IL-6/STAT3转录激活微小RNA-224通过胞内和胞外途径调控胆管癌细胞侵袭转移的分子机制

Interleukin-6(IL-6)/Signal Transduction and Activator 3 (STAT3) involves into the invasion and migration of cholangiocarcinoma cells, but the mechanism is not fully understood. miRNA can regulate the invasion and migration of tumor cell through intracellular and extracellular manners mediated by exosome in tumor microenvironment. However, such exosome-mediated mechanism was not reported in cholangiocarcinoma. In our preliminary studies, we found that the expression of miR-224 was promoted in cholangiocarcinoma cells stimulated by IL-6 in vitro, and the up-regulation of miR-224 can enhance the invasion and migration ability of cholangiocarcinoma cells. It was predicted by bioinformatics analysis that the promoter region of miR-224 contains multiple biding sites for STAT3 and Smad4 is the target gene for miR-224. Accordingly, we proposed our scientific hypothesis that IL-6/STAT3 promotes the miR-224 transcription, inhibits the Smad4 expression, and enhances ability of invasion and migration of cholangiocarcinoma cells. At the same time, miR-224 from cholangiocarcinoma cells can be packed into the exosomes and secreted into the tumor microenvironment, which is uptaken by adjacent tumour cells and regulates their Smad4 expression and metastasis. This project intends to clarify the mechanism how IL-6/STAT3 pathway regulates miR-224 transcription, clear the role of miR-224/Smad4 signaling pathway in the metastasis of cholangiocarcinoma and elaborate the mechanism that miR-224 regulates the invasion and metastasis of cholangiocarcinoma cells by intracellular and extracellular ways. This project is expected to provide a new theoretical basis for the mechanism of invasion and migration of cholangiocarcinoma and potential therapeutic target for treatment of cholangiocarcinoma.

文献表明，IL-6/STAT3参与胆管癌的侵袭转移，机制尚不完全清楚；肿瘤微环境外泌体可介导微小RNA通过胞内外途径调控细胞侵袭转移，但在胆管癌中无报道。本课题前期研究发现IL-6刺激胆管癌细胞可促进miR-224表达进而增强细胞的侵袭转移；信息预测STAT3与miR-224启动子区有结合、Smad4为miR-224的靶基因。据此提出科学假说：IL-6/STAT3促进miR-224转录，从而靶向抑制Smad4而增强胆管癌细胞的侵袭转移。同时，癌细胞中miR-224可通过外泌体到肿瘤微环境中，调控临近癌细胞的侵袭转移。本项目拟阐明IL-6/STAT3调控miR-224转录机制，在细胞和动物水平上明确miR-224/Smad4调控胆管癌侵袭转移作用机制，阐述miR-224通过胞内外途径调控胆管癌侵袭转移机理。本项目有望为胆管癌侵袭转移机制研究提供新的理论依据，为胆管癌治疗提供可能的用药靶点。

IL-6/STAT3参与胆管癌的侵袭转移，机制尚不完全清楚；肿瘤微环境外泌体可介导微小RNA通过胞内外途径调控细胞侵袭转移，但在胆管癌中无报道。本课题前期.研究发现IL-6刺激胆管癌细胞可促进miR-224表达进而增强细胞的侵袭转移；信息预测STAT3与miR-224启动子区有结合、Smad4为miR-224的靶基因。据此提出科学假说：IL-6/STAT3促进miR-224转录，从而靶向抑制Smad4而增强胆管癌细胞的侵袭转移。同时，癌细胞中miR-224可通过外泌体到肿瘤微环境中，调控临近癌细胞的侵袭转移。本项研究在细胞和动物水平上进一步明确了miR-224/Smad4调控胆管癌侵袭转移作用机制，阐述了miR-224通过胞内外途径调控胆管癌侵袭转移机理，验证了miR-244调控胆管癌的靶基因SMAD4，为胆管癌侵袭转移机制研究提供新的理论依据，为胆管癌治疗提供可能的用药靶点。