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      Insights into the Regulatory Role of Non-coding RNAs in Cancer Metabolism

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          Abstract

          Cancer represents a complex disease originated from alterations in several genes leading to disturbances in important signaling pathways in tumor biology, favoring heterogeneity that promotes adaptability and pharmacological resistance of tumor cells. Metabolic reprogramming has emerged as an important hallmark of cancer characterized by the presence of aerobic glycolysis, increased glutaminolysis and fatty acid biosynthesis, as well as an altered mitochondrial energy production. The metabolic switches that support energetic requirements of cancer cells are closely related to either activation of oncogenes or down-modulation of tumor-suppressor genes, finally leading to dysregulation of cell proliferation, metastasis and drug resistance signals. Non-coding RNAs (ncRNAs) have emerged as one important kind of molecules that can regulate altered genes contributing, to the establishment of metabolic reprogramming. Moreover, diverse metabolic signals can regulate ncRNA expression and activity at genetic, transcriptional, or epigenetic levels. The regulatory landscape of ncRNAs may provide a new approach for understanding and treatment of different types of malignancies. In this review we discuss the regulatory role exerted by ncRNAs on metabolic enzymes and pathways involved in glucose, lipid, and amino acid metabolism. We also review how metabolic stress conditions and tumoral microenvironment influence ncRNA expression and activity. Furthermore, we comment on the therapeutic potential of metabolism-related ncRNAs in cancer.

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          Most cited references162

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          On the origin of cancer cells.

          O WARBURG (1956)
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            miR-126 regulates angiogenic signaling and vascular integrity.

            Precise regulation of the formation, maintenance, and remodeling of the vasculature is required for normal development, tissue response to injury, and tumor progression. How specific microRNAs intersect with and modulate angiogenic signaling cascades is unknown. Here, we identified microRNAs that were enriched in endothelial cells derived from mouse embryonic stem (ES) cells and in developing mouse embryos. We found that miR-126 regulated the response of endothelial cells to VEGF. Additionally, knockdown of miR-126 in zebrafish resulted in loss of vascular integrity and hemorrhage during embryonic development. miR-126 functioned in part by directly repressing negative regulators of the VEGF pathway, including the Sprouty-related protein SPRED1 and phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2/p85-beta). Increased expression of Spred1 or inhibition of VEGF signaling in zebrafish resulted in defects similar to miR-126 knockdown. These findings illustrate that a single miRNA can regulate vascular integrity and angiogenesis, providing a new target for modulating vascular formation and function.
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              Akt stimulates aerobic glycolysis in cancer cells.

              Cancer cells frequently display high rates of aerobic glycolysis in comparison to their nontransformed counterparts, although the molecular basis of this phenomenon remains poorly understood. Constitutive activity of the serine/threonine kinase Akt is a common perturbation observed in malignant cells. Surprisingly, although Akt activity is sufficient to promote leukemogenesis in nontransformed hematopoietic precursors and maintenance of Akt activity was required for rapid disease progression, the expression of activated Akt did not increase the proliferation of the premalignant or malignant cells in culture. However, Akt stimulated glucose consumption in transformed cells without affecting the rate of oxidative phosphorylation. High rates of aerobic glycolysis were also identified in human glioblastoma cells possessing but not those lacking constitutive Akt activity. Akt-expressing cells were more susceptible than control cells to death after glucose withdrawal. These data suggest that activation of the Akt oncogene is sufficient to stimulate the switch to aerobic glycolysis characteristic of cancer cells and that Akt activity renders cancer cells dependent on aerobic glycolysis for continued growth and survival.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                08 August 2016
                2016
                : 7
                : 342
                Affiliations
                Cancer Genomics Laboratory, National Institute of Genomic Medicine Mexico City, Mexico
                Author notes

                Edited by: Firas H. Kobeissy, University of Florida, USA

                Reviewed by: Guanglong Jiang, Indiana University School of Medicine, USA; Noriko Hiroi, Keio University, Japan

                *Correspondence: Alfredo Hidalgo-Miranda ahidalgo@ 123456inmegen.gob.mx
                Sandra L. Romero-Cordoba sromero_cordoba@ 123456hotmail.com

                This article was submitted to Systems Biology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2016.00342
                4976125
                27551267
                a5d0322e-152e-4229-9981-f6a3072e0836
                Copyright © 2016 Beltrán-Anaya, Cedro-Tanda, Hidalgo-Miranda and Romero-Cordoba.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 25 May 2016
                : 25 July 2016
                Page count
                Figures: 5, Tables: 4, Equations: 0, References: 244, Pages: 21, Words: 15785
                Categories
                Physiology
                Review

                Anatomy & Physiology
                metabolic reprogramming,cancer metabolism,ncrna regulation,mirnas
                Anatomy & Physiology
                metabolic reprogramming, cancer metabolism, ncrna regulation, mirnas

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