miR-1207-5p and miR-1266 suppress gastric cancer growth and invasion by targeting telomerase reverse transcriptase.
miR-1207-5p and miR-1266 suppress gastric cancer growth and invasion by targeting telomerase reverse transcriptase.
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DOI：
10.1038/cddis.2013.553
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发表时间：
2014-01-30
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
hTERT是端粒酶复合物的催化亚基。hTERT的高表达与胃肿瘤的浸润和转移有关。在这项研究中，我们的目的是确定新的肿瘤抑制miRNAs抑制hTERT的表达。我们用miRNA微阵列开始筛选靶向hTERT的miRNA。通过生物信息学分析、不同细胞系中的一般表达模式、对hTERT蛋白的功能获得效应以及这些效应抑制hTERT 3′非翻译区（3′UTR）荧光素酶活性的潜力来进一步筛选miRNA候选物。通过实时RT-PCR评估两种miRNA（miR-1207- 5 p和miR-1266）的临床相关性。采用CCK-8、流式细胞仪和transwell法检测这些miRNAs对胃癌细胞生长、细胞周期和侵袭能力的影响。最后，还研究了这些miRNA抑制移植肿瘤的能力。使用生物信息学和miRNA微阵列分析的组合鉴定了14种miRNA。在这14种miRNAs中，9种在hTERT阳性细胞系中的表达水平显著低于hTERT阴性细胞系，5种可下调hTERT蛋白表达。只有miR-1207- 5 p和miR-1266与hTERT的3′ UTR相互作用，且这两种miRNA在胃癌组织中的表达水平显著降低。这两种miRNAs在体外和体内也能抑制胃肿瘤的生长。总之，miR-1207- 5 p和miR-1266被确定为胃癌中的hTERT抑制因子，并且这两种miRNA的递送代表了胃癌治疗的新的治疗策略。
hTERT is the catalytic subunit of the telomerase complex. Elevated expression of hTERT is associated with the expansion and metastasis of gastric tumor. In this study, we aimed to identify novel tumor suppressor miRNAs that restrain hTERT expression. We began our screen for hTERT-targeting miRNAs with a miRNA microarray. miRNA candidates were further filtered by bioinformatic analysis, general expression pattern in different cell lines, gain-of-function effects on hTERT protein and the potential of these effects to suppress hTERT 3′ untranslated region (3′UTR) luciferase activity. The clinical relevance of two miRNAs (miR-1207-5p and miR-1266) was evaluated by real-time RT-PCR. The effects of these miRNAs on cell growth, cell cycle and invasion of gastric cancer cells were measured with CCK-8, flow cytometry and transwell assays. Finally, the ability of these miRNAs to suppress the transplanted tumors was also investigated. Fourteen miRNAs were identified using a combination of bioinformatics and miRNA microarray analysis. Of these fourteen miRNAs, nine were expressed at significantly lower levels in hTERT-positive cell lines compared with hTERT-negative cell lines and five could downregulate hTERT protein expression. Only miR-1207-5p and miR-1266 interacted with the 3′ UTR of hTERT and the expression levels of these two miRNAs were significantly decreased in gastric cancer tissues. These two miRNAs also inhibited gastric tumor growth in vitro and in vivo. Altogether, miR-1207-5p and miR-1266 were determined to be hTERT suppressors in gastric cancer, and the delivery of these two miRNAs represents a novel therapeutic strategy for gastric cancer treatment.
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