miR-409-3p通过多靶基因抑制结直肠癌转移的分子机制

The clinical outcome and prognosis of colorectal cancer is largely restricted by its metastasis. However, its mechanism has not yet been fully understood. MiRNAs are proven to regulate tumor metastasis. In our previous study, we have found: 1) miR-409-3p targets angiogenin, a tumor metastasis related protein; 2) this miRNA was down-regulated in colorectal cancer and correlated with tumor metastasis after analyzing 79 cases of clinical samples; 3) miR-409-3p inhibited cell migration when it was overexpressed in colorectal cancer cells; 4) three new targets of this miRNA were identified in colorectal cancer cells, which are involved in tumor metastasis. To explore the role and mechanism of miR-409-3p in colorectal cancer metastasis, we plan to first confirm the association of miR-409-3p expression with colorectal cancer metastasis by expanding the number of clinical tissue samples, then validate the regulatory role of miR-409-3p in colorectal cancer metastasis in both cell assays and mouse models. Considering that this miRNA might play its role through multiple targets, we will systematically screen its metastasis-related targets and reveal the down-stream signal pathways by combining protein microarray and bioinformatics analysis. We believe this project will fully elucidate the role of miR-409-3p in colorectal cancer metastasis and its underlying mechanism, which will provide new clues for developing new diagnosis and/or treatment approaches for metastatic colorectal cancers.

结直肠癌转移是制约其临床治疗效果和预后的关键因素，但其分子机制尚未完全阐明。已有证据显示miRNAs可以调控肿瘤转移。在本项目组对miR-409-3p的前期研究中，发现它可以靶向下调肿瘤转移相关蛋白angiogenin；对79例结直肠癌临床标本的分析显示，该miRNA表达下调，与癌转移存在一定相关性；高表达miR-409-3p可抑制结直肠癌细胞迁移；初步鉴定了其与结直肠癌转移相关的3个新靶基因。本项目拟扩大临床样本量，明确miR-409-3p与结直肠癌转移的相关性及其临床意义；在细胞和动物水平确证miR-409-3p对结直肠癌转移的抑制作用；同时，利用蛋白质芯片结合生物信息学方法全面筛选miR-409-3p调控结直肠癌转移的靶基因，并深入分析对相关信号通路的影响。通过以上研究，本项目将系统揭示miR-409-3p抑制结直肠癌转移的分子机制，为发展转移性结直肠癌诊断和治疗新方法打下基础。

转移是导致结直肠癌（CRC）患者死亡的主要原因，但其具体机制尚未阐明；miRNAs可以通过转录后水平调控基因表达而影响CRC转移过程。因此，明确CRC转移中的关键miRNAs并阐明其分子通路，不仅有助于全面了解CRC转移的具体机制，还能为转移性CRC的早期诊断和干预治疗等提供新线索。为此，我们设计并完成了本项目研究，并取得以下结果：1）miR-409-3p在CRC中表达下调，并与CRC转移发生呈负相关性；2）miR-409-3p通过抑制CRC细胞的迁移和侵袭能力而调控CRC转移；3）下调GAB1表达是miR-409-3p抑制结直肠癌细胞转移的重要途径；4）受miR-409-3p靶向调控的ANG可通过剪切tRNA产生tiRNA而促进细胞迁移。我们的研究成果将为转移性CRC早期诊断和干预治疗新方案提供新的切入点。通过本项目研究，已发表论文8篇，包括4篇SCI收录论文，培养博士后2名、博士研究生3名，圆满完成原计划的研究目标和预期指标。