奥沙利铂为主的化疗方案是晚期结直肠癌的主要治疗手段，但如何筛选优势人群给予个体化治疗，并通过对耐药机制的深入研究有效逆转耐药，对于提高其临床治疗效果具有重要意义。我们在前期工作中筛选出与奥沙利铂敏感性相关的一组血清miRNA，并发现其中miR-661通过影响切除修复交叉互补基因（ERCC1）参与了奥沙利铂耐药的形成。本项目拟扩大样本量验证前期所筛选的血清miRNA，得到一组稳定差异表达的结直肠癌奥沙利铂化疗疗效相关的血清miRNA；并通过临床标本检测以及体内外实验，验证miR-661在奥沙利铂耐药中的作用及其机制，进一步探索有效的调控手段以逆转耐药。通过本项目的研究，能够建立奥沙利铂治疗优势人群筛选的分子标志物和预测模型，并阐明miRNA参与奥沙利铂耐药的作用机制，建立有效的调控手段，为提高晚期结直肠的治疗效果奠定理论基础。

Oxaliplatin-based chemotherapy regimen is the main treatment for advanced colorectal carcinoma (CRC), however, CRC patients initially respond to oxaliplatin-based chemotherapy ultimately will develop progressive disease because of drug resistance. Therefore, how to select the potentially responsive population to provide individualized therapy and effectively reverse drug resistance to oxaliplatin is crucial for the improvement of clinical therapeutic efficacy. Our previous study identified a group of serum miRNAs which is closely related with chemosensitivity to oxaliplatin, moreover, we found that miR-661 was involved in the drug resistance to oxaliplatin by regulation of excision repair cross-complementation group 1 (ERCC1). In order to further understand the mechanism of drug resistance to oxaliplatin and the function of related miRNAs, our project will increase sample sizes to validate these serum miRNAs, and then to obtain a group of serum miRNA which is related with oxaliplatin therapeutic efficacy but differentially expressed between patients who were identified as chemosensitive and chemoresistant. Subsequently, with clinical sample detection and in vivo and in vitro experiment, we will investigate if miR-661 could induce oxaliplatin resistance by regulation of ERCC1 to inhibit the covalent cross-linking between oxaliplatin and DNA. And further to explore effective method for reversing drug resistance. Taken together, with this project we would establish the bimarkers and predictive model for oxaliplatin treatment responsive population, and to elucidate the mechanism of miRNA involved in resistance to oxaliplatin, hopefully to find an effective approach to regulate the process, and therefore provide the theoretical base for the improvement of advanced colorectal carcinoma treatment.