PDGF-BB/PDGFR-β介导口腔鳞癌细胞诱导成纤维细胞重编程活化为癌相关成纤维细胞的作用及机制

In the process of tumor development，interactions between tumor cells and stromal cells are focused. Compared with normal fibroblasts, stromal fibroblasts in carcinoma named carcinoma-associated fibroblasts are in the activation state. But the activation mechanism is still unclear. Our previous study found that fibroblasts can be induced activation by oral squamous cell carcinoma cells and it was closely related with PDGF-BB/PDGFR-β axis. For this study, a co-cultured model between oral squamous cell carcinoma cells and fibroblasts will be established to explore reprogramming normal fibroblasts into carcinoma-associated fibroblasts by oral carcinoma cells through PDGF-BB/PDGFR-β axis and the feedback effect of carcinoma-associated fibroblasts on carcinoma cells. Related signal transduction pathways and key factors will be detected with chip technology. The related factors which inhibit fibroblast activation and reverse features of carcinoma-associated fibroblasts will be analyzed through function gain or loss. Associated factors will be detected in clinical specimens of oral tongue squamous cell carcinoma. Through the above study, we will define the role of PDGF-BB in fibroblast activation and identify the relevant signaling molecules, interpret the molecular mechanisms of carcinogenesis, reveal the intrinsic relationship between the carcinoma cells and stromal cells, and explore a new way to revere carcinoma invasion and metastasis through antagonism and intervention of PDGF-BB/PDGFR-β axis signal pathway.

肿瘤演进过程中，肿瘤细胞与基质细胞的相互作用备受关注。与正常成纤维细胞相比，肿瘤基质成纤维细胞即癌相关成纤维细胞处于活化状态，但其活化机制尚不全明了。我们前期研究发现口腔鳞癌细胞能诱导成纤维细胞活化，并与血小板衍生生长因子PDGF-BB/受体PDGFR-β密切相关。本研究拟通过建立口腔鳞癌细胞与成纤维细胞共培养模型，探索PDGF-BB/PDGFR-β介导癌细胞诱导成纤维细胞重编程活化为癌相关成纤维细胞及其对癌细胞的反哺作用；芯片检测等分析相关信号转导途径的活性状态及关键节点；功能获得或缺失分析相关因子抑制成纤维细胞活化及逆转癌相关成纤维细胞特性的作用；并行口腔舌鳞癌临床标本检测验证。明确PDGF-BB诱导成纤维细胞活化的作用及调节因子，从基质角度阐明肿瘤演进机理并诠释癌细胞与基质成纤维细胞的内在关系及其分子事件，为探索通过干预PDGF-BB/PDGFR-β通路逆转肿瘤侵袭转移奠定基础。

肿瘤演进过程中，肿瘤细胞与基质细胞的相互作用备受关注。与正常成纤维细胞相比，肿瘤基质成纤维细胞即癌相关成纤维细胞处于活化状态，但其活化机制尚不全明了。本研究在蛋白芯片检测筛选口腔癌细胞与正常口腔黏膜角化细胞差异分泌PDGF-BB因子的基础上，通过建立口腔鳞癌细胞与成纤维细胞共培养模型，探索了PDGF-BB/PDGFR-β介导癌细胞诱导成纤维细胞重编程活化为癌相关成纤维细胞及其对癌细胞的反哺作用；芯片检测等分析了相关信号转导途径的活性状态及关键节点；功能获得或缺失分析了相关因子抑制成纤维细胞活化及逆转癌相关成纤维细胞特性的作用；并行口腔舌鳞癌临床标本检测验证。结果发现：PDGF-BB是口腔黏膜成纤维细胞活化关键诱导因子，其可能通过与其受体PDGFR-β结合，下调miR-26a-5p表达，解除miR-26a-5p对TAB3靶向抑制作用，从而激活NF-κB信号通路，诱导成纤维细胞活化；PDGF-BB/PDGFR-β在口腔鳞状细胞癌组织中高表达，是诱导成纤维细胞活化为癌相关成纤维细胞的一个重要因素，可能是影响口腔鳞状细胞癌发生颈淋巴结转移的因素之一。研究首次从PDGF-BB/受体PDGFR-β角度探索了口腔鳞癌发生发展机制，明确了癌细胞源性的PDGF-BB诱导成纤维细胞活化的作用、相关信号通路及关键调节因子，从肿瘤细胞的“教育”诱导作用角度诠释了肿瘤演进的分子机制，揭示和证实了癌细胞与癌相关成纤维细胞的内在关系，为肿瘤防治提供了新的靶点。