Omeprazole Inhibits Cell Proliferation and Induces G0/G1 Cell Cycle Arrest through Up-regulating miR-203a-3p Expression in Barrett's Esophagus Cells.
Omeprazole Inhibits Cell Proliferation and Induces G0/G1 Cell Cycle Arrest through Up-regulating miR-203a-3p Expression in Barrett's Esophagus Cells.
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奥美拉唑通过上调 Barrett 食管细胞中 miR-203a-3p 的表达来抑制细胞增殖并诱导 G0/G1 细胞周期停滞
DOI：
10.3389/fphar.2017.00968
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发表时间：
2017
影响因子：
5.6
通讯作者：
Xiong H
中科院分区：
文献类型：
--
作者：
Hou Y;Hu Q;Huang J;Xiong H
现有数据表明，质子泵抑制剂（PPI），特别是奥美拉唑，在单药治疗和/或联合化疗中具有显著的抗肿瘤作用。Hedgehog（Hh）信号通路是Barrett食管（BE）的重要分子调节因子。研究表明，BE进展中的miRNA减少，然而，关于miRNA在BE细胞中的潜在抗肿瘤作用知之甚少。在此，我们研究奥美拉唑是否可以通过调节Hh通路来抑制BE进展，并探索BE细胞中有希望的Hh靶向miRNA。我们通过qRT-PCR和免疫印迹法评估奥美拉唑对CP-A和CP-B细胞中Hh信号组分和miR-203 a-3 p表达的影响。通过生物信息学方法预测miR-203 a-3 p的靶基因，并通过荧光素酶和qRT-PCR方法进行验证。观察奥美拉唑对BE细胞增殖及细胞周期分布的影响。进行miR-203 a-3 p的过表达或沉默以测试其抗增殖作用。最后，进行了miR-203 a-3 p抑制剂减轻奥美拉唑降低Gli 1 mRNA、蛋白和荧光素酶水平的作用的挽救实验。机制研究表明，奥美拉唑可以抑制Gli 1的表达和Gli 1的核定位。此外，奥美拉唑可选择性上调miR-203 a-3 p的表达，Gli 1是miR-203 a-3 p的真正靶点。miR-203 a-3 p抑制剂可减轻奥美拉唑对Gli 1荧光素酶活性、mRNA和蛋白水平的抑制作用。功能检测结果显示，奥美拉唑可剂量依赖性地抑制BE细胞生长，并诱导细胞周期阻滞于G 0/G1期。此外，BE细胞中miR-203 a-3 p的过表达和沉默破坏细胞周期进程，分别导致抑制和加速细胞增殖。综上所述，这些数据提供了奥美拉唑通过调节miR-203 a-3 p表达从而抑制BE细胞中Hh/Gli 1信号传导的潜在抗肿瘤作用的新机制。
Existing data suggest that proton pump inhibitors (PPIs), particularly omeprazole, have significant anti-tumor action in monotherapy and or combination chemotherapy. Hedgehog (Hh) signaling pathway represents a leading candidate as a molecular mediator of Barrett’s esophagus (BE). Studies have indicated reduced miRNAs in BE progression, however, little is known about the latent anti-neoplasm effects of miRNAs in BE cells. Here, we investigated whether omeprazole could inhibit BE progression by regulating Hh pathway and explored the promising Hh-targeted miRNAs in BE cells. We conducted qRT-PCR and immunoblotting assay to evaluate the effects of omeprazole on the expression of Hh signaling components and miR-203a-3p in CP-A and CP-B cells. The promising target genes of miR-203a-3p were predicted by bioinformatics methods, and verified by luciferase assays and qRT-PCR. The effects of omeprazole on BE cell proliferation and cell cycle distribution were determined. The overexpression or silencing of miR-203a-3p was performed to test its anti-proliferative effects. Finally, rescue experiments that miR-203a-3p inhibitor alleviated the effects of omeprazole on decreasing the levels of Gli1 mRNA, protein and luciferase were performed. Mechanistic studies showed that omeprazole could inhibit the expression of Gli1 and the nuclear localization of Gli1. Moreover, we determined that omeprazole could selectively up-regulated the expression of miR-203a-3p, and Gli1 was a bona fide target of miR-203a-3p. miR-203a-3p inhibitor alleviated the suppressing effects of omeprazole on Gli1 luciferase activity, mRNA and protein level. The functional assay suggested that omeprazole could dose-dependently inhibit BE cell growth and induce cell cycle arrest in G0/G1 phase. Additionally, overexpression and silencing of miR-203a-3p in BE cells disrupted cell cycle progress, resulting in suppressing and accelerating cell proliferation, respectively. Taken together, these data provide a novel mechanism of potentially anti-neoplastic effects for omeprazole through modulation of miR-203a-3p expression and thus suppressing Hh/Gli1 signaling in BE cells.
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影响因子：
9.7
作者：
Oladapo HO;Tarpley M;Sauer SJ;Addo KA;Ingram SM;Strepay D;Ehe BK;Chdid L;Trinkler M;Roques JR;Darr DB;Fleming JM;Devi GR;Williams KP
通讯作者：
Williams KP
影响因子：
29.4
作者：
Falk GW;Buttar NS;Foster NR;Ziegler KL;Demars CJ;Romero Y;Marcon NE;Schnell T;Corley DA;Sharma P;Cruz-Correa MR;Hur C;Fleischer DE;Chak A;Devault KR;Weinberg DS;Della'Zanna G;Richmond E;Smyrk TC;Mandrekar SJ;Limburg PJ;Cancer Prevention Network
通讯作者：
Cancer Prevention Network
影响因子：
11.2
作者：
Kasiri S;Shao C;Chen B;Wilson AN;Yenerall P;Timmons BC;Girard L;Tian H;Behrens C;Wistuba II;Gazdar AF;Kim J
通讯作者：
Kim J
影响因子：
--
作者：
Long, Bing;Wang, Le-Xun;Liu, Quentin
通讯作者：
Liu, Quentin
影响因子：
10.3
作者：
Luciani, F;Spada, M;Fais, S
通讯作者：
Fais, S