轉(zhuǎn)移是臨床上成功治療胃癌的一大障礙,，大多數(shù)胃癌患者的死亡率與轉(zhuǎn)移密切相關(guān)。近來(lái),，microRNAs通過(guò)調(diào)控多種信號(hào)通路已成為影響轉(zhuǎn)移的關(guān)鍵因子。
近日，刊登在Oncogene雜志上的一項(xiàng)研究證實(shí)在高轉(zhuǎn)移性胃癌細(xì)胞株和腫瘤轉(zhuǎn)移組織中miR-7的表達(dá)都顯著下調(diào),。上調(diào)和降低其表達(dá)的兩項(xiàng)實(shí)驗(yàn)表明，miR-7表達(dá)的增加能降低胃癌細(xì)胞的遷移和侵襲能力,，而miR-7表達(dá)的降低能顯著增強(qiáng)腫瘤細(xì)胞的遷移和侵襲能力,。
在體內(nèi)轉(zhuǎn)移實(shí)驗(yàn)研究中，過(guò)表達(dá)miR-7顯著抑制胃癌轉(zhuǎn)移,。此外,，胰島素樣生長(zhǎng)因子1受體（IGF1R）基因人癌癥患者中經(jīng)常發(fā)生突變或過(guò)表達(dá)，IGF1R是一個(gè)重要的細(xì)胞生長(zhǎng)和腫瘤浸潤(rùn)調(diào)節(jié)因子,，研究證實(shí)IGF1R是miR-7的直接作用靶蛋白,。
研究人員使用siRNA沉默IGF1R的表達(dá),，miR-7具有抗腫瘤轉(zhuǎn)移潛能，而恢復(fù)IGF1R的表達(dá)會(huì)抑制胃癌細(xì)胞中miR-7的功能,。
此外,，該研究還證實(shí)miR-7通過(guò)靶向作用于IGF1R抑制Snail，進(jìn)而增加E-鈣粘素的表達(dá),，部分逆轉(zhuǎn)上皮間質(zhì)轉(zhuǎn)化（EMT）,。最后胃癌淋巴結(jié)轉(zhuǎn)移組織芯片數(shù)據(jù)分析發(fā)現(xiàn)胃癌中miR-7表達(dá)與IGF1R的表達(dá)呈負(fù)相關(guān)性。這項(xiàng)研究揭示了miR-7對(duì)腫瘤轉(zhuǎn)移生物學(xué)行為的影響,，理解miR-7/IGF1R/Snail信號(hào)軸將有助于開(kāi)發(fā)一種新的治療方法來(lái)治療胃癌轉(zhuǎn)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
