IL-1β通过miR-144-3p靶向调控WT1D影响肺腺癌细胞增殖的研究

Immunity and inflammation are key factors for occurance and development of lung adenocarcinoma (LUAD). IL-1β was demonstrated to be essencial cytokine for inflammation initiation and could promote cell proliferation through NF-κB/COX-2/HIF-1 pathway. However, The therapeutic stratergy of LUAD by blocking the above-mentioned pathway using Celecoxib showed dichotomous effect and cause progression on some occasion..Our prophase results showed an aberrant high level of serous IL-1β in LUAD patients, which was negatively correlated with miR-144-3p. Both IL-1β and miR-144-3p were independent risk factors of prognosis of LUAD patients. IL-1β could suppress miR-144-3p at transcriptional level, hence promote WT1D expression and enhance cell proliferation in LUAD cell line. In the present project, bio-informatics analysis on clinical data from both our cancer center and TCGA database, in vitro and in vivo experiment were carried out to manifest the hypothesis of IL-1β/miR-144-3p/WT1D pathway and explore the synchronized function with IL-1β/NF-κB/COX-2/HIF1 pathway on LUAD cell proliferation. .This project may enrich the "from inflammation to cancer" evolution mechanism and provide new understanding of LUAD and clinical implication for designing new intervention therapy.

免疫及炎症对肺腺癌的发生和发展有重要影响。IL-1β是炎症启动的关键因子，通过NF-κB/COX-2/HIF-1通路促进细胞增殖，但目前采用药物阻断上述通路的疗效尚不确切，部分患者疾病甚至出现进展。. 前期研究发现，IL-1β在肺腺癌患者血清中异常增高，与miR-144-3p呈负相关，两者均为患者预后的独立影响因素；IL-1β可在转录水平抑制miR-144-3p，进而促进WT1D表达及肿瘤细胞增殖。鉴此，本项目拟结合TCGA数据库，预测IL-1β/miR-144-3p/WT1D信号转导对患者预后的影响；通过体外和动物实验，阐明IL-1β/miR-144-3p/WT1D和IL-1β/NF-κB/COX-2/HIF-1通路的协同效应；结合实验数据及回顾性临床分析，揭示肺腺癌患者使用COX-2抑制剂后肿瘤进展的机制。本研究将丰富“炎症与肿瘤”演化学说，为肺腺癌临床诊治提供新思路。

免疫及炎症对肺腺癌的发生和发展有重要影响。IL-1β是炎症启动的关键因子，通过NF-κB/COX-2/HIF-1通路促进细胞增殖，但目前采用药物阻断上述通路的疗效尚不确切，部分患者疾病甚至出现进展。. 本项研究发现IL-1β在肺腺癌患者血清中异常增高，与miR-144-3p呈负相关，两者均为患者预后的独立影响因素；IL-1β可在转录水平抑制miR-144-3p，进而促进WT1D表达及肿瘤细胞增殖。通过体外实验和动物实验，项目组证明IL-1β抑制miR-144-3p转录，进而促进WT1D的蛋白表达并最终调控LUAD细胞增殖；同时IL-1β信号激活NF-κB，启动COX-2/HIF-1细胞通路（可被NSAID阻断），促进LUAD细胞增殖；在转录水平，WT1D可能促进NF-κB的表达，IL-1β/miR-144-3p/WT1D与IL-1β/NF-κB/COX-2/HIF-1信号通路之间可能存在交互效应，共同调控NSCLC的细胞增殖。. 本项研究揭示肺腺癌患者使用COX-2抑制剂后肿瘤进展的机制，丰富了“炎症与肿瘤”演化学说，为肺腺癌临床诊治提供新思路。