MicroRNA-409-3p suppresses colorectal cancer invasion and metastasis partly by targeting GAB1 expression
MicroRNA-409-3p suppresses colorectal cancer invasion and metastasis partly by targeting GAB1 expression
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MicroRNA-409-3p部分通过靶向GAB1表达抑制结直肠癌侵袭和转移
DOI：
10.1002/ijc.29607
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发表时间：
2015-11-15
影响因子：
6.4
通讯作者：
Xu, Zhengping
中科院分区：
文献类型：
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作者：
Bai, Rongpan;Weng, Chunhua;Xu, Zhengping
结直肠癌(CRC)是世界上最常见的癌症之一，其转移是造成死亡的主要原因。然而，CRC进展的分子机制还没有得到很好的描述。在本研究中，我们发现miR409-3p是结直肠癌的肿瘤抑制因子。在结直肠癌组织中，miR-409-3p的表达明显低于癌旁组织，且miR-409-3p的表达降低与结直肠癌的转移有关。体外和体内研究表明，miR-409-3p负性调节结直肠癌的转移能力，包括抑制癌细胞的迁移、侵袭和转移。为了探讨miR-409-3p的作用机制，我们采用了基于途径和病理生理事件的靶点筛选和验证方法，发现了9个已知的转移相关基因作为潜在靶点。候选基因与miR-409-3p之间的3‘-UTR结合实验表明，只有GAB1、NR4A2和LMO4受到miRNA的直接调控。然而，内源性表达分析表明，只有GAB1在mRNA和蛋白水平上受到miR-409-3p的调控。此外，我们提供的证据表明，GAB1在miR-409-3p介导的转移中起部分作用。综上所述，我们的数据表明miR-409-3p是一种转移抑制因子，而对癌蛋白GAB1的转录后抑制是该miRNA的作用机制之一。我们的发现提示miR-409-3p可能成为治疗结直肠癌转移的新靶点。
Colorectal cancer (CRC) is one of the most common cancers worldwide and its metastasis accounts for the majority of deaths. However, the molecular mechanisms underlying CRC progression are not well characterized. In this study, we identified miR409-3p as a tumor suppressor of CRC. MiR-409-3p expression was significantly downregulated in CRC tissue compared to adjacent non-tumor tissue, and reduced miR-409-3p expression was correlated with CRC metastasis. In vitro and in vivo studies revealed that miR-409-3p negatively regulated CRC metastatic capacities, including suppressing cancer cell migration, invasion and metastasis. To explore the mechanism of action of miR-409-3p, we adopted a pathway and pathophysiological event-based target screening and validation approach, and found nine known metastasis-related genes as potential targets. The 3'-UTR binding assays between the candidates and miR-409-3p suggested that only GAB1, NR4A2 and LMO4 were directly regulated by the miRNA. However, endogenous expression analysis revealed that only GAB1 was modulated by miR-409-3p in CRC cells at both the mRNA and protein levels. Furthermore, we provided evidence to conclude that GAB1 was partially responsible for miR-409-3p-mediated metastasis. Taken together, our data demonstrate that miR-409-3p is a metastatic suppressor, and post-transcriptional inhibition of the oncoprotein GAB1 is one of the mechanisms of action of this miRNA. Our finding suggests miR-409-3p might be a novel target for CRC metastasis treatment.