肿瘤微环境中炎症因子介导Snail调控EMT与口腔黏膜鳞癌侵袭转移机制研究

Most of patients with oral squamous cell carcinoma (OSCC) died of the metastasis or reoccurrence of the tumor. However, key mediating mechanism for invasion and metastasis of this carcinoma is still undefined. Recent researches have been focused on the relationship between cancer-related inflammation microenvironment and invasion and metastasis of carcinoma cells. This study is based on our previous researches from the point of view of tumor microenvironment, in order to determine the inflammatory factors in regulation of epithelial-mesenchymal transition (EMT) in OSCC invasion area promoting invasion and metastasis and further explore the corresponding mechanism. In our study, we constructed an inflammatory microenvironment model for screening key inflammatory factors which regulated cancer cell phenotype transformation, invasion, metastasis and stably expressed snail. Then we studied the possible mechanism of oral carcinoma stable expressing snail and detected whether the effects of this inflammatory microenvironment on cancer phenotype transformation,invasion and metastasis mediated by snail signal. In order to indentify the connections of key inflammatory factors promoting invasion and metastasis and Snail and EMT in vivo,we proceeded to establish the xenograft and metastatic tumor model underlying inflammatory environment. In addition, we collected postoperative tissue samples from OSCC, analyzed the relationship of cell phenotype differentiation and the expression of snail and inflammatory factors in microenvironment, and then further clarified the possible invasion and metastasis mechanism for cancer-related inflammation regulating EMT in cells within invasion area by OSCC. Our researches may provide theoretical and experimental basis for designing more efficient and specific therapeutic method against cancer invasion and metastasis.

口腔黏膜鳞癌（口腔癌）患者多数死于肿瘤的转移或复发，然而其侵袭转移的机制尚不明确。目前，炎症微环境与口腔癌侵袭转移的关系逐渐成为研究热点。本课题在原有研究基础上，从肿瘤微环境角度出发，探讨炎症因子调控口腔癌浸润区发生上皮间质转化（EMT）促其侵袭转移的机制。首先，构建炎症微环境模型，筛选调控癌细胞表型转化、侵袭转移及Snail稳定表达的关键炎症因子。利用炎症微环境模型，研究口腔癌细胞Snail稳定表达的调控机制，检测炎症微环境对癌细胞表型转化、侵袭转移的影响是否通过Snail信号介导。其次，建立炎症环境下口腔癌移植瘤和转移瘤模型，检测关键炎症因子促其侵袭转移与Snail及EMT的关系。最后，以口腔癌临床标本为对象，分析微环境中炎症因子与Snail表达及肿瘤细胞表型转化的关系，进一步阐明炎症微环境调控口腔癌浸润区发生EMT促其侵袭转移的机制，为设计新的抗肿瘤侵袭转移治疗奠定理论和实验基础

口腔黏膜鳞癌（口腔癌）患者多数死于肿瘤的转移或复发，然而其侵袭转移的机制尚不明确。近年来，炎症微环境与口腔癌侵袭转移的关系逐渐成为研究热点。本课题从肿瘤微环境角度出发，体外成功构建了模拟肿瘤细胞生长的炎症微环境，提示肿瘤相关巨噬细胞（TAMs）能诱导口腔癌细胞发生EMT，侵袭转移能力增强，TAMs通过激活NF-κB通路，增加转录抑制因子Twist, Snail及ZEB等的表达诱导EMT发生。同时，在这个过程中，筛选出了关键炎症因子TGF-β和TNF-α，提示TAMs能分泌TGF-β诱导口腔癌细胞发生EMT，侵袭和增殖能力增强，但是随着外源性TGF-β加入后，口腔癌细胞发生EMT能力减弱，侵袭和增殖能力减弱。研究发现TAMs还能分泌TNF-α诱导口腔癌细胞发生EMT，侵袭和增殖能力增强，TNF-α通过促Id2表达调控Snail诱导口腔癌细胞发生EMT，并能激活NF-κB信号通路。在此基础上，以口腔癌临床标本为对象，发现TAMs浸润与EMT密切相关，同时，癌细胞表达CD68和CD163与EMT密切相关。最后，建立了炎症微环境下口腔癌移植瘤和转移瘤的模型，体内探讨炎症微环境与EMT的关系。本研究结果阐述了炎症微环境在促口腔癌浸润区细胞发生上皮-间质转化中的作用及可能机制，丰富了口腔癌侵袭转移的理论机制，为口腔癌治疗方案的选择、预后评估及设计新的抗侵袭转移治疗奠定理论和实验基础。