Genomic Instability from Loss of XPG, a BRCA1/2 Partner: Role in Ovarian Cancer?

XPG（BRCA1/2 伙伴）缺失导致基因组不稳定：在卵巢癌中的作用？

• 批准号: 8885778
• 负责人: Priscilla K. Cooper
• 金额: $ 21.47万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-03 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885778
• 关键词: Adenocarcinoma Cell; Anchorage-Independent Growth; Apoptosis; BRCA1 Mutation; BRCA1 Protein; BRCA1 gene; BRCA2 gene; CA-125 Antigen; Camptothecin; Cancer Etiology; Cancer cell line; Carboplatin; Cell Line; Cells; Cessation of life; Chromosomal Instability; Chromosome abnormality; Cisplatin; Coupled; DNA Double Strand Break; DNA repair protein; Data Set; Defect; Development; Down-Regulation; ERCC5 gene; Epithelial; Epithelial Cells; Etiology; Event; Frequencies; Gene Expression; Genes; Genetic Predisposition to Disease; Genome Stability; Genomic Instability; Genomics; Health; Impairment; Inherited; Investigation; Ionizing radiation; Lead; Left; Link; Maintenance; Malignant neoplasm of ovary; Mammalian Oviducts; Measures; Mutation; Neoplastic Cell Transformation; Nucleotide Excision Repair; Ovarian; Ovarian Serous Adenocarcinoma; Pathway interactions; Patients; Play; Predisposition; Proteins; Regulation; Resistance; Risk; Role; Serous; Simian virus 40; Staging; Stress; Surface; Syndrome; Testing; The Cancer Genome Atlas; Therapeutic; Tumor Suppressor Proteins; Up-Regulation; Woman; XPGC protein; adduct; cancer cell; cancer risk; carcinogenesis; cell growth; cell type; chemotherapeutic agent; homologous recombination; improved; inhibitor/antagonist; knock-down; member; metaplastic cell transformation; micronucleus; novel; novel marker; novel therapeutic intervention; novel therapeutics; ovarian neoplasm; p53-binding protein 1; precursor cell; protein protein interaction; recombinase; recombinational repair; scaffold; tumor

DESCRIPTION (provided by applicant): Ovarian cancer is the fifth leading cause of cancer death among U.S. women, primarily from advanced high-grade serous ovarian adenocarcinoma (HGS-OvCa). Inherited mutation of BRCA1 and BRCA2, which function in homologous recombination repair (HRR), leads to a substantial increase in ovarian cancer risk. The Cancer Genome Atlas (TCGA) project recently identified unusually high genomic instability as a prominent feature of HGS-OvCa tumors and estimated that ~50% have HRR defects. Since this frequency significantly exceeds that of BRCA mutations, it is likely that changes in HRR genes not known to be associated with inherited predisposition syndromes are important in the etiology of sporadic ovarian cancer. This project will explore a novel role for the highly multifunctional DNA repair protein XPG as a driver in ovarian carcinogenesis. Surprising recent findings have established that XPG functions in HRR through direct interaction with several members of the HRR pathway, notably including both BRCA proteins as well as the RAD51 recombinase, and that loss of XPG has significant consequences for impairment of BRCA1 and BRCA2 functions. Knockdown of XPG leads to reduced HRR, inability to restart stalled replication forks, and a dramatic increase in genomic instability. Conversely, the enzymatic function of XPG is required in nucleotide excision repair (NER) to remove adducts formed by many chemotherapeutic agents, and acquired resistance to first-line therapies such as cisplatin and carboplatin has been linked to over-expression of NER proteins including XPG. Importantly for development of new therapeutic approaches, tumors with diminished HRR due to low expression of XPG may be particularly sensitive to PARP inhibitors. The hypothesis to be tested by the proposed exploratory studies is that XPG is a novel tumor suppressor for ovarian carcinogenesis that its loss or down- regulation is a previously unidentified factor in the etiology of ovarian cancer, and that understanding XPG protein regulation and activity in ovarian cancer cells has direct therapeutic implications. This hypothesis will be tested through two specific aims. (1) The effect of XPG loss on genomic instability and cellular transformation in immortalized, non-tumorigenic ovarian surface epithelial (OSE) cells and fallopian tube secretory epithelial cells (FTSEC), which have each been proposed to be the precursor cell types for ovarian carcinogenesis, will be determined. (2) XPG protein amounts, function, and regulation will be examined in a panel of ovarian cancer cell lines that have been shown to most closely resemble primary HGS-OvCa tumors, including several that are known to have XPG mutations. If the hypothesis is correct that XPG, newly identified as an important HRR protein, plays a role in the initiating events in HGS-OvCa, these results have the potential to provide a new marker for ovarian cancer susceptibility, new therapeutic strategies, and improved understanding of mechanisms involved in ovarian carcinogenesis.

描述（由申请人提供）：卵巢癌是美国女性癌症死亡的第五大原因，主要来自晚期高级别浆液性卵巢腺癌（HGS-OvCa）。BRCA 1和BRCA 2在同源重组修复（HRR）中发挥作用，其遗传突变导致卵巢癌风险大幅增加。癌症基因组图谱（TCGA）项目最近确定了异常高的基因组不稳定性作为HGS-OvCa肿瘤的突出特征，并估计约50%具有HRR缺陷。由于这一频率明显超过BRCA突变，可能是HRR基因的变化，不知道与遗传易感综合征是重要的散发性卵巢癌的病因。该项目将探索高度多功能的DNA修复蛋白XPG作为卵巢癌发生的驱动因素的新作用。最近令人惊讶的发现已经确定XPG通过与HRR途径的几个成员直接相互作用而在HRR中起作用，特别是包括BRCA蛋白以及RAD 51重组酶，并且XPG的丧失对BRCA 1和BRCA 2功能的损害具有显著后果。XPG的敲低导致HRR降低，无法重新启动停滞的复制叉，以及基因组不稳定性的急剧增加。相反，XPG的酶功能在核苷酸切除修复（NER）中是必需的，以去除由许多化学治疗剂形成的加合物，并且对一线疗法如顺铂和卡铂的获得性抗性已与包括XPG的NER蛋白的过表达有关。对于开发新的治疗方法重要的是，由于XPG的低表达而导致HRR降低的肿瘤可能对PARP抑制剂特别敏感。拟通过探索性研究验证的假设是，XPG是卵巢癌发生的一种新型肿瘤抑制因子，其缺失或下调是卵巢癌病因学中先前未确定的因素， 了解卵巢癌细胞中XPG蛋白的调节和活性具有直接的治疗意义。这一假设将通过两个具体目标进行检验。(1)将确定XPG缺失对永生化的非致瘤性卵巢表面上皮（OSE）细胞和输卵管分泌上皮细胞（FTSEC）中的基因组不稳定性和细胞转化的影响，所述OSE细胞和输卵管分泌上皮细胞各自被认为是卵巢癌发生的前体细胞类型。(2)将在一组卵巢癌细胞系中检查XPG蛋白的量、功能和调节，这些细胞系已被证明与原发性HGS-OvCa肿瘤最相似，包括几种已知具有XPG突变的细胞系。如果假设是正确的，XPG，新确定的一个重要的HRR蛋白，在HGS-OvCa的起始事件中发挥作用，这些结果有可能提供一个新的标志物卵巢癌的易感性，新的治疗策略，并提高对卵巢癌发生机制的理解。