TNFAIP2蛋白通过AXL促进非小细胞肺癌转移的机制研究

Inflammatory cytokines play critical roles in the progression of lung cancer. However, the underlying mechanism is complicated and related target drugs are failed in clinical trials. Therefore, it is important to search inflammatory cytokines-regulated genes, which may act as the anti-tumor therapeutic target. In this study, through mRNA expression profiling analysis, we tested and compared the expression of inflammatory-related genes between normal paracancerous tissues and lung cancer tissues and found that the expression of tumor necrosis factor alpha inducible protein 2 (TNFAIP2) was significantly increased in lung cancer tissues. Clinical samples analysis indicated the expression of TNFAIP2 is closely related with the prognosis of patients. In vitro study suggested that TNFAIP2 can promote the EMT, invasion and metastasis of lung cancer cells. In order to explore the specific molecular mechanism, by using immunoprecipitation-mass spectrometry analyses, we found that TNFAIP2 interacted with AXL. AXL protein has been reported to promote tumor EMT through Akt, NF-KB and other signaling pathways. Therefore, we speculated that TNFAIP2 may promote lung cancer metastasis through AXL protein. In this project, based on the previous work, we will clarify the biological significance and function of TNFAIP2 in non-small cell lung cancer by in vitro and in vivo experiments. Also we will elucidate the specific regulation mechanism by which TNFAIP2 may promote the invasion and metastasis of lung cancer through AXL. The implementation of this project will help to elucidate the important clinical significance of TNFAIP2, a downstream of inflammation factor, in the progression of lung cancer and clarify the potential value of TNFAIP2 as a drug target for lung cancer treatment and lay a foundation for subsequent translational medicine research.

炎性因子在肺癌侵袭和转移过程中发挥重要作用。但调控机制复杂，相应的靶向药物未获成功。因此，寻找其下游的促癌因子作为抗肿瘤的治疗靶点尤为重要。我们前期通过基因芯片筛选肺癌组织中炎性诱导相关基因，发现TNFAIP2的表达量显著上调。结合临床样本分析发现TNFAIP2与患者预后相关。细胞模型证明TNFAIP2促进肺癌发生EMT。通过免疫沉淀结合质谱分析，发现TNFAIP2与AXL有较强的作用。AXL可以促进发生EMT。据此我们推测TNFAIP2可能通过AXL促进肺癌转移。在此研究基础上，本项目计划利用体内外模型深入研究TNFAIP2在肺癌转移中的调控作用，通过生化分子生物学和细胞生物学等方法阐明TNFAIP2通过AXL促进肺癌侵袭和转移的具体机制。本课题的实施将有助于阐明炎症下游因子TNFAIP2在肺癌进展中的作用，明确TNFAIP2作为肺癌的药物靶点的潜在应用价值，为后续转化医学研究奠定基础。

非小细胞肺癌(NSCLC)约占所有肺癌病例的85%，其在所有实体肿瘤中死亡率最高。NSCLC具有早期转移的特点，研究NSCLC进展和转移的分子机制对于开发治疗靶点至关重要。在本研究中，我们发现TNF-α诱导蛋白2(TNFAIP2)在NSCLC中显著上调，而TNFAIP2表达的增加与NSCLC患者的不良预后相关。在机制上，我们发现TNFAIP2直接与E-cadherin在质膜及细胞黏附处相互作用。TMEM139可促进E-cadherin的溶酶体降解，增强非小细胞肺癌细胞的EMT、迁移和侵袭能力。本研究不仅拓展了我们对非小细胞肺癌转移的认识，而且为开发新的治疗策略提供了理论基础。