Oncogene：microRNA-7促进胃癌转移的机制

转移是临床上成功治疗胃癌的一大障碍，大多数胃癌患者的死亡率与转移密切相关。近来，microRNAs通过调控多种信号通路已成为影响转移的关键因子。

近日，刊登在Oncogene杂志上的一项研究证实在高转移性胃癌细胞株和肿瘤转移组织中miR-7的表达都显著下调。上调和降低其表达的两项实验表明，miR-7表达的增加能降低胃癌细胞的迁移和侵袭能力，而miR-7表达的降低能显著增强肿瘤细胞的迁移和侵袭能力。

在体内转移实验研究中，过表达miR-7显著抑制胃癌转移。此外，胰岛素样生长因子1受体（IGF1R）基因人癌症患者中经常发生突变或过表达，IGF1R是一个重要的细胞生长和肿瘤浸润调节因子，研究证实IGF1R是miR-7的直接作用靶蛋白。

研究人员使用siRNA沉默IGF1R的表达，miR-7具有抗肿瘤转移潜能，而恢复IGF1R的表达会抑制胃癌细胞中miR-7的功能。

此外，该研究还证实miR-7通过靶向作用于IGF1R抑制Snail，进而增加E-钙粘素的表达，部分逆转上皮间质转化（EMT）。最后胃癌淋巴结转移组织芯片数据分析发现胃癌中miR-7表达与IGF1R的表达呈负相关性。这项研究揭示了miR-7对肿瘤转移生物学行为的影响，理解miR-7/IGF1R/Snail信号轴将有助于开发一种新的治疗方法来治疗胃癌转移。

doi:10.1038/onc.2012.156
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MicroRNA-7 functions as an anti-metastatic microRNA in gastric cancer by targeting insulin-like growth factor-1 receptor.

Zhao X, Dou W, He L, Liang S, Tie J, Liu C, Li T, Lu Y, Mo P, Shi Y, Wu K, Nie Y, Fan D.

Metastasis is a major clinical obstacle in the treatment of gastric cancer (GC) and it accounts for the majority of cancer-related mortality. MicroRNAs have recently emerged as regulators of metastasis by acting on multiple signaling pathways. In this study, we found that miR-7 is significantly downregulated in highly metastatic GC cell lines and metastatic tissues. Both gain-of-function and loss-of-function experiments showed that increased miR-7 expression significantly reduced GC cell migration and invasion, whereas decreased miR-7 expression dramatically enhanced cell migration and invasion. In vivo metastasis assays also demonstrated that overexpression of miR-7 markedly inhibited GC metastasis. Moreover, the insulin-like growth factor-1 receptor (IGF1R) oncogene, which is often mutated or amplified in human cancers and functions as an important regulator of cell growth and tumor invasion, was identified as a direct target of miR-7. Silencing of IGF1R using small interefering RNA (siRNA) recapitulated the anti-metastatic function of miR-7, whereas restoring the IGF1R expression attenuated the function of miR-7 in GC cells. Furthermore, we found that suppression of Snail by miR-7, through targeting IGF1R, increased E-cadherin expression and partially reversed the epithelial-mesenchymal transition (EMT). Finally, analyses of miR-7 and IGF1R levels in human primary GC with matched lymph node metastasis tissue arrays revealed that miR-7 is inversely correlated with IGF1R expression. The present study provides insight into the specific biological behavior of miR-7 in EMT and tumor metastasis. Targeting this novel miR-7/IGF1R/Snail axis would be helpful as a therapeutic approach to block GC metastasis