Departments of Obstetrics and Gynecology, University of Occupational and Environmental Health School of Medicine, Kitakyushu, Japan.
Cancer Sci. 2012 Feb;103(2):239-444. doi: 10.1111/j.1349-7006.2011.02156.x. Epub 2011 Dec 23.
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.
线粒体转录因子 A（mtTFA）对于线粒体 DNA（mtDNA）的转录和维持都是必需的。最近，我们报道 mtTFA 不仅在线粒体中表达，而且在核中也表达。然而，mtTFA 在核中的功能尚未清楚阐明。在本研究中，我们使用免疫组织化学分析检查了 60 个浆液性卵巢癌组织样本中的核 mtTFA 表达，发现 56.7%的浆液性卵巢癌患者 mtTFA 阳性，而 43.3%为阴性。单因素生存分析显示，mtTFA 阳性癌症患者的总 5 年生存率明显低于 mtTFA 阴性癌症患者（分别为 32%和 42%；P=0.021）。为了阐明核中 mtTFA 的功能，我们研究了 mtTFA 的靶基因 BCL2L1。在 7 个卵巢癌细胞系和临床卵巢癌标本中，核 mtTFA 表达与 BCL2L1 表达之间存在显著相关性。转染 mtTFA 表达质粒后，细胞 BCL2L1 表达下调，而转染 mtTFA siRNA 后，BCL2L1 启动子活性增加。染色质免疫沉淀分析显示 mtTFA 结合于 BCL2L1 启动子区域。这些结果表明，mtTFA 是卵巢癌不良预后的一个预后因素，可能作为一种抗凋亡因子，调节 BCL2L1 等基因。此外，mtTFA 可能是治疗卵巢癌的有前途的分子靶点。
