FAM135B促进食管鳞癌发生发展的机制及其临床价值研究

Esophageal cancer is the one of the most common malignant tumors in China, with the fourth highest incidence rate and the tumor-related mortality rate. The pathological type of esophageal cancer in China is mainly esophageal squamous cell carcinoma (ESCC), accounting for about 86.1%. However, the pathogenesis of ESCC is still unclear, which has posed obstacle to the development of new diagnosis and treatment methods for ESCC. In our previous study, we performed whole genome sequencing and discovered that FAM135B is a novel ESCC related gene for the first time. Our results in the pre-project phase suggested that FAM135B plays a role in promoting tumor malignant phenotypes, and Granulin was the interacting protein, based on which, we proposed that there is a FAM135B/Granulin/PI3K-AKT-mTOR positive feedback loop which may account for the mechanism of FAM135B. Next, we intend to further elucidate the role of FAM135B as a driving gene and its underling mechanism in the initiation and development of ESCC from aspects of molecules, cells, transgenic mice and human ESCC tissues. Another aim of this project is to reveal the potential value of FAM135B as a new prognostic predictor for ESCC.

食管癌是国内发病率和肿瘤相关死亡率都排名第4的恶性肿瘤。我国食管癌病理类型以食管鳞癌为主，约占全部食管癌的86.1%。然而，人们对食管鳞癌的发病机制的认识仍很有限，这给食管鳞癌的诊疗技术进步带来了很多困难。本课题组前期通过全基因组测序，首次发现FAM135B是一个新型的食管鳞癌相关基因，本项目前期研究结果表明FAM135B具有促进食管鳞癌细胞恶性表型的功能，并初步探讨了其作用机制，提出FAM135B/Granulin/PI3K-AKT-mTOR正反馈假说。在此基础上，本项目拟进一步阐明FAM135B作为驱动基因在食管鳞癌发生发展中的功能和分子机制，并结合食管鳞癌组织样本，探索FAM135B作为食管鳞癌新的预后评估指标的临床应用价值。

食管鳞状细胞癌（Esophageal Squamous Cell Carcinoma，ESCC）是我国最常见、恶性程度最高的恶性肿瘤之一。目前，关于食管鳞癌的发病机制仍然不是很清楚。课题组前期发现FAM135B是一个新型的食管鳞癌相关基因，其突变率为6.8% (6/88)，并且该基因突变的患者生存预后较差。本课题研究发现，FAM135B蛋白在食管癌组织中的表达了显著高于癌旁对照组织，其FAM135B高表达组的患者生存预后显著差于低表达组。进一步研究发现，外源性过表达FAM135B促进了食管癌细胞系的增殖以及对顺铂诱导凋亡的抵抗作用。通过免疫共沉淀和质谱鉴定确定自分泌生长因子GRN是FAM135B的相互作用蛋白。FAM135B和GRN以及Akt/mTOR信号通路形成正反馈循环。进一步通过组织芯片分析发现，同时过表达FAM135B和GRN的ESCC患者生存预后极差，5年生存率为0，且多因素回归分析显示FAM135B和GRN共同过表达是独立于后因素。此外，FAM135B转基因小鼠在4-NQO诱导下食管癌的发生率显著高于野生型小鼠，且生存期也相对较短。转基因小鼠血浆GRN的浓度高于野生型小鼠。以上结果表明，FAM135B在食管鳞癌发生发展过程中起到了重要促癌作用，且是食管癌潜在的治疗靶点。