环状RNA circIPO7在鼻咽癌转移中的作用和分子机制研究

Distant metastasis is the main reason for the treatment failure of nasopharyngeal carcinoma (NPC). Finding the crucial molecules underlying NPC metastasis is the key to effectively screen high-risky patients for NPC individualized treatment and eventually reduce metastasis rate. Circular circRNAs has been found to play an important role in tumor metastasis. Our previous study found that firstly circIPO7 was obviously upregulated in NPC cell lines with high metastatic potential and tissues with distant metastasis. Knocking-down of circIPO7 could inhibit NPC cell migration and invasion. Moreover, circIPO7 could bind with miR-1287, and silencing miR-1287 could reverse the decreased migration ability of the sicircIPO7 in NPC cells. However, the detailed mechanism remains unknown. In 80 clinical samples, we found that patients with high circIPO7 expression showed poorer distant-metastasis free survival. On the basis of the preliminary results, we will study the function and mechanism of circIPO7 in NPC metastasis through in vitro and in vivo functional experiments and target genes searching. We will also examine the expression level of circIPO7 in 350 NPC clinical samples, evaluate the predictive value of circIPO7 in NPC metastasis and prognosis. Through this project, it could provide new prognostic markers and molecular targets for individual classification and treatment of nasopharyngeal carcinoma.

远处转移是鼻咽癌治疗失败的主要原因，发现鼻咽癌转移的关键分子，有效筛选高风险患者开展个体化治疗，是进一步提高疗效的关键。环状circRNAs被发现在肿瘤进展中起重要作用，我们的前期发现：①circIPO7在高转移潜能鼻咽癌细胞株和发生远处转移鼻咽癌组织中表达升高，敲减circIPO7表达可抑制鼻咽癌细胞的迁移和侵袭能力；circIPO7可与miR-1287结合，且敲减circIPO7后回补miR-1287 的抑制剂可逆转鼻咽癌细胞迁移的抑制作用，但具体机制不详；②小样本量检测发现circIPO7高表达与无远处转移生存差相关。本项目拟开展以下研究：①通过体内外功能、分子实验及下游靶点的筛选与验证，阐明circIPO7在鼻咽癌转移中的功能和机制；②检测350例鼻咽癌组织中circIPO7的表达水平，明确其在鼻咽癌远处转移和预后中的价值，为鼻咽癌个体化治疗提供新的预后分子和治疗干预靶点。

远处转移是制约鼻咽癌疗效提高的关键原因，因此亟需探索鼻咽癌转移的分子机制、鉴定转移的关键分子指导转移风险预测和个体化治疗。在本课题的资助下，我们课题组取得了如下成果：①阐明了环状RNA circIPO7结合YBX1蛋白促进其核转运从而导致鼻咽癌转移和顺铂化疗抵抗的分子机制，以及circCRIM1内源性竞争结合miR-422a解除其对FOXQ1的抑制从而导致鼻咽癌患者转移和多西他赛化疗抵抗的分子机制，为鼻咽癌抗转移和耐药治疗提供潜在分子靶点；②发现了circIPO7、circCRIM1高表达的鼻咽癌患者具有较高远处转移风险且化疗耐药，与不良预后相关，为鼻咽癌的转移风险预测提供潜在分子指标。申请人以最后通讯/共同通讯作者身份已发表SCI收录论文2篇，包括Mol Cancer和J Immunother Cancer杂志。