Αρχειοθήκη ιστολογίου

Κυριακή 28 Αυγούστου 2016

mir-22 oncosuppressor network in Rhabdomyosarcoma

Current therapeutic options for the pediatric cancer rhabdomyosarcoma (RMS) have not improved significantly, especially for metastatic RMS. In the present work, we performed a deep microRNA profiling of the three major human RMS subtypes, along with cell lines and normal muscle, to identify novel molecular circuits with therapeutic potential. The signature we determined could discriminate RMS from muscle, revealing a subset of muscle-enriched microRNA (myomiR), including miR-22 which was strongly underexpressed in tumors. miR-22 was physiologically induced during normal myogenic differentiation and was transcriptionally regulated by MyoD, confirming its identity as a myomiR. Once introduced into RMS cells, miR-22 decreased cell proliferation, anchorage-independent growth, invasiveness and promoted apoptosis. Moreover, restoring miR-22 expression blocked tumor growth and prevented tumor dissemination in vivo. Gene expression profiling analysis of miR-22-expressing cells suggested TACC1 and RAB5B as possible direct miR-22 targets. Accordingly, loss and gain of function experiments defined the biological relevance of these genes in RMS pathogenesis. Finally, we demonstrated the ability of miR-22 to intercept and overcome the intrinsic resistance to MEK inhibition based on ERBB3 upregulation. Overall our results identified a novel miR-22 regulatory network with critical therapeutic implications in RMS.

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