自分泌胞外基质Serglycin上调其受体CD44以正反馈环方式维持鼻咽癌细胞干性

Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in Southern China. Approximately 30% of the patients will develop relapse and distant metastases after radiotherapy and chemotherapy, it’s the main clinical problem. Cancer stem cells established the biological foundation for tumor initiation, therapy resistance, relapse and metastasis, including extracellular matrix (ECM) which is one part of tumor microenvironment also plays an important role in maintaining the stemness characteristics. We performed genome-wide expression profiling of clinical samples and found ECM remodeling pathway was closely related to NPC. We also established the highly metastatic S18 cells and lowly metastatic S26 cells and performed genomic expression profiling, found that secreted serglycin promoted EMT and metastasis as an ECM gene, and it significantly correlated with poor prognosis. The NPC stem cell biomarker CD44 was the receptor of serglycin and we have preliminarily observed that serglycin upregulated its receptor CD44 dependent on activating β-catenin signaling pathway . So we speculate that autocrine proteoglycan can constitute tumor microenvironment and activate stem cell signaling pathways by recognizing the receptor CD44, as a result, it maintains the stemness characteristics through a positive feedback and promotes tumor progression. The project bases on the theory and techniques of cancer stem cells, and further explores the autocrine serglycin as microenvironment ECM how to influence its stem characteristics and differentiation phenotype. We also intend to investigate the molecular mechanism and clinical significance that serglycin/CD44 axis maintains the stemness characteristics, in order to establish the theoretical foundation of targeted treatment of nasopharyngeal carcinoma stem cells and prevention of recurrence and distant metastasis.

鼻咽癌高发于我国华南地区，约30%病人放化疗后复发转移是目前临床所遇到的主要问题，肿瘤干细胞奠定肿瘤启动、治疗抗性及复发转移的细胞生物学基础，包括胞外基质ECM在内的肿瘤微环境在维持干性特征方面起关键作用。我们芯片筛查临床样本发现ECM再造与鼻咽癌密切相关，并利用我们建立的高、低转移单克隆细胞株S18及S26，筛选到一个自分泌的促进EMT及转移的ECM基因Serglycin并与预后差相关，而鼻咽癌干细胞表面标志物CD44为该基因的候选受体，预实验发现Serglycin上调β-catenin依赖的CD44的表达。我们推测该自分泌蛋白多糖构成细胞ECM微环境并与CD44受体识别激活干细胞信号通路，正反馈调节维持干性特征促进肿瘤进展。本项目深入探讨ECM启动的自动调节轴Serglycin/CD44在NPC干性维持的信号通路等分子机制及临床意义，为靶向鼻咽癌干细胞治疗、预防复发及转移奠定理论基础。

鼻咽癌高发于我国华南地区，约30%病人放化疗后复发转移是目前临床所遇到的主要问题，肿瘤干细胞奠定肿瘤启动、治疗抗性及复发转移的细胞生物学基础，包括胞外基质ECM在内的肿瘤微环境在维持干性特征方面起关键作用。我们芯片筛查临床样本发现ECM再造与鼻咽癌密切相关，并利用我们建立的高、低转移单克隆细胞株S18及S26，筛选到一个自分泌的促进EMT及转移的ECM基因Serglycin并与预后差相关，而鼻咽癌干细胞表面标志物CD44为该基因的候选受体，预实验发现Serglycin上调β-catenin依赖的CD44的表达。我们推测该自分泌蛋白多糖构成细胞ECM微环境并与CD44受体识别激活干细胞信号通路，正反馈调节维持干性特征促进肿瘤进展。本项目深入探讨ECM启动的自动调节轴Serglycin/CD44在NPC干性维持的信号通路等分子机制及临床意义，为靶向鼻咽癌干细胞治疗、预防复发及转移奠定理论基础。