T/B淋巴细胞上皮样转化在口腔癌肿瘤干细胞发生中的作用及机制研究

Mesenchymal epithelial transformation (MET) is an important step in induced pluripotent stem cells(iPS). Several studies have found that the T and B lymphocytes also have the capacity to be fully reprogrammed, and can differentiate into epithelial cells. Based on our previous studies, we propose the hypothesis: in the chronic inflammatory microenvironment, by partial iPS process and MET, T/B cell reprogramme into a small amount of squamous carcinoma cancer stem cells, and then develope into squamous cell carcinomas. This project developes as following: 1.analyzing the homology between oral squamous cancer cells and the T/B cell lineage through microdissection, Ig/TCR chips etc; 2.exploring the mechanism of T/B cells transformation into epithelial-like cell by bioinformatics analysis on reprogramming-factor-related element in inflammatory microenvironment, up/down regulating the expression and studing the mechanism; 3. designing in vivo and in vitro experiments to analyze the tumor-related characteristics of transformed cells; 4. Developing the targeted tumor treatment strategy to the process of transformation or TCR/BCR tags. By studying the effect of inflammatory microenvironment to the transition of T/B cell to epithelial-like cancer stem cells, the origin of cancer stem cell in oral squamous cel carcinoma and strategies on high specific therapeutic target will be better understood and developed.

间充质上皮转化（MET）是iPS细胞诱导过程中的一个重要反应步骤，近年陆续发现T、B淋巴细胞也具有完全的iPS能力，可分化形成上皮细胞。结合前期的实验结果我们推测：在长期慢性炎症微环境的作用下，T/B细胞发生了部分的重编程，经由MET等过程，在局部微环境的重塑下形成了少量的几个鳞癌肿瘤干细胞，通过克隆增殖发展形成鳞癌。我们拟从以下几方面展开工作: 1.采用显微切割、Ig/TCR芯片等分析口腔鳞癌细胞与T/B细胞谱系的同源性；2.利用生物信息学、过表达/低表达重编程因子相关指标分析炎症微环境诱导的T/B细胞发生上皮样细胞转化的机制；3.体内、体外实验分析转化细胞的肿瘤生物学特性；4.干预转化过程、靶向谱系标记物对肿瘤治疗的可行性及有效性的分析。通过研究炎症微环境对T/B细胞重编程为鳞癌肿瘤干细胞的影响，深化对肿瘤干细胞来源的认识和高效特异性靶向治疗的研究。

肿瘤干细胞（CSCs）是肿瘤细胞中一小群具有无限增殖、自我更新及多分化潜能的细胞。研究表明，口腔鳞癌的启动、发展、侵袭及转移同 CSCs 密切相关。长期慢性炎性微环境刺激对肿瘤干细胞的形成具有重要作用，但是促使“炎癌转化”过程发生的具体分子机制仍不明确；此外T/B等免疫细胞在肿瘤干细胞形成过程中扮演何种角色也不清楚。在本项目中，我们探索了慢性炎性微环境调控口腔鳞癌干细胞的形成的潜在机制；除此之外，我们还探索了肿瘤干细胞与免疫细胞的关系。在已完成的试验中，我们可以得出以下结论：① p-STAT3信号通路参与调控口腔鳞癌肿瘤干细胞的发生；②抑制 p-STAT3活化增加 CD4和CD8 T细胞的数目；③天然免疫重要分子TRAF6的过表达能够增加口腔鳞癌的干性；④炎性因子IL-1β在口腔鳞癌中的水平上调，抑制其产生能够增加 CD4和CD8 T细胞的数目；⑤NLRP3/IL-1β通路的活化能够促进口腔鳞癌肿瘤干细胞的产生。