title: Mitochondrial transcription factor A regulates BCL2L1 gene expression and is a prognostic factor in serous ovarian cancer.
abstract: Mitochondrial transcription factor A (mtTFA) is necessary for both transcription and maintenance of mitochondrial DNA (mtDNA). Recently, we reported that mtTFA is expressed not only in mitochondria, but also in nuclei. However, the function of mtTFA in the nucleus has not been clearly elucidated. In the present study, we examined nuclear mtTFA expression in 60 tissue samples of serous ovarian cancer using immunohistochemical analysis and found that 56.7% of serous ovarian cancer patients were positive for mtTFA, whereas 43.3% were negative. Univariate survival analysis showed that the overall 5-year survival rate was significantly worse for patients with mtTFA-positive cancer compared with mtTFA-negative cancer (32%vs 42%, respectively; P = 0.021). To elucidate the function of mtTFA in the nucleus, we investigated BCL2L1, a target gene of mtTFA. There was a significant correlation between nuclear mtTFA expression and BCL2L1 expression in seven ovarian cancer cell lines and in specimens of clinical ovarian cancer. Cellular BCL2L1 was downregulated following transfection of siRNA against mtTFA. BCL2L1 promoter activity was increased after transfection of mtTFA expression plasmid, but decreased after siRNA knockdown of mtTFA. Chromatin immunoprecipitation assays showed that mtTFA was bound to the BCL2L1 promoter region. These results suggest that mtTFA is a prognostic factor for a poor outcome of ovarian cancer and may function as an antiapoptotic factor, regulating genes such as BCL2L1. Furthermore, mtTFA may be a promising molecular target for novel therapeutic strategies for the treatment of ovarian cancer.
authors.affiliation: Departments of Obstetrics and Gynecology, University of Occupational and Environmental Health School of Medicine, Kitakyushu, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kurita
authors.forename: Hiroto
authors.initials: H
authors.lastname: Izumi
authors.forename: Seiji
authors.initials: S
authors.lastname: Kagami
authors.forename: Toshinori
authors.initials: T
authors.lastname: Kawagoe
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Toki
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Matsuura
authors.forename: Toru
authors.initials: T
authors.lastname: Hachisuga
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Kohno
mesh_terms: D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism*
chemical_list: C494811:BCL2L1 protein, human; D014408:Biomarkers, Tumor; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D051020:bcl-X Protein; C422562:mitochondrial transcription factor A