CCBE1蛋白介导肿瘤相关成纤维细胞调节甲状腺癌增殖与侵袭转移分子机制的研究

肿瘤微环境对肿瘤发生发展有着重要影响，但在甲状腺癌中研究甚少。本课题组着眼于肿瘤微环境前期报道了肿瘤相关巨噬细胞调节甲状腺乳头状癌(PTC)的机制。本项目拟针对微环境中另一组分肿瘤相关成纤维细胞(CAF)，利用成熟的微环境研究平台和丰富的临床资源，阐明CAF在甲癌中的作用及其与肿瘤细胞互作的分子机制。我们前期发现α-SMA阳性CAF在PTC中显著增高，且与侵袭性正相关；CAF促进PTC细胞增殖和侵袭，且TSH对CAF有调节作用；进一步通过全基因组表达谱及分泌蛋白谱分析筛选出CAF特异的高分泌蛋白CCBE1。本研究拟通过细胞实验、裸鼠甲状腺原位种植肿瘤模型及CCBE1成纤维细胞特异敲除小鼠阐明CCBE1对PTC增殖侵袭的作用，鉴定肿瘤细胞中受CCBE1调节的下游途径及可能受体，探讨CCBE1受肿瘤细胞及TSH调节的机制，评估CCBE1与临床病理及预后的相关性，为寻找新的诊断治疗靶点提供线索。

The tumor micro-environment (TME) plays an important role in the development process of cancers, while its effects in thyroid cancers are largely unknown. In our previous work, we revealed the relationship between tumor-associated macrophage (TMA) and lymph node metastasis in papillary thyroid cancer. In this study, we focus on the cancer-associated fibroblasts (CAF), another important factor in TME. We will use our well-built platform for TME research and the clinical resources to analyze the molecular mechanism of interaction between CAF and cancer cell. We found that ɑ-SMA+ fibroblasts were associated with the clinic pathological characteristics of papillary thyroid cancer (PTC) and CAF facilitated PTC cell proliferation and invasion both in vivo and in vitro. Moreover, TSH has effect on CAF. An extracellular matrix (ECM) protein CCBE1 was further identified as the molecule link between CAF and cancer cell via whole-genome expression profiles. We will try to reveal the molecule mechanism of CCBE1 mediating interaction between CAF and cancer cells and related downstream pathway through cell lines and mice. Moreover, whether CCBE1 mediated the effect of TSH on tumor cells will be analyzed. The research can provide clues for targets of prognosis and therapy.