Clip170/Lis1介导肾癌索拉非尼耐药及其在三氧化二砷逆转耐药中的分子机制

转移性肾细胞癌恶性程度高，预后差，索拉非尼作为一线药物被广泛应用，但用药6-15个月会出现耐药现象。前期研究表明Clip170在转移性肾癌组织高表达且与不良预后相关，过表达Clip170可增加转移性肾癌细胞血管生成能力，为肾癌远处转移提供“绿色通道”，同时促进侵袭性伪足小体形成，增加转移能力。由此推测：Clip170以锌指结构特异性结合Lis1，分别通过MGP/VEGF和Cortactin/MT1-MMP信号通路促进肾癌相关血管生成和侵袭性伪足形成，三氧化二砷通过干扰Clip170/Lis1复合体的锌指结构而逆转上述过程。为此，本项目拟用索拉非尼耐药性肾癌细胞系和转移性肾癌组织芯片，深入研究Clip170介导索拉非尼靶向治疗耐药的分子机制，并结合活组织切片离体培养、肾癌类器官和人源肿瘤异种移植模型等临床前模型验证针对三氧化二砷增强索拉非尼抗转移性肾癌治疗有效性，为治疗转移性肾癌提供新思路。

Metastatic renal cell carcinoma is one of the most lethal urinary malignancies, largely due to the advanced stage at diagnosis. Sorafenib is widely used as a first-line drug, but drug resistance occurs after 6-15 months of treatment, and there is no effective targeted therapy for these patients currently. We found that Clip170 was not only highly expressed in advanced renal cell carcinoma, but also associated with poor prognosis. In sorafenib-resistant renal cancer cells with high invasive ability, overexpression of Clip170 could increase angiogenic capacity and MMP2/9 content which provided a "expressway" for distant metastasis, and promote formation of invadopodia which increased the ability of invasion and transfer. In current study, we proposed to investigate if Clip170 binding to zinc finger structure of Lis1 complex affected formation of tumor-associated vascular and invadopodia through MGP/VEGF and Cortactin/MT1-MMP signaling pathways, respectively. Moreover, arsenic trioxide could reverse the above process by interfering with the zinc finger structure in the Clip170/Lis1 complex. Herein, using the sorafenib-resistant renal cell carcinoma cell line and clinically resistant advanced renal cell carcinoma tissue microarray, we propose to investigate molecular mechanisms by which Clip170 confers resistance to sorafenib-targeted therapy. We will also integrate preclinical models, including renal cancer cell lines, patient-derived xenografts, ex vivo explant culture model as well as organoid models, to evaluate the therapeutic effects of arsenic trioxide. The current study aims to identify effective therapeutic strategies that overcome resistance to sorafenib treatment.