (the distal transcription start site was denoted +1) as a cis-regulatory region, and the treatment of SN38 induced luciferase activity in this region. An in silico and chromatin immunoprecipitation analysis estimated that SP1 bound to the cis-regulatory region of HB-EGF in OCCC cells. Real-time PCR and cell viability assays showed that the transfection of a small interfering RNA targeting SP1 suppressed the expression of HB-EGF induced by SN38, resulting in the enhanced sensitivity of SN38. Taken together, these results indicate that induction of HB-EGF expression contributed to defense mechanism against treatment of SN38 through the transcriptional activity of SP1 in OCCC cells.
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan; Department of Biochemistry, Faculty of Medicine, Fukuoka University, Fukuoka, Japan; Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka, Japan; Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, Japan.
authors: Kohei
authors: K
authors: Miyata
authors: Fusanori
authors: F
authors: Yotsumoto
authors: Sung Ouk
authors: SO
authors: Nam
authors: Takashi
authors: T
authors: Odawara
authors: Sadao
authors: S
authors: Manabe
authors: Toyokazu
authors: T
authors: Ishikawa
authors: Hiroaki
authors: H
authors: Itamochi
authors: Junzo
authors: J
authors: Kigawa
authors: Shuji
authors: S
authors: Takada
authors: Hiroshi
authors: H
authors: Asahara
authors: Masahide
authors: M
authors: Kuroki
authors: Shingo
authors: S
authors: Miyamoto
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics* / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016329:Sp1 Transcription Factor / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D066257:Heparin-binding EGF-like Growth Factor; D016329:Sp1 Transcription Factor; D000077146:Irinotecan; D002166:Camptothecin
keywords: Chemotherapy; HB-EGF; gene transcriptional regulation; ovarian cancer