microRNA-214在结直肠癌肝转移中的作用及机制研究

The liver is the most common site of distant metastasis from colorectal cancer and parts of the colorectal cancer metastasis only occurred in liver. However, the mechanism of the liver metastasis of colorectal cancer is still not clear. We compared primary cancer tissues and liver metastasis tissue in 16 colorectal cancer patients by miRNA array, and the expression of miR-214 was significantly decreased in the liver metastasis tissues compared with their relatively primary cancer tissues. We confirmed the result by q-PCR in other pairs of frozen tissues of 11 cases. At the same time,we found that miR-214 may be relative with the metastasis tested by our preliminary experiments. In this project, we plan to ① explore the role and mechanism of miR-214 in liver metastasis of colorectal cancer in vitro; ② study the role of miR-214 in liver metastasis of colorectal cancer in vivo by the model of liver metastasis of colorectal cancer in mice; ③ analyze the clinical data to explore the relationship between the expression of miR-214 or its target genes and the patients clinical prognosis. Understanding the function and contribution of miR-214 to cancer metastasis may provide a new therapeutic strategy for the treatment of human colorectal cancer.

结直肠癌的转移大部分发生在肝脏，更有部分晚期结直肠癌的转移仅限于肝脏，但其原因不明。在匹配的16对结直肠癌原发病灶与肝转移灶组织中，我们进行了miRNAs谱的检测，发现miR-214的表达水平在结直肠癌肝转移灶中较原发灶下调最为明显；且这一结果在另外11对相应组织中得以验证。同时，我们预实验也证实了miR-214与结直肠癌细胞转移负相关。本项目拟深入展开：①在细胞水平进一步明确miR-214在结直肠癌转移中的作用及其机理；②在结直肠癌肝转移动物模型中，验证miR-214的作用和机理；③探讨miR-214及其靶基因的临床意义。本项目的完成，将明确miR-214在结肠癌肝转移中的作用、及其机理和临床意义，可能为结直肠癌肝转移提供新的预测指标和治疗靶点。

本研究的目的在于鉴定出在结直肠癌肝转移中起关键作用的microRNA并阐明其可能的分子机制。我们总共从16对结直肠癌组织（有肝转移和无肝转移）鉴定出39个差异表达的miRNAs，其中的8个microRNA得到了验证。我们进一步在99例（44例有肝转移vs. 55例无肝转移）结直肠癌的组织中检测这些差异表达的miRNA，发现只有miR-214具有显著的差异表达。miR-214在结直肠癌肝转移中表达下调，而且miR-214的低表达与结直肠癌的不良预后显著相关。在结直肠癌细胞中过表达miR-214后可显著抑制细胞生长、迁移和侵袭。进一步的研究表明FGFR1是miR-214作用的下游基因。过表达miR-214后可以下调FGFR1的水平。敲低FGFR1可以模拟miR-214的抑制效果，而FGFR1恢复可以抵消miR-214的抑制效果。并且，miR-214的水平和FGFR1的表达水平呈互相关。结论：miR-214的下调和FGFR1的表达水平呈互相关，这导致了结直肠癌肝转移的发展，miR-214可作为一个预后指标，miR-214-FGFR1调控轴可以作为结直肠癌的靶标。