microRNA-200b and microRNA-200c promote colorectal cancer cell proliferation via targeting the reversion-inducing cysteine-rich protein with Kazal motifs
microRNA-200b and microRNA-200c promote colorectal cancer cell proliferation via targeting the reversion-inducing cysteine-rich protein with Kazal motifs
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DOI：
10.1080/15476286.2015.1017208
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发表时间：
2015-03-01
期刊：
影响因子：
4.1
通讯作者：
Chen, Xi
中科院分区：
文献类型：
--
作者：
Pan, Yi;Liang, Hongwei;Chen, Xi
MicroRNA-200b和microRNA-200c(miR-200b/c)是结直肠癌细胞中表达上调最频繁的两种癌基因。然而，miR-200b/c在结直肠肿瘤发生中的作用尚不清楚。在本研究中，我们报道miR-200b/c可以通过靶向逆转诱导的带有Kazal基序的富含半胱氨酸的蛋白(RECK)来促进结直肠癌细胞的增殖。首先，生物信息学分析预测RECK是miR-200b/c的保守靶点。通过在结直肠癌细胞中过表达或敲除miR-200b/c，我们从实验上证实了miR200b/c是RECK的直接调控因子。其次，在人结直肠癌组织和细胞系中，miR-200b/c和RECK蛋白的表达水平呈负相关。第三，我们证明了miR-200b/c抑制RECK后，在结直肠癌细胞中引起了Skp2(S期蛋白相关蛋白2)的表达上调和p27(Kip1)(也称为细胞周期蛋白依赖性蛋白抑制因子1B)的降解，最终促进了癌细胞的增殖。最后，在异种移植小鼠模型中也观察到miR-200b/c靶向RECK促进肿瘤细胞的生长。综上所述，我们的结果表明miR-200b/c通过抑制RECK的表达，进而触发Skp2的上调和p27(Kip1)的降解，在促进结直肠肿瘤的发生中发挥了关键作用。
MicroRNA-200b and microRNA-200c (miR-200b/c) are 2 of the most frequently upregulated oncomiRs in colorectal cancer cells. The role of miR-200b/c during colorectal tumorigenesis, however, remains unclear. In the present study, we report that miR-200b/c can promote colorectal cancer cell proliferation via targeting the reversion-inducing cysteine-rich protein with Kazal motifs (RECK). Firstly, bioinformatics analysis predicted RECK as a conserved target of miR-200b/c. By overexpressing or knocking down miR-200b/c in colorectal cancer cells, we experimentally validated that miR200b/c are direct regulators of RECK. Secondly, an inverse correlation between the levels of miR-200b/c and RECK protein was found in human colorectal cancer tissues and cell lines. Thirdly, we demonstrated that repression of RECK by miR-200b/c consequently triggered SKP2 (S-phase kinase-associated protein 2) elevation and p27(Kip1) (also known as cyclin-dependent kinase inhibitor 1B) degradation in colorectal cancer cells, which eventually promotes cancer cell proliferation. Finally, promoting tumor cell growth by miR-200b/c-targeting RECK was also observed in the xenograft mouse model. Taken together, our results demonstrate that miR-200b/c play a critical role in promoting colorectal tumorigenesis through inhibiting RECK expression and subsequently triggering SKP2 elevation and p27(Kip1) degradation.