miR-143 and miR-145 are downregulated in ulcerative colitis: putative regulators of inflammation and protooncogenes.
miR-143 and miR-145 are downregulated in ulcerative colitis: putative regulators of inflammation and protooncogenes.
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DOI：
10.1002/ibd.21742
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发表时间：
2012-01
影响因子：
4.9
通讯作者：
Bissonnette, Marc
中科院分区：
文献类型：
--
作者：
Pekow, Joel R.;Dougherty, Urszula;Mustafi, Reba;Zhu, Hongyan;Kocherginsky, Masha;Rubin, David T.;Hanauer, Stephen B.;Hart, John;Chang, Eugene B.;Fichera, Alessandro;Joseph, Loren J.;Bissonnette, Marc
miR-143和miR-145被认为是结肠癌肿瘤抑制因子，因为它们抑制结肠癌细胞生长并且在散发性结肠肿瘤中下调。我们推测，miR-143和miR-145也可能下调，并有助于长期溃疡性结肠炎（UC）结肠上皮的恶性转化。从静止期UC患者和正常对照者肛门近端20 cm处获得活检组织。提取RNA和蛋白质并进行测量。通过真实的时间PCR定量miR-143和miR-145，并且还通过原位杂交评估miR-145。通过蛋白质印迹法确定这些miRNA的推定靶点K-RAS、API 5、MEK-2（miR-143）和IRS-1（miR-145）。为了评估miR-143和miR-145对这些预测靶点的影响，用miR-143和miR-145转染HCT 116和HCA-7结直肠癌细胞，并测量这些蛋白质的表达水平。在UC中，与正常结肠相比，miR-143和miR-145分别显著下调8.3倍（3.4-20.1）（p < 0.0001）和4.3倍（2.3-7.8）（p < 0.0001）。相反，IRS-1、K-RAS、API 5和MEK-2在溃疡性结肠炎中上调，这与它们作为这些miRNA的靶点的分配一致。此外，转染的miR-143和miR-145在HCT 116或HCA 7细胞中显著下调这些蛋白。与正常结肠黏膜相比，慢性溃疡性结肠炎中miR-143和miR-145显著下调，其预测靶点IRS-1、K-RAS、API 5和MEK-2上调。我们推测这些肿瘤抑制miRNAs的缺失易导致IBD的慢性炎症和肿瘤进展。
miR-143 and miR-145 are believed to function as colon cancer tumor suppressors as they inhibit colon cancer cell growth and are down-regulated in sporadic colonic tumors. We speculated that miR-143 and miR-145 might also be down-regulated and contribute to malignant transformation of colonic epithelium in longstanding ulcerative colitis (UC). Biopsies were obtained 20 cm proximal to the anus from individuals with quiescent UC and from normal controls. RNA and proteins were extracted and measured. miR-143 and miR-145 were quantified by real time PCR and miR-145 was also assessed by in situ hybridization. Putative targets of these miRNAs, K-RAS, API5, MEK-2 (miR-143), and IRS-1 (miR-145) were determined by Western blotting. To assess the effects of miR-143 and miR-145 on these predicted targets, HCT116 and HCA-7 colorectal cancer cells were transfected with miR-143 and miR-145 and expression levels of these proteins were measured. In UC, miR-143 and miR-145 were significantly down-regulated 8.3-fold (3.4–20.1) (p < 0.0001) and 4.3-fold (2.3–7.8) (p < 0.0001), respectively, compared to normal colon. In contrast, IRS-1, K-RAS, API5, and MEK-2 were up-regulated in ulcerative colitis consistent with their assignments as targets of these miRNAs. Furthermore, transfected miR-143 and miR-145 significantly down-regulated these proteins in HCT116 or HCA7 cells. Compared to normal colonic mucosa, in chronic ulcerative colitis miR-143 and miR-145 were significantly down-regulated and their predicted targets, IRS-1, K-RAS, API5, and MEK-2 were up-regulated. We postulate that loss of these tumor suppressor miRNAs predispose to chronic inflammation and neoplastic progression in IBD.
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影响因子：
3.1
作者：
Nathanson, Jeffrey W.;Yadron, Nicole E.;Rubin, David T.
通讯作者：
Rubin, David T.
影响因子：
29.4
作者：
Gupta, Roopali Bansal;Harpaz, Noam;Ullman, Thomas
通讯作者：
Ullman, Thomas
影响因子：
6.4
作者：
Akao, Y.;Nakagawa, Y.;Naoe, T.
通讯作者：
Naoe, T.
影响因子：
3.8
作者：
Gunter, Marc J.;Hayes, Richard B.;Peters, Ulrike
通讯作者：
Peters, Ulrike
影响因子：
8
作者：
Chen, X.;Guo, X.;Zhang, C-Y
通讯作者：
Zhang, C-Y