Loss of function of miR-342-3p results in MCT1 over-expression and contributes to oncogenic metabolic reprogramming in triple negative breast cancer
Por:
Romero-Cordoba S.L., Rodriguez-Cuevas S., Bautista-Pina V., Maffuz-Aziz A., D’Ippolito E., Cosentino G., Baroni S., Iorio M.V., Hidalgo-Miranda A.
Publicada:
1 ene 2018
Categoría:
Multidisciplinary
Resumen:
Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive neoplasia lacking the expression of hormonal receptors and human epidermal growth factor receptor-2. Accumulating evidence has highlighted the importance of miRNAs dysregulation in the establishment of cancer programs, but the functional role of many miRNAs remains unclear. The description of miRNAs roles might provide novel strategies for treatment. In the present work, an integrated analysis of miRNA transcriptional landscape was performed (N = 132), identifying the significant down-modulation of miR-342-3p in TNBC, probably because of the aberrant activity of estrogen receptor, which serves as a transcription factor of the miRNA, as demonstrated by a siRNA-knockdown approach. The enhanced expression of miR-342-3p significantly decreased cell proliferation, viability and migration rates of diverse TN cells in vitro. Bioinformatic and functional analyses revealed that miR-342-3p directly targets the monocarboxylate transporter 1 (MCT1), which promotes lactate and glucose fluxes alteration, thus disrupting the metabolic homeostasis of tumor cells. Optical metabolic imaging assay defined a higher optical redox ratio in glycolytic cells overexpressing miR-342-3p. Furthermore, we found that hypoxic conditions and glucose starvation attenuate miR-342-3p expression, suggesting a crosstalk program between these metabolic factors. Consistently, miR-342-3p down-modulation is associated with an increased MCT1 expression level and glycolytic score in human triple negative tumors. Overall, we described for the first time the regulatory activity of miR-342-3p on relevant metabolic carcinogenic pathways in TN breast cancers. © 2018, The Author(s).
Filiaciones:
Romero-Cordoba S.L.:
Cancer Genomics Laboratory, National Institute of Genomic Medicine, Mexico City, Mexico
Start Up Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Rodriguez-Cuevas S.:
Instituto de Enfermedades de la Mama FUCAM, Mexico City, Mexico
Bautista-Pina V.:
Instituto de Enfermedades de la Mama FUCAM, Mexico City, Mexico
Maffuz-Aziz A.:
Instituto de Enfermedades de la Mama FUCAM, Mexico City, Mexico
D’Ippolito E.:
Start Up Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Cosentino G.:
Start Up Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Baroni S.:
Start Up Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Iorio M.V.:
Start Up Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Hidalgo-Miranda A.:
Cancer Genomics Laboratory, National Institute of Genomic Medicine, Mexico City, Mexico
All Open Access, Gold
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