染色体13q12.12肺癌易感区域TNFRSF19介导B细胞浸润抑制癌变的机制研究

与遗传变异关联抑制肺癌发生的功能基因仍知之甚少。申请人硕博期间深入解析13q12.12肺癌易感区增强子13q-Enh的功能，发现在肺癌中下调的TNFRSF19（简称T19）是其发挥抑癌效应的关键靶基因。基于此开展预实验示：T19显著抑制肺癌细胞LLC在体内成瘤；T19可保护支气管上皮细胞正常表型、抑制致癌物NNK诱导的恶变。生信分析提示肺癌中T19表达与B细胞浸润高度正相关，机制初探示：在恶变细胞中T19可通过NF-κB途径诱导B细胞趋化因子CXCL13表达。故提出“T19通过NF-κB通路上调CXCL13表达介导B细胞向肺癌组织浸润，从而发挥抑癌功能”的假说。本项目拟结合动物细胞实验明确T19抑制肺癌癌变的生物学功能，设计拯救实验阐明T19诱导B细胞浸润的分子机制，结合肺癌临床样本验证T19及下游节点分子的相关性。有关T19抑制肺癌癌变的功能及机制未见报道，本研究可为肺癌防治提供新策略。

The functional genes associated with genetic variation that inhibit the occurrence of lung cancer are still poorly understood. The applicant deeply analyzed the function of the enhancer 13q-Enh in the 13q12.12 lung cancer susceptible region and found that the down-regulated TNFRSF19 (abbreviated as T19) in lung cancer is the key target gene for enhancer exerts anti-tumor effect. Based on this, preliminary experiments showed that T19 significantly inhibited tumor formation in LLC lung cancer cells; T19 could protect the normal phenotype of bronchial epithelial cells and inhibit the malignant transformation induced by the carcinogen NNK. Bioinformatics analysis suggests that the expression of T19 in lung cancer is highly positively correlated with B cell infiltration. The preliminary exploration of the mechanism showed that T19 induced the expression of B cell chemokine CXCL13 through the NF-κB pathway in malignant cells. Therefore, we hypothesis that T19 up-regulates the expression of CXCL13 through the NF-κB pathway to mediate the infiltration of B cells into lung cancer tissues, thereby exerting a tumor suppressor function. This project intends to combine animal and cell experiments to clarify the biological function of T19 in inhibiting lung cancer carcinogenesis, design rescue experiments to clarify the molecular mechanism of T19 inducing B cell infiltration, and to verify the correlation between T19 and downstream node molecules in combination with lung cancer clinical samples. There are no reports on the function and mechanism of T19 in lung cancer. This study could provide new strategies for the prevention and treatment of lung cancer.