Journal
ONCOTARGET
Volume 8, Issue 16, Pages 26298-26311Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.15459
Keywords
microRNA; embryonic stem cells; melanoma; miR-183 similar to 96 similar to 182 cluster; KLF4
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Funding
- NCI/NIH Grant [5R01CA155234]
- Instituto de Salud Carlos III [CP11/00052, RD12/0036/0016]
- European Regional Development Fund (ERDF)
- European Commission's Framework Programme 7 through the Marie Curie Career Integration Grants
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MicroRNAs (miRNAs) are a class of endogenous non-coding small RNAs that post-transcriptionally control the translation and stability of target mRNAs in a sequence-dependent manner. MiRNAs are essential for key cellular processes including proliferation, differentiation, cell death and metabolism, among others. Consequently, alterations of miRNA expression contribute to developmental defects and a myriad of diseases. The expression of miRNAs can be altered by several mechanisms including gene copy number alterations, aberrant DNA methylation, defects of the miRNA processing machinery or unscheduled expression of transcription factors. In this work, we sought to analyze the regulation of the miR-182 cluster, located at the 7q32 locus, which encodes three different miRNAs that are abundantly expressed in human embryonic stem cells and de-regulated in cancer. We have found that the Kruppel-like factor 4 (KLF4) directly regulates miR-182 cluster expression in human embryonic stem cells (hESCs) and in melanoma tumors, in which the miR-182 cluster is highly expressed and has a pro-metastatic role. Furthermore, higher KLF4 expression was found to be associated with metastatic progression and poor patient outcome. Loss of function experiments revealed that KLF4 is required for melanoma cell maintenance. These findings provide new insights into the regulation of the miR-182 cluster expression and new opportunities for therapeutic intervention in tumors in which the KLF4-miR-182 cluster axis is deregulated.
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