13q12.12肺癌风险染色质区TNFRSF19：一个新的肺癌抑癌基因的功能和机制研究

染色体13q12.12为肺癌风险区，我们在此区域鉴定了一个肺组织特异性抑癌增强子，并证明TNFRSF19是该增强子的关键靶基因，具有肺癌抑癌基因的重要潜能（2019 Genome Biology）。进一步预实验显示，致癌物NNK可通过激活Wnt/β-Catenin通路诱导支气管上皮细胞恶性转化，TNFRSF19与Wnt3a相互作用并下调Wnt/β-Catenin活性。蛋白三维模型预测TNFRSF19-Wnt3a可阻碍LRP6-Wnt3a相互作用。本课题旨在上述工作基础上综合利用TNFRSF19基因敲除细胞系、条件敲除小鼠及细胞和分子手段，深入阐述TNFRSF19的抑癌功能和机制，验证研究假设：TNFRSF19是一个新的具有重要肿瘤生物学意义的肺癌抑癌基因，通过与共受体LRP6竞争结合Wnt3a抑制Wnt/β-Catenin通路异常激活，进而抑制致癌物诱导的支气管上皮细胞恶变。

Our previous study has identified an important lung tissue specific enhancer with cancer suppressor potential in the 13q12.12 lung cancer risk region, and proved that TNFRSF19 is a key target gene of the enhancer and has the potential of lung cancer suppressor gene (Genome Biology 2019). Further preliminary experiments showed that NNK, a carcinogen, induced malignant transformation of bronchial epithelial cells by activating Wnt / β - Catenin pathway, and TNFRSF19 interacted with Wnt3a to decrease Wnt / β - Catenin activity. Three dimensional protein models suggested that TNFRSF1919-Wnt3a interfered with LRP6-Wnt3a interaction. We hypothesize that TNFRSF19 is a new lung cancer suppressor gene. It can inhibit carcinogen induced malignant transformation of bronchial epithelial cells and lung carcinogenesis by competing with co-receptor LRP6 to bind Wnt3a to suppress Wnt / β - Catenin pathway activation. The aim of this project is to test our hypothesis by integrating cellular and molecular biological methods, knockout cell line, conditional knockout mice and carcinogen induced lung cancer mouse model. The study will provide theoretical and experimental basis for understanding the pathogenesis of lung cancer from a new perspective.