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Oncogene. 2014 Aug 21;33(34):4296-306. doi: 10.1038/onc.2013.385. Epub 2013 Sep 23.

miR-26a enhances miRNA biogenesis by targeting Lin28B and Zcchc11 to suppress tumor growth and metastasis.

Author information

1
Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
2
1] Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA [2] Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
3
Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
4
1] Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA [2] Department of Molecular Pharmacology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
5
1] Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA [2] Department of Cancer Immunotherapy and Tumor Immunology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
6
1] Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA [2] Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.

Abstract

Human cancers often exhibit attenuated microRNA (miRNA) biogenesis and global underexpression of miRNAs; thus, targeting the miRNA biogenesis pathway represents a novel strategy for cancer therapy. Here, we report that miR-26a enhances miRNA biogenesis, which acts as a common mechanism partially accounting for miR-26a function in diverse cancers including melanoma, prostate and liver cancer. miR-26a was broadly reduced in multiple cancers, and overexpression of miR-26a significantly suppressed tumor growth and metastasis both in vitro and in vivo, including melanoma, prostate and liver cancers. Notably, miR-26a overexpression was accompanied by global upregulation of miRNAs, especially let-7, and let-7 expression was concordant with miR-26a expression in cancer cell lines, xenograft tumors and normal human tissues, underscoring their biological relevance. We showed that miR-26a directly targeted Lin28B and Zcchc11-two critical repressors of let-7 maturation. Furthermore, we have demonstrated that Zcchc11 promoted tumor growth and metastasis, and it was prominently overexpressed in human cancers. Our findings thus provide a novel mechanism by which a miRNA acts as a modulator of miRNA biogenesis. These results also define a role of the miR-26a and Zcchc11 in tumorigenesis and metastasis and have implications to develop new strategies for cancer therapy.

PMID:
24056962
PMCID:
PMC4873289
DOI:
10.1038/onc.2013.385
[Indexed for MEDLINE]
Free PMC Article
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