TGFbetaR2 is a major target of miR-93 in nasopharyngeal carcinoma aggressiveness

MiR-17-92 cluster and its paralogues have emerged as crucial regulators of many oncogenes and tumor suppressors. Transforming growth factor-beta receptor II (TGFbetaR2), 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 TGFbetaR2. 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 TGFbetaR2 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 TGFbetaR2 in NPC. In vitro and in vivo studies were performed to further investigate the effects of miRNA-mediated TGFbetaR2 down-regulation on NPC aggressiveness.

Finally, mechanism studies were conducted to explore the associated pathway and genes influenced by this miRNA-mediated TGFbetaR2 down-regulation.

Results:
TGFbetaR2 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 TGFbetaR2-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 TGFbetaR2, promoting cell proliferation, invasion and metastasis in vitro and in vivo. Moreover, miR-93 resulted in the attenuation of Smad-dependent TGF-beta signaling and the activation of PI3K/Akt pathway by suppressing TGFbetaR2, further promoting NPC cell uncontrolled growth, invasion, metastasis and EMT-like process.

Impressively, the knockdown of TGFbetaR2 by siRNA displayed a consentaneous phenocopy with the effect of miR-93 in NPC cells, supporting TGFbetaR2 is a major target of miR-93. Our findings were also substantiated by investigation of the clinical signatures of miR-93 and TGFbetaR2 in NPC.

Conclusion:
The present study reports an involvement of miR-93-mediated TGFbetaR2 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.

Author: Xiaoming LyuWeiyi FangHang ZhengLongmei CaiYanfen YeLan ZhangJinbang liHong PengWilliam C ChoEna WangFrancesco M MarincolaKaitai YaoHongbing CaiJiliang LiXin Li
Credits/Source: Molecular Cancer 2014, 13:51

Published on: 2014-03-08

News Provider: 7thSpace Interactive

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