TGF?R2 is a major target of miR-93 in nasopharyngeal carcinoma aggressiveness.

ABSTRACT: BACKGROUND:MiR-17-92 cluster and its paralogues have emerged as crucial regulators of many oncogenes and tumor suppressors. Transforming growth factor-? receptor II (TGF?R2), 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 TGF?R2. 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. METHODS:We firstly evaluated the clinical signature of TGF?R2 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 TGF?R2 in NPC. In vitro and in vivo studies were performed to further investigate the effects of miRNA-mediated TGF?R2 down-regulation on NPC aggressiveness. Finally, mechanism studies were conducted to explore the associated pathway and genes influenced by this miRNA-mediated TGF?R2 down-regulation. RESULTS:TGF?R2 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 TGF?R2-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 TGF?R2, promoting cell proliferation, invasion and metastasis in vitro and in vivo. Moreover, miR-93 resulted in the attenuation of Smad-dependent TGF-? signaling and the activation of PI3K/Akt pathway by suppressing TGF?R2, further promoting NPC cell uncontrolled growth, invasion, metastasis and EMT-like process. Impressively, the knockdown of TGF?R2 by siRNA displayed a consentaneous phenocopy with the effect of miR-93 in NPC cells, supporting TGF?R2 is a major target of miR-93. Our findings were also substantiated by investigation of the clinical signatures of miR-93 and TGF?R2 in NPC. CONCLUSION:The present study reports an involvement of miR-93-mediated TGF?R2 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.

SUBMITTER: Lyu X 

PROVIDER: S-EPMC4016586 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature