Novel evidence for an oncogenic role of microRNA-21 in colitis-associated colorectal cancer
Novel evidence for an oncogenic role of microRNA-21 in colitis-associated colorectal cancer
复制标题
microRNA-21 在结肠炎相关结直肠癌中致癌作用的新证据
DOI：
10.1136/gutjnl-2014-308455
复制
发表时间：
2016-09-01
期刊：
影响因子：
24.5
通讯作者：
Goel, Ajay
中科院分区：
文献类型：
--
作者：
Shi, Chenzhang;Yang, Yongzhi;Goel, Ajay
目的 发现 miR-21 在 UC 和结直肠癌（CRC）患者的结肠组织和血清中过度表达；然而，miR-21 在结肠炎相关 CRC 中的确切作用仍不清楚。我们研究的目的是调查 miR-21 在结肠炎相关结肠癌 (CAC) 中的生物学机制。在来自中国的 62 名 CRC 患者以及来自日本和奥地利的 37 名结肠炎相关肿瘤组织的肿瘤中检测了设计的 miR-21 表达。使用一系列体外、体内和临床方法研究了 miR-21 的生物学功能。结果 62 名 CRC 患者、22 名 CAC 患者以及 CAC 小鼠模型的肿瘤中 miR-21 水平显着上调。在氧化偶氮甲烷和葡聚糖硫酸钠干预后，与对照组小鼠相比，miR-21敲除小鼠的促炎和致癌细胞因子（白细胞介素（IL）6、IL-23、IL-17A和IL-21）的表达减少，肿瘤的大小和数量减少。 miR-21的缺失导致CAC小鼠肿瘤中Ki67表达减少和肿瘤细胞增殖减弱，同时E-钙粘蛋白增加，β-连环蛋白和SOX9减少。此外，miR-21 的缺失会增加其靶基因 PDCD4 的表达，并随后调节核因子 (NF)-κB 的激活。同时，miR-21的缺失减少了STAT3和Bcl-2的激活，导致CAC小鼠肿瘤细胞凋亡增加。结论 这些观察结果为 miR-21 阻断是减少 CAC 的关键策略提供了新的证据。
Objective miR-21 was found to be overexpressed in the colon tissues and serum of patients with UC and colorectal cancer (CRC); however, the exact roles of miR-21 in colitis-associated CRC remain unclear. The aim of our study was to investigate the biological mechanisms of miR-21 in colitis-associated colon cancer (CAC). Design miR-21 expression was examined in the tumours of 62 patients with CRC from China and 37 colitis-associated neoplastic tissues from Japan and Austria. The biological functions of miR-21 were studied using a series of in vitro, in vivo and clinical approaches. Results miR-21 levels were markedly upregulated in the tumours of 62 patients with CRC, 22 patients with CAC, and in a mouse model of CAC. Following azoxymethane and dextran sulfate sodium intervention, miR-21-knockout mice showed reduced expression of proinflammatory and procarcinogenic cytokines (interleukin (IL) 6, IL-23, IL-17A and IL-21) and a decrease in the size and number of tumours compared with the control mouse group. The absence of miR-21 resulted in the reduced expression of Ki67 and the attenuated proliferation of tumour cells with a simultaneous increase in E-cadherin and decrease in β-catenin and SOX9 in the tumours of CAC mice. Furthermore, the absence of miR-21 increased the expression of its target gene PDCD4 and subsequently modulated nuclear factor (NF)-κB activation. Meanwhile, miR-21 loss reduced STAT3 and Bcl-2 activation, causing an increase in the apoptosis of tumour cells in CAC mice. Conclusions These observations provide novel evidence for miR-21 blockade to be a key strategy in reducing CAC.