Oncogene‐dependent control of miRNA biogenesis and metastatic progression in a model of undifferentiated pleomorphic sarcoma

JK Mito, HD Min, Y Ma, JE Carter… - The Journal of …, 2013 - Wiley Online Library
JK Mito, HD Min, Y Ma, JE Carter, BE Brigman, L Dodd, D Dankort, M McMahon, DG Kirsch
The Journal of pathology, 2013Wiley Online Library
Undifferentiated pleomorphic sarcoma (UPS) is one of the most common soft tissue
malignancies. Patients with large, high‐grade sarcomas often develop fatal lung
metastases. Understanding the mechanisms underlying sarcoma metastasis is needed to
improve treatment of these patients. Micro‐RNAs (miRNAs) are a class of small RNAs that
post‐transcriptionally regulate gene expression. Global alterations in miRNAs are frequently
observed in a number of disease states including cancer. The signalling pathways that …
Abstract
Undifferentiated pleomorphic sarcoma (UPS) is one of the most common soft tissue malignancies. Patients with large, high‐grade sarcomas often develop fatal lung metastases. Understanding the mechanisms underlying sarcoma metastasis is needed to improve treatment of these patients. Micro‐RNAs (miRNAs) are a class of small RNAs that post‐transcriptionally regulate gene expression. Global alterations in miRNAs are frequently observed in a number of disease states including cancer. The signalling pathways that regulate miRNA biogenesis are beginning to emerge. To test the relevance of specific oncogenic mutations in miRNA biogenesis in sarcoma, we used primary soft tissue sarcomas expressing either BrafV600E or KrasG12D. We found that BrafV600E mutant tumours, which have increased MAPK signalling, have higher levels of mature miRNAs and enhanced miRNA processing. To investigate the relevance of oncogene‐dependent alterations in miRNA biogenesis, we introduced conditional mutations in Dicer and showed that Dicer haploinsufficiency promotes the development of distant metastases in an oncogene‐dependent manner. These results demonstrate that a specific oncogenic mutation can cooperate with mutation in Dicer to promote tumour progression in vivo.Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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