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Cancer Res. 2016 Jun 15;76(12):3629-43. doi: 10.1158/0008-5472.CAN-15-2665. Epub 2016 May 2.

Activation of the Lin28/let-7 Axis by Loss of ESE3/EHF Promotes a Tumorigenic and Stem-like Phenotype in Prostate Cancer.

Author information

1
Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland.
2
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
3
IRCCS Multimedica, Milan, Italy.
4
Department of Pathology, University of Insubria, Varese, Italy.
5
Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland. Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland. Department of Oncology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. pina.carbone@ior.iosi.ch carlo.catapano@ior.iosi.ch.
6
Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland. Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland. pina.carbone@ior.iosi.ch carlo.catapano@ior.iosi.ch.

Abstract

Although cancer stem-like cells (CSC) are thought to be the most tumorigenic, metastatic, and therapy-resistant cell subpopulation within human tumors, current therapies target bulk tumor cells while tending to spare CSC. In seeking to understand mechanisms needed to acquire and maintain a CSC phenotype in prostate cancer, we investigated connections between the ETS transcription factor ESE3/EHF, the Lin28/let-7 microRNA axis, and the CSC subpopulation in this malignancy. In normal cells, we found that ESE3/EHF bound and repressed promoters for the Lin28A and Lin28B genes while activating transcription and maturation of the let-7 microRNAs. In cancer cells, reduced expression of ESE3/EHF upregulated Lin28A and Lin28B and downregulated the let-7 microRNAs. Notably, we found that deregulation of the Lin28/let-7 axis with reduced production of let-7 microRNAs was critical for cell transformation and expansion of prostate CSC. Moreover, targeting Lin28A/Lin28B in cell lines and tumor xenografts mimicked the effects of ESE3/EHF and restrained tumor-initiating and self-renewal properties of prostate CSC both in vitro and in vivo These results establish that tight control by ESE3/EHF over the Lin28/let-7 axis is a critical barrier to malignant transformation, and they also suggest new strategies to antagonize CSC in human prostate cancer for therapeutic purposes. Cancer Res; 76(12); 3629-43.

PMID:
27197175
DOI:
10.1158/0008-5472.CAN-15-2665
[Indexed for MEDLINE]
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