基于 CTNNB1-miRNA cross-talk 提高口腔鳞癌化疗敏感性的机制

Accumulating data revealed that both Wnt signaling pathway and miRNAs involve in drug resistance. However, the cross talk between CTNNB1 (encode β-catenin) and miRNAs, and their cooperative effects on chemoresistance as well, is unclear. Our previous study showed that the expression of β-catenin and its downstream targets were upregulated in cisplatin-resistance cells. Furthermore, we found that the differentially expressed genes and miRNAs associated with drug resistance were categorized by Wnt pathway, p53, cell adhesion signaling pathway, and so on. These findings suggest that CTNNB1 activation and miRNA alteration attribute to drug resistance in oral squamous cell carcinoma (OSCC). This grant aims to investigate the expression and subcelluar location of CTNNB1, its upstream and downstream miRNAs, and their cross talk in development of resistance. The cooperative effects of CTNNB1 and miRNA on restoring drug sensitivity in OSCC will also be determined both in vitro and in vivo. The successfully fulfill of this study will shed light to mechanisms of chemoresistance, provide novel targets and design targeted therapy corresponding to a specific mechanism.

Wnt信号传导通路和miRNAs与肿瘤耐药密切相关，但有关CTNNB1（编码β-catenin蛋白）与miRNAs的相互调控及其对耐药的影响，目前尚不清楚。本课题组前期研究发现，顺铂耐药细胞中β-catenin及其下游耐药基因表达水平明显升高；进一步研究表明，耐药相关miRNAs与Wnt通路、p53、细胞粘附信号通路等相关；这提示CTNNB1激活与miRNA表达异常很可能是导致口腔鳞癌化疗耐药的重要原因。本项目拟在此基础上，构建体内外耐药研究模型，功能性评价CTNNB1表达及定位改变对口腔鳞癌耐药性的影响，深入探讨CTNNB1与其上、下游耐药相关miRNA的交叉网络表达调控机制以及两者联合协同提高肿瘤化疗敏感的可行性。本项目旨在进一步阐明肿瘤化疗耐药的分子机制，寻找新靶标，并为提高口腔鳞癌化疗敏感性提供理论实验依据。

Wnt信号传导通路和miRNAs与肿瘤耐药密切相关，但有关CTNNB1（编码β-catenin蛋白）与miRNAs的相互调控及其对耐药的影响，目前尚不清楚。本项目在前期工作基础上，成功构建体内、外耐药研究模型，通过系列研究证实β-catenin表达上调及核内转位可促进口腔鳞癌化疗耐药；MG132和bortezomib可调节E-cadherin/β-catenin复合体，导致β-catenin在细胞浆内聚集，增强口腔鳞癌对CDDP的化疗敏感性；筛选获得一批可与β-catenin发生“交互对话”的耐药相关miRNAs，证实miR-218 可调控PPP2R5A-Wnt信号通路，促进口腔鳞癌化疗耐药；初步阐明口腔癌化疗耐药的分子机制，为提高口腔鳞癌化疗敏感性提供了理论实验依据。