表皮生长因子受体的单克隆抗体——cetuximab（西妥昔单抗，简称C）在KRAS基因野生型转移性结直肠癌的靶向治疗中有好的疗效，但临床研究发现仍有部分该类肠癌患者对C耐药，且机制未明。在前期工作中，本课题组利用C耐药的肠癌组织及肠癌细胞株进行lncRNA芯片筛查并结合大样本验证，原创性地鉴定了1个与C耐药相关的lncRNA，即lncRNA-AC006159.3(简称A)。信息学分析发现其邻近存在c-Met 编码基因，而后者已被证实与C耐药存在关联；我们后续工作进一步提示A可通过上调c-Met介导C在肠癌治疗中的耐药。在此基础上，本项目拟重点研究A调控c-Met的精细机制，从直接相互作用或通过中间蛋白调节来系统探讨其调控形式，以阐明A介导c-Met影响C耐药的分子途径。本研究将有助于从lncRNA 角度深入理解C在肠癌中耐药的分子机制，为预测抗EGFR靶向治疗效果及逆转耐药提供新思路。

Cetuximab is an epidermal growth factor receptor (EGFR) monoclonal antibody, and cetuximab combined therapy has been approved to bring a favorable effect on survival or tumor response in the patients with KRAS wild-type metastatic colorectal cancer (mCRC). However, still a subset of mCRC patients exhibit either de novo or acquired resistance to cetuximab-based therapy with unknown mechanisms. In our preliminary work, by using lncRNA array for screen and test in samples of mCRC with cetuximab resistance, we found one novel lncRNA, named with lncRNA-AC006159.3. This down-expressed lncRNA could promote CRC cell acquired resistance to cetuximab, which had been tested and verified in cell and nude mice. Moreover, we found a known coding gene-c-Met, associated with cetuximab-resistance, was adjacent to lncRNA-AC006159.3. Our preliminary work further showed that thus lncRNA might play a key role in cetuximab-resistance by promoting the expression of c-Met gene. On the above base, this project aimed to study the mechanism of how the lncRNA-AC006159.3 regulate the c-Met, where two way would be designed: one way is the lncRNA-AC006159.3 may directly link up with SPARC; the other w ay is the lncRNA-AC006159.3 may first recruit one median protein, then together combine with c-Met and adjust the expression. This study could help not only to rich the mechanism of cetuximab-resistance, but also to establish a theoretical basis of conquer the cetuximab resistance based on lncRNA.