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Translational Dysregulation in Cancer: Molecular Insights and Potential Clinical Applications in Biomarker Development

Although transcript levels have been traditionally used as a surrogate measure of gene expression, it is increasingly recognized that the latter is extensively and dynamically modulated at the level of translation (messenger RNA to protein). Over the recent years, significant progress has been made...

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Autores principales: Vaklavas, Christos, Blume, Scott W., Grizzle, William E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526920/
https://www.ncbi.nlm.nih.gov/pubmed/28798901
http://dx.doi.org/10.3389/fonc.2017.00158
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author Vaklavas, Christos
Blume, Scott W.
Grizzle, William E.
author_facet Vaklavas, Christos
Blume, Scott W.
Grizzle, William E.
author_sort Vaklavas, Christos
collection PubMed
description Although transcript levels have been traditionally used as a surrogate measure of gene expression, it is increasingly recognized that the latter is extensively and dynamically modulated at the level of translation (messenger RNA to protein). Over the recent years, significant progress has been made in dissecting the complex posttranscriptional mechanisms that regulate gene expression. This advancement in knowledge came hand in hand with the progress made in the methodologies to study translation both at gene-specific as well as global genomic level. The majority of translational control is exerted at the level of initiation; nonetheless, protein synthesis can be modulated at the level of translation elongation, termination, and recycling. Sequence and structural elements and epitranscriptomic modifications of individual transcripts allow for dynamic gene-specific modulation of translation. Cancer cells usurp the regulatory mechanisms that govern translation to carry out translational programs that lead to the phenotypic hallmarks of cancer. Translation is a critical nexus in neoplastic transformation. Multiple oncogenes and signaling pathways that are activated, upregulated, or mutated in cancer converge on translation and their transformative impact “bottlenecks” at the level of translation. Moreover, this translational dysregulation allows cancer cells to adapt to a diverse array of stresses associated with a hostile microenviroment and antitumor therapies. All elements involved in the process of translation, from the transcriptional template, the components of the translational machinery, to the proteins that interact with the transcriptome, have been found to be qualitatively and/or quantitatively perturbed in cancer. This review discusses the regulatory mechanisms that govern translation in normal cells and how translation becomes dysregulated in cancer leading to the phenotypic hallmarks of malignancy. We also discuss how dysregulated mediators or components of translation can be utilized as biomarkers with potential diagnostic, prognostic, or predictive significance. Such biomarkers have the potential advantage of uniform applicability in the face of inherent tumor heterogeneity and deoxyribonucleic acid instability. As translation becomes increasingly recognized as a process gone awry in cancer and agents are developed to target it, the utility and significance of these potential biomarkers is expected to increase.
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spelling pubmed-55269202017-08-10 Translational Dysregulation in Cancer: Molecular Insights and Potential Clinical Applications in Biomarker Development Vaklavas, Christos Blume, Scott W. Grizzle, William E. Front Oncol Oncology Although transcript levels have been traditionally used as a surrogate measure of gene expression, it is increasingly recognized that the latter is extensively and dynamically modulated at the level of translation (messenger RNA to protein). Over the recent years, significant progress has been made in dissecting the complex posttranscriptional mechanisms that regulate gene expression. This advancement in knowledge came hand in hand with the progress made in the methodologies to study translation both at gene-specific as well as global genomic level. The majority of translational control is exerted at the level of initiation; nonetheless, protein synthesis can be modulated at the level of translation elongation, termination, and recycling. Sequence and structural elements and epitranscriptomic modifications of individual transcripts allow for dynamic gene-specific modulation of translation. Cancer cells usurp the regulatory mechanisms that govern translation to carry out translational programs that lead to the phenotypic hallmarks of cancer. Translation is a critical nexus in neoplastic transformation. Multiple oncogenes and signaling pathways that are activated, upregulated, or mutated in cancer converge on translation and their transformative impact “bottlenecks” at the level of translation. Moreover, this translational dysregulation allows cancer cells to adapt to a diverse array of stresses associated with a hostile microenviroment and antitumor therapies. All elements involved in the process of translation, from the transcriptional template, the components of the translational machinery, to the proteins that interact with the transcriptome, have been found to be qualitatively and/or quantitatively perturbed in cancer. This review discusses the regulatory mechanisms that govern translation in normal cells and how translation becomes dysregulated in cancer leading to the phenotypic hallmarks of malignancy. We also discuss how dysregulated mediators or components of translation can be utilized as biomarkers with potential diagnostic, prognostic, or predictive significance. Such biomarkers have the potential advantage of uniform applicability in the face of inherent tumor heterogeneity and deoxyribonucleic acid instability. As translation becomes increasingly recognized as a process gone awry in cancer and agents are developed to target it, the utility and significance of these potential biomarkers is expected to increase. Frontiers Media S.A. 2017-07-26 /pmc/articles/PMC5526920/ /pubmed/28798901 http://dx.doi.org/10.3389/fonc.2017.00158 Text en Copyright © 2017 Vaklavas, Blume and Grizzle. http://creativecommons.org/licenses/by/4.0/ 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.
spellingShingle Oncology
Vaklavas, Christos
Blume, Scott W.
Grizzle, William E.
Translational Dysregulation in Cancer: Molecular Insights and Potential Clinical Applications in Biomarker Development
title Translational Dysregulation in Cancer: Molecular Insights and Potential Clinical Applications in Biomarker Development
title_full Translational Dysregulation in Cancer: Molecular Insights and Potential Clinical Applications in Biomarker Development
title_fullStr Translational Dysregulation in Cancer: Molecular Insights and Potential Clinical Applications in Biomarker Development
title_full_unstemmed Translational Dysregulation in Cancer: Molecular Insights and Potential Clinical Applications in Biomarker Development
title_short Translational Dysregulation in Cancer: Molecular Insights and Potential Clinical Applications in Biomarker Development
title_sort translational dysregulation in cancer: molecular insights and potential clinical applications in biomarker development
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526920/
https://www.ncbi.nlm.nih.gov/pubmed/28798901
http://dx.doi.org/10.3389/fonc.2017.00158
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