CCAT1 lncRNA Promotes Inflammatory Bowel Disease Malignancy by Destroying Intestinal Barrier via Downregulating miR-185-3p
CCAT1 lncRNA Promotes Inflammatory Bowel Disease Malignancy by Destroying Intestinal Barrier via Downregulating miR-185-3p
复制标题
CCAT1 lncRNA 通过下调 miR-185-3p 破坏肠道屏障促进炎症性肠病恶性肿瘤
DOI：
10.1093/ibd/izy381
复制
发表时间：
2019-05-01
影响因子：
4.9
通讯作者：
Hong, Jie
中科院分区：
文献类型：
--
作者：
Ma, Dan;Cao, Yingying;Hong, Jie
背景资料：结肠癌相关转录本1（CCAT 1）在肿瘤的发生发展中起着重要作用。虽然炎症和癌症发生之间的联系已经很好地建立，但CCAT 1是否参与炎症并促进炎症性肠病（IBD）恶性肿瘤仍然不确定。本研究旨在探讨CCAT 1在IBD中的表达及CCAT 1过表达对肠上皮屏障功能的影响。实时荧光定量PCR和Western blot检测基因表达。使用跨上皮电阻（TEER）和FD-4通量测量来测试CCAT 1和miR-185- 3 p对肠上皮屏障功能的影响。结果：基因集富集分析显示，CCAT 1高表达组中有多个炎症相关基因富集。进一步证实了CCAT 1与IBD患者炎症激活的关系。CCAT 1表达与MLCK呈正相关，MLCK作为蛋白激酶磷酸化肌球蛋白轻链并诱导紧密连接蛋白分布，而IBD组织中CCAT 1表达与miR-185- 3 p呈负相关。我们还确定，CCAT 1过表达增加Caco-2单层通透性和上调MLCK。结论：CCAT 1/miR-185 - 3 p/MLCK信号通路被强烈激活，破坏屏障功能，促进IBD的发病。
Background: The long noncoding RNA (lncRNA) colon cancer-associated transcript-1 (CCAT1) has been reported to play a vital role in the development of cancer. Although the link between inflammation and cancer initiation is well established, whether CCAT1 is involved in inflammation and promotes inflammatory bowel disease (IBD) malignancy remains undetermined. We aimed to investigate the expression of CCAT1 in IBD and the effect of CCAT1 overexpression on intestinal epithelial barrier function.Methods: The relationship between CCAT1 and the inflammation-related pathway was analyzed in both colorectal cancer (CRC) and IBD patients. Gene expression was detected by real-time polymerase chain reaction and Western blot. Transepithelial electrical resistance (TEER) and FD-4 flux measurement were used to test the effect of CCAT1 and miR-185-3p on intestinal epithelial barrier function. Luciferase assay was performed to validate the target site of miR-185-3p on 3'-UTR of MLCK mRNA.Results: Gene set enrichment analysis revealed that several inflammation-related genes were enriched in the CCAT1 high-expressed group of CRC patients. The relationship between CCAT1 and inflammation activation in IBD patients was further confirmed. CCAT1 expression positively correlated with MLCK, which acts as a protein kinase to phosphorylate myosin light chain and induces tight junction protein distribution, whereas it was negatively correlated with miR-185-3p in IBD tissues. We also determined that CCAT1 overexpression increased Caco-2 monolayer permeability and upregulated MLCK. Furthermore, CCAT1-induced MLCK overexpression and IBD disease progression were significantly attenuated by miR-185-3p.Conclusions: The CCAT1/miR-185-3p/MLCK signaling pathway is strongly activated to destroy barrier function and promotes the pathogenesis of IBD.