Potential involvement of miR-375 in the premalignant progression of oral squamous cell carcinoma mediated via transcription factor KLF5.
Potential involvement of miR-375 in the premalignant progression of oral squamous cell carcinoma mediated via transcription factor KLF5.
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miR-375 可能参与转录因子 KLF5 介导的口腔鳞状细胞癌癌前进展。
DOI：
10.18632/oncotarget.5502
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发表时间：
2015-11-24
期刊：
影响因子：
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通讯作者：
Zhou D
中科院分区：
文献类型：
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作者：
Shi W;Yang J;Li S;Shan X;Liu X;Hua H;Zhao C;Feng Z;Cai Z;Zhang L;Zhou D
为了阐明慢性炎症癌前进展中涉及的遗传效应，我们对同一患者的口腔扁平苔藓 (OLP)、口腔鳞状细胞癌 (OSCC) 和正常组织进行了 microRNA 和 mRNA 分析。我们证明了抑制性 microRNA（miR-375）通过 KLF5（一种调节促进增殖和凋亡的基因表达的转录因子）参与了癌前进展的调节。我们发现，随着从正常状态发展到 OLP，随后发展到 OSCC，组织中 miR-375 丰度降低。通过将合成模拟物转导至 OSCC 细胞来恢复 miR-375，可抑制细胞增殖并促进细胞凋亡，同时下调 KLF5，反之亦然。进一步证实了miR-375与KLF5 3'非翻译区的直接结合。此外，KLF5 的靶标 Survivin (BIRC5) 也受到 miR-375 的调节，这解释了 miR-375 模拟转染细胞对细胞凋亡的敏感性。对临床样本的进一步分析表明，KLF5和BIRC5的表达在从炎症到癌症的进展过程中上调。我们的研究结果为 microRNA 在炎症发展为癌症过程中的参与提供了新的见解，并提出了口腔癌潜在的早期生物标志物或治疗靶点。
To elucidate the genetic effect involved in the premalignant progression of chronic inflammation to cancer, we performed microRNA and mRNA profiling in oral lichen planus (OLP), oral squamous cell carcinoma (OSCC), and normal tissue from the same patients. We demonstrate the involvement of a suppressive microRNA, miR-375, in the regulation of this premalignant progression via KLF5, a transcription factor that modulates the expression of genes contributing to proliferation and apoptosis. We found that miR-375 abundance decreased in tissues with progression from the normal state to OLP and subsequently to OSCC. Restoration of miR-375 by transduction of a synthetic mimic into OSCC cells repressed cellular proliferation and promoted apoptosis, with concomitant down-regulation of KLF5, and vice versa. The direct binding of miR-375 to the 3′-untranslated region of KLF5 was further confirmed. Additionally, Survivin (BIRC5), a target of KLF5, was also regulated by miR-375, explaining the susceptibility of miR-375-mimic transfected cells to apoptosis. Further analysis of clinical specimens suggested that expression of KLF5 and BIRC5 is up-regulated during the progression from inflammation to cancer. Our findings provide novel insights into the involvement of microRNAs in progression of inflammation to carcinoma and suggest a potential early-stage biomarker or therapy target for oral carcinoma.