OLC1基因调控BRCA1分子通路与人食管癌变机理的研究

OLC1 is a new gene which was cloned and named in our State Key Laboratory of Molecular Oncology. In the previous study, the applicant of this project found that OLC1 protein was over-expressed in human esophageal cancer. The OLC1 over-expression disrupted the delicate balance between cell proliferation and apoptosis, and further promoted malignant cellular transformation. OLC1 regulated the expression of BRCA1 which is important tumor suppressor gene in post-transcriptional levels. The project will generate integrated study in the multiple levels with clinical esophageal cancer specimens, OLC1-overexpressing and OLC1-interfering esophageal cancer cell lines and OLC1 transgenic mice, to study the molecular mechanisms of OLC1 regulated BRCA1 molecular pathway and its biological role in human esophageal carcinogenesis. The study will clarify how the abnormally expressed OLC1 regulates the molecular pathway of BRCA1, and affects the BRCA1 function in the balance of cell proliferation and apoptosis. Study on OLC1, a new molecular, has important theoretical significance and potential application for the discovery of molecular targets in early diagnosis and individualized treatment of esophageal cancer.

OLC1基因是我们分子肿瘤学国家重点实验室发现、克隆并命名的一个新基因。在前期的研究中，本项目申请人研究发现OLC1蛋白在中国人食管癌组织中有明显的异常高表达。OLC1异常表达导致人食管癌细胞增殖/凋亡平衡失调，促进细胞的恶性转化，并发现OLC1在转录后调控水平影响重要抑癌基因BRCA1的表达。本项目将利用临床食管癌不同阶段组织、OLC1稳定高表达和OLC1敲降食管癌细胞系、OLC1转基因小鼠模型， 在临床组织水平、细胞水平、转基因动物等多个层次上, 整合性研究OLC1异常表达对BRCA1和相关分子通路的作用机制，及其在人类食管癌变中的生物学作用。阐明OLC1异常表达通过调控BRCA1分子通路，从而影响BRCA1调控细胞增殖/凋亡的功能。阐释OLC1这一个新分子的功能, 对发现与食管癌早诊和个体化治疗相关的分子靶点有重要理论意义和应用前景。

OLC1是我们克隆鉴定并命名的一个新的潜在的癌基因，其在人类食管鳞癌中的作用尚不清楚。本研究在正常食管，癌前病变和食管癌组织中评估了OLC1在人类食管鳞癌的表达及OLC1异常表达在食管癌的发生发展过程中的作用和机制。我们采用免疫组化等实验技术，利用收集的214例配对的食管鳞癌标本，以及另外28例食管癌前病变标本，分析OLC1表达与病理特征之间的相关性；我们还建立了OLC1稳定过表达和OLC1干扰的食管癌细胞系，研究OLC1异常表达的生物学功能和机制。我们的研究结果显示，OLC1的表达从正常食管组织、食管不典型增生到食管鳞状细胞癌的发展过程中逐步表达增高。我们的研究表明，OLC1异常改变引起食管癌细胞增殖和凋亡平衡失调；OLC1过表达抑制细胞凋亡与caspase-3激活和Bcl-2的稳定性增加有关；OLC1的异常表达在食管癌发生发展过程中的生物学作用与BRCA1分子调控相关。我们的研究证据表明OLC1异常可能有助于人类食管癌的发生发展，并有重要的潜在的临床意义。