miR-18a promotes malignant progression by impairing microRNA biogenesis in nasopharyngeal carcinoma

Zhaohui Luo, Yafei Dai, Liyang zhang, Chen Jiang, Zheng Li, Jianbo Yang, James B. McCarthy, Xiaoling She, Wenling Zhang, Jian Ma, Wei Xiong, Minghua Wu, Jianhong Lu, Xiayu Li, Xiaoling Li, Juanjuan Xiang, Guiyuan Li

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

Abstract

Dysregulation of microRNA (miRNA) biogenesis is implicated in cancer development and progression. Dicer and Drosha are established regulators of miRNA biogenesis. In this study, we used a miRNA array to evaluate the miRNA expression profiles in nasopharyngeal carcinoma (NPC) samples. The significance analysis of microarrays showed a global downregulation of miRNA expression in NPC samples compared with normal nasopharyngeal epithelial tissues. Notably, miR-18a, a member of the oncogenic miR-17-92 cluster, was upregulated in the NPC samples and ell lines. Clinical parameter studies showed that higher levels of miR-18a correlated with NPC advanced stage, lymph node metastasis, Epstein-Barr virus infection and a higher death rate from NPC, indicating oncogenic roles in NPC development. The expression levels of miR-18a and Dicer1 were inversely related in NPC tissues. Further studies demonstrated that miR-18a negatively regulated Dicer1 by binding to the 3' untranslated regions of Dicer1. In vitro and in vivo biological function assays showed that miR-18a promoted the growth, migration and invasion of NPC cells by regulating Dicer1 expression, which caused the global downregulation of miRNA expression levels including miR-200 family and miR-143. Furthermore, we found that the epithelial mesenchymal transition marker E-cadherin and the oncogene K-Ras were aberrantly expressed after miR-18a transduction, and these alterations were directly induced by downregulation of the miR-200 family and miR-143. Collectively, our findings indicate that miR-18a plays an oncogenic role in the development of NPC by widespread downregulation of the miRNome and could be a potential therapeutic target for NPC.

Original languageEnglish (US)
Pages (from-to)415-425
Number of pages11
JournalCarcinogenesis
Volume34
Issue number2
DOIs
StatePublished - Feb 2013

Bibliographical note

Funding Information:
National Natural Science Foundation, China (81272255, 81000882, 91229122, 81172189); National Training and Research Base for Talents of Principles of Carcinogenesis Foundation (111 project: 111-2-12); Hunan Natural Science Foundation (10JJ7003).

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