耐药是导致结肠癌化疗失败最主要的原因，严重阻碍化疗方案的实施，寻找新的生物学标记从而实现个体化治疗结肠癌刻不容缓。我们前期工作发现：miR-19a在结肠癌组织中高表达；miR-19a显著降低结肠癌细胞对奥沙利铂的药物敏感性；miR-19a的靶基因是TP53INP1；在奥沙利铂耐药细胞株中miR-19a表达显著增加，TP53INP1蛋白表达明显下降。我们推测miR-19a通过调节TP53INP1影响结肠癌对奥沙利铂药物敏感性。本研究通过慢病毒介导载体研究miR-19a对药物敏感性的影响；利用悬液芯片及2-D凝胶电泳技术，从miRNA及蛋白层面阐明肿瘤细胞的耐药机制；建立移植瘤动物模型观察奥沙利铂对移植瘤的作用；临床观察miR-19a及TP53INP1对术后化疗的影响。本项目旨在通过对miR-19a系统研究，深入探讨miR-19a对奥沙利铂药物敏感性的影响，为临床结肠癌治疗提供新的思路。

Colon cancer(CC) is one of the most common types of malignant tumors in the western world, so is in China. Oxaliplatin-based chemotherapy is a major protocol for CC therapy in both adjuvant and metastatic setting. However, resistance to chemotherapeutic reagents is the most challenging issue in the treatment of CC, leading to relapse and poor patient prognosis. Therefore, discovering novel biomarkers for CC treatment is crucial to realize the aim of personalized medicine.The development of drug resistance is often a multifactor process, which involves multiple genetic and cellular mechanisms. microRNAs (miRNAs) are endogenous small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. miRNAs regulate a large number of genes by interacting with complementary sites in the 3'untranslated region (3'UTR) of target genes. Currently, extensive studies have indicated that the acquisition of drug resistance by cancer cells may also be modulated via the changes in miRNA levels. In various types of cancers, many miRNAs are differently expressed and can serve as either oncogenes or tumor suppressors. Our previous studies have demonstrated that miR-19a was highly expressed in colon cancer tissue; miR-19a could significantly reduce the sensitivity of colon cancer cells to oxaliplatin; the target gene of miR-19a was TP53INP1; in the oxaliplatin-resistant cell line miR-19a was highly expressed and TP53INP1 expression was reduced. The hypothesis of our study is that miR-19a may reduce the sensitivity to oxaliplatin for colon cancer by targeting TP53INP1. We will investigate the impact of miR-19a on the sensitivity to oxaliplatin via lentiviral vectors; explore the mechanism of oxaliplatin resistance in the level of miRNA and proteins by the suspension array system and 2-D gel chromatography; construct an animal model to observe the influence of oxaliplatin on the implanted tumor; and investigate the impact of miR-19a and TP53INP1 on colon cancer patients after surgery. We aim to provide a new clue for the treatment of oxaliplatin resistance by serial investigations of the impacts and mechanisms of miR-19a on oxaliplatin sensitivity.