Dicer suppresses cytoskeleton remodeling and tumorigenesis of colorectal epithelium by miR-324-5p mediated suppression of HMGXB3 and WASF-2.
Dicer suppresses cytoskeleton remodeling and tumorigenesis of colorectal epithelium by miR-324-5p mediated suppression of HMGXB3 and WASF-2.
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Dicer 通过 miR-324-5p 介导的 HMGXB3 和 WASF-2 抑制来抑制结直肠上皮的细胞骨架重塑和肿瘤发生
DOI：
10.18632/oncotarget.18218
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发表时间：
2017-08-22
期刊：
影响因子：
--
通讯作者：
Li JM
中科院分区：
文献类型：
--
作者：
Sun LN;Xing C;Zhi Z;Liu Y;Chen LY;Shen T;Zhou Q;Liu YH;Gan WJ;Wang JR;Xu Y;Li JM
新的证据表明，microRNA是一类小型且保守的非编码RNA，参与许多生理和病理过程。 RNase III 核酸内切酶 DICER 是 microRNA 生物发生的关键酶之一。在这里，我们发现结直肠癌 (CRC) 患者的肿瘤样本中 DICER 在 mRNA 和蛋白质水平上均下调。重要的是，肠上皮细胞（IEC）特异性缺失的 Dicer 小鼠在给予氧化偶氮甲烷和葡聚糖硫酸钠（DSS）后会产生更多的肿瘤。有趣的是，在给予或不给予 DSS 的小鼠中，IEC 特异性删除 Dicer 会导致严重的慢性炎症和上皮层重塑。对 3 对 Dicer 缺失 CRC 细胞系的微阵列分析表明，miR-324-5p 是减少最显着的 miRNA 之一。在 IEC 特异性缺失的 Dicer 小鼠的肠上皮中，miR-324-5p 也被发现显着减少。从机制上讲，miR-324-5p直接与参与细胞运动和细胞骨架重塑的两种关键蛋白HMG-box contains 3 (HMGXB3)和WAS蛋白家族成员2 (WASF-2)的3'非翻译区(3'UTR)结合，以抑制其表达。在 DSS 诱导的 IEC 特异性缺失 Dicer 小鼠中，腹腔注射 miR-324-5p AgomiR（miR-324-5p 的激动剂）可减少结直肠上皮的慢性炎症和细胞骨架重塑，并恢复肠道屏障功能。因此，我们的研究揭示了 DICER/miR-324-5p/HMGXB3/WASF-2 轴通过调节细胞骨架重塑和维持肠道屏障的完整性在 CRC 肿瘤发生中的关键作用。
Emerging evidence indicates that microRNAs, a class of small and well-conserved noncoding RNAs, participate in many physiological and pathological processes. RNase III endonuclease DICER is one of the key enzymes for microRNA biogenesis. Here, we found that DICER was downregulated in tumor samples of colorectal cancer (CRC) patients at both mRNA and protein levels. Importantly, intestinal epithelial cell (IEC)-specific deletion of Dicer mice got more tumors after azoxymethane and dextran sulfate sodium (DSS) administration. Interestingly, IEC-specific deletion of Dicer led to severe chronic inflammation and epithelium layer remodeling in mice with or without DSS administration. Microarray analysis of 3 paired Dicer deletion CRC cell lines showed that miR-324-5p was one of the most significantly decreased miRNAs. In the intestinal epithelium of IEC-specific deletion of Dicer mice, miR-324-5p was also found to be markedly reduced. Mechanistically, miR-324-5p directly bound to the 3′untranslated regions (3′UTRs) of HMG-box containing 3 (HMGXB3) and WAS protein family member 2 (WASF-2), two key proteins participated in cell motility and cytoskeleton remodeling, to suppress their expressions. Intraperitoneal injection of miR-324-5p AgomiR (an agonist of miR-324-5p) curtailed chronic inflammation and cytoskeleton remodeling of colorectal epithelium and restored intestinal barrier function in IEC-specific deletion of Dicer mice induced by DSS. Therefore, our study reveals a key role of a DICER/miR-324-5p/HMGXB3/WASF-2 axis in tumorigenesis of CRC by regulation of cytoskeleton remodeling and maintaining integrity of intestinal barriers.
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