Mir-376a functions as a tumor suppressor in nasopharyngeal carcinoma

Abstract

Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer usually originating from ostium of the Eustachian tube in the lateral wall of the nasopharynx. Although NPC is a rare cancer in most part of the world, it is a leading cancer in certain geographic regions and for people of certain ethnic origin. The highest incidence is seen in the Cantonese population in southern China. MicroRNA deregulation is known to contribute to the initiation and progression of human cancers. In this study, we try to identify microRNAs with tumor suppressor function in NPC. Through a quantitative PCR-based microRNA screening platform, we found that the expression levels of mir-376a were obviously downregulated in two NPC-derived cell lines. Through WST-1-based proliferation assays, we also found that overexpression of mir-376a can suppress cell growth in both NPC cell lines. Mir-376a is located in the Dlk1-Gtl2 domain of chromosome 14, which is known to be frequently silenced by epigenetic mechanisms in several other cancer types. This suggests that miR376a has a general tumor suppression function. By bioinformatic analysis, Ezrin, a member of the ezrin-radixin-moesin family of proteins, and MYC, an oncogenic transcriptional factor, were predicted to be direct targets of miR-376a. By both luciferase reporter assays and Western blotting analysis, we confirmed that the two candidate genes are real targets of mir-376a. Ezrin is usually involved in cell migration and invasion and is known to be over-expressed in different cancer types. This suggests that Ezrin could be involved in metastasis of NPC. As a transcription factor, MYC is one of the best known oncogenes in human cancer. Over-expression of MYC stimulates cell proliferation, cell survival and angiogenesis. Thus both Ezrin and MYC represent critical targets of mir-376a in NPC. In summary, our work suggested that miR-376a can function as a tumor suppressor in NPC by directly targeting Ezrin and MYC, both of which are known oncogenic proteins over-expressed in many cancer types.

Date of Award	2012
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology