State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China.
Oncogene. 2013 Mar 14;32(11):1363-72. doi: 10.1038/onc.2012.156. Epub 2012 May 21.
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.
转移是胃癌（GC）治疗中的一个主要临床障碍，它是癌症相关死亡的主要原因。miRNA 最近被发现通过作用于多个信号通路来调节转移。在这项研究中，我们发现 miR-7 在高转移性 GC 细胞系和转移性组织中显著下调。功能获得和功能丧失实验均表明，miR-7 表达增加可显著降低 GC 细胞的迁移和侵袭，而 miR-7 表达减少则可显著增强细胞的迁移和侵袭。体内转移实验也表明，miR-7 的过表达可显著抑制 GC 的转移。此外，胰岛素样生长因子-1 受体（IGF1R）癌基因，其在人类癌症中经常发生突变或扩增，作为细胞生长和肿瘤侵袭的重要调节因子，被鉴定为 miR-7 的直接靶标。用小干扰 RNA（siRNA）沉默 IGF1R 可重现 miR-7 的抗转移功能，而恢复 IGF1R 的表达则减弱了 miR-7 在 GC 细胞中的功能。此外，我们发现 miR-7 通过靶向 IGF1R 抑制 Snail 的表达，增加了 E-钙黏蛋白的表达，并部分逆转了上皮-间充质转化（EMT）。最后，对具有匹配淋巴结转移组织阵列的人类原发性 GC 中 miR-7 和 IGF1R 水平的分析表明，miR-7 与 IGF1R 的表达呈负相关。本研究深入了解了 miR-7 在 EMT 和肿瘤转移中的特定生物学行为。靶向该新型 miR-7/IGF1R/Snail 轴可能有助于作为阻断 GC 转移的治疗方法。
