TGFβR2 is a major target of miR-93 in nasopharyngeal carcinoma aggressiveness

Molecular Cancer

Research

Jinbang li¹  Xin Li¹  Xiaoming Lyu¹  Longmei Cai¹  Weiyi Fang¹  Yanfen Ye¹  Kaitai Yao¹  Hang Zheng²  William C S Cho³  Hong Peng⁴  Lan Zhang⁴  Ena Wang⁵  Francesco M Marincola⁵  Jiliang Li⁶  Hongbing Cai⁷ 

[1] Cancer Research Institute and the Provincial Key Laboratory of Functional Proteomics, Southern Medical University, Guangzhou, China;Cancer Research Institute and the Provincial Key Laboratory of Functional Proteomics, Southern Medical University, Guangzhou, China;Departments of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China;Department of Clinical Oncology, Queen Elizabeth Hospital, Guangzhou, Hong Kong;Department of Otorhinolaryngology, Nanfang Hospital, Southern Medical University, Guangzhou, China;Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, USA;School of Biotechnology, Southern Medical University, Guangzhou, China;Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK;School of Chinese Traditional Medicine, Southern Medical University, Guangzhou, China;

关键词: miR-93;    TGFβR2;    Aggressiveness;    PI3K/Akt;    Nasopharyngeal carcinoma;   

DOI  :  10.1186/1476-4598-13-51

 received in 2013-12-26, accepted in 2014-03-01,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundMiR-17-92 cluster and its paralogues have emerged as crucial regulators of many oncogenes and tumor suppressors. Transforming growth factor-β receptor II (TGFβR2), as an important tumor suppressor, is involved in various cancer types. However, it is in cancer that only two miRNAs of this cluster and its paralogues have been reported so far to regulate TGFβR2. MiR-93 is oncogenic, but its targetome in cancer has not been fully defined. The role of miR-93 in nasopharyngeal carcinoma (NPC) still remains largely unknown.MethodsWe firstly evaluated the clinical signature of TGFβR2 down-regulation in clinical samples, and next used a miRNA expression profiling analysis followed by multi-validations, including Luciferase reporter assay, to identify miRNAs targeting TGFβR2 in NPC. In vitro and in vivo studies were performed to further investigate the effects of miRNA-mediated TGFβR2 down-regulation on NPC aggressiveness. Finally, mechanism studies were conducted to explore the associated pathway and genes influenced by this miRNA-mediated TGFβR2 down-regulation.ResultsTGFβR2 was down-regulated in more than 50% of NPC patients. It is an unfavorable prognosis factor contributing to clinical NPC aggressiveness. A cluster set of 4 TGFβR2-associated miRNAs was identified; they are all from miR-17-92 cluster and its paralogues, of which miR-93 was one of the most significant miRNAs, directly targeting TGFβR2, promoting cell proliferation, invasion and metastasis in vitro and in vivo. Moreover, miR-93 resulted in the attenuation of Smad-dependent TGF-β signaling and the activation of PI3K/Akt pathway by suppressing TGFβR2, further promoting NPC cell uncontrolled growth, invasion, metastasis and EMT-like process. Impressively, the knockdown of TGFβR2 by siRNA displayed a consentaneous phenocopy with the effect of miR-93 in NPC cells, supporting TGFβR2 is a major target of miR-93. Our findings were also substantiated by investigation of the clinical signatures of miR-93 and TGFβR2 in NPC.ConclusionThe present study reports an involvement of miR-93-mediated TGFβR2 down-regulation in NPC aggressiveness, thus giving extended insights into molecular mechanisms underlying cancer aggressiveness. Approaches aimed at blocking miR-93 may serve as a promising therapeutic strategy for treating NPC patients.

【 授权许可】

Unknown   
© Lyu et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.