MiR-375 frequently downregulated in gastric cancer inhibits cell proliferation by targeting JAK2
MiR-375 frequently downregulated in gastric cancer inhibits cell proliferation by targeting JAK2
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MiR-375 在胃癌中频繁下调，通过靶向 JAK2 抑制细胞增殖
DOI：
10.1038/cr.2010.79
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发表时间：
2010-07-01
期刊：
影响因子：
44.1
通讯作者：
Zhou, Tianhua
中科院分区：
文献类型：
--
作者：
Ding, Ling;Xu, Yanjun;Zhou, Tianhua
新出现的证据表明异常表达的microRNAs（miRNAs）与肿瘤的发生和进展相关。然而，关于miRNAs在胃癌发生中的潜在作用知之甚少。本研究利用miRNA芯片技术筛选胃癌及其癌旁组织中差异表达的miRNA，发现miR-375在胃癌组织中表达显著下调。定量实时PCR分析证实，与接受胃切除术的患者的非肿瘤对应物相比，超过90%的原发性胃癌中miR-375表达显著降低。过表达miR-375可显著抑制胃癌细胞的体外和体内增殖。miR-375在胃癌细胞中的强制表达显著降低了Janus激酶2（JAK 2）的蛋白水平，并抑制了携带JAK 2 3′-非翻译区的荧光素酶报告基因的活性，该活性被预测的miR-375结合位点的突变所消除，表明JAK 2可能是miR-375的靶基因。AG 490抑制JAK 2活性或RNAi沉默JAK 2抑制胃癌细胞增殖，类似于miR-375过表达。此外，JAK 2的异位表达可部分逆转miR-375对细胞增殖的抑制作用。最后，我们发现胃癌中miR-375表达与JAK 2蛋白水平呈显著负相关。因此，这些数据表明，miR-375可能作为肿瘤抑制因子通过靶向JAK 2癌基因调节胃癌细胞增殖，暗示miR-375在胃癌发病机制中的作用。
Emerging evidence has shown the association of aberrantly expressed microRNAs (miRNAs) with tumor development and progression. However, little is known about the potential role of miRNAs in gastric carcinogenesis. Here, we performed miRNA microarray to screen miRNAs differentially expressed in the paired gastric cancer and their adjacent nontumor tissues and found that miR-375 was greatly downregulated in gastric cancer tissues. Quantitative real-time PCR analysis verified that miR-375 expression was significantly decreased in more than 90% of primary gastric cancers compared with their nontumor counterparts from patients undergoing gastric resection. Overexpression of miR-375 significantly inhibited gastric cancer cell proliferation in vitro and in vivo. Forced expression of miR-375 in gastric cancer cells significantly reduced the protein level of Janus kinase 2 (JAK2) and repressed the activity of a luciferase reporter carrying the 3′-untranslated region of JAK2, which was abolished by mutation of the predicted miR-375-binding site, indicating that JAK2 may be a miR-375 target gene. Either inhibition of JAK2 activity by AG490 or silencing of JAK2 by RNAi suppressed gastric cancer cell proliferation resembling that of miR-375 overexpression. Moreover, ectopic expression of JAK2 can partially reverse the inhibition of cell proliferation caused by miR-375. Finally, we found a significant inverse correlation between miR-375 expression and JAK2 protein level in gastric cancer. Thus, these data suggest that miR-375 may function as a tumor suppressor to regulate gastric cancer cell proliferation potentially by targeting the JAK2 oncogene, implicating a role of miR-375 in the pathogenesis of gastric cancer.