Potential involvement of miR-375 in the premalignant progression of oral squamous cell carcinoma mediated via transcription factor KLF5
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Wen Shi1,2, Jing Yang2,*, Siyuan Li1, Xiaofeng Shan1, Xiaosong Liu3, Hong Hua3, Chuanke Zhao2, Zhendong Feng2, Zhigang Cai1, Lihe Zhang2, Demin Zhou2
1Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China
2State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
3Department of Oral Medicine, Peking University School and Hospital of Stomatology, Beijing, China
*These authors have contributed equally to this work
Demin Zhou, e-mail: firstname.lastname@example.org
Zhigang Cai, e-mail: email@example.com
Keywords: miR-375, OSCC, KLF5, OLP, malignant progression
Received: July 13, 2015 Accepted: September 30, 2015 Published: October 12, 2015
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.
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