经西妥昔单抗靶向治疗后高发的获得性耐药是导致转移性结直肠癌（mCRC）患者预后不良的重要原因。课题组前期研究发现miR-196b在耐药后肿瘤组织中的表达显著低于治疗前，获得性耐药的结肠癌细胞中miR-196b水平显著低于其原始细胞，而QKI-5及GATA6水平显著高于其原始细胞，改变miR-196b水平可影响细胞对西妥昔单抗的敏感性，GATA6是miR-196b的靶基因。鉴此，提出“QKI-5抑制miR-196b表达，使GATA6水平上调，激活Wnt/β-catenin信号通路介导mCRC西妥昔单抗获得性耐药”的假说。本项目拟研究miR-196b对提高西妥昔单抗抑瘤效果的作用及机制，关注miR-196b下调所致Wnt/β-catenin信号活化，探究提高miR-196b水平逆转西妥昔单抗获得性耐药的可行性。课题将进一步揭示西妥昔单抗获得性耐药的分子机制，为治疗mCRC提供新的药物靶点。

High incidence of acquired cetuximab resistance is an important cause of poor prognosis in patients with metastatic colorectal cancer (mCRC). Our previous work identified that the expression of miR-196b was significantly lower in tumor tissue after acquired cetuximab resistance than that before cetuximab treatment. The levels of miR-196b in two colon cancer cell lines with acquired cetuximab resistance were significantly lower than those of their original cell lines. While the levels of QKI-5 and GATA6 in cells with acquired cetuximab resistance were significantly higher than those of their original cells. Regulating the expression of miR-196b significantly affected the sensitivity of colon cancer cells to cetuximab. We also found that the GATA6 transcription factor is a target of miR-196b. Based on these, the hypothesis was proposed that QKI-5 can inhibit the expression of miR-196b, leading to the increased expression of GATA6, which can activate Wnt/β-catenin signaling pathway and mediate acquired resistance to cetuximab. This project aims to study the effect and mechanism of miR-196b increasing the inhibition of cetuximab on cell proliferation, focus on Wnt/β-catenin signaling pathway activation caused by the down regulation of miR-196b, and then explore the feasibility of reversing the acquired cetuximab resistance in mCRC, and provide a new drug target for mCRC treatment.