Cargando…

Clinically relevant HIF-1α-dependent metabolic reprogramming in oropharyngeal squamous cell carcinomas includes coordinated activation of CAIX and the miR-210/ISCU signaling axis, but not MCT1 and MCT4 upregulation

Metabolic reprogramming is a very heterogeneous phenomenon in cancer. It mostly consists on increased glycolysis, lactic acid formation and extracellular acidification. These events have been associated to increased activity of the hypoxia inducible factor, HIF-1α. This study aimed at defining the m...

Descripción completa

Detalles Bibliográficos
Autores principales: Sáenz-de-Santa-María, Inés, Bernardo-Castiñeira, Cristóbal, Secades, Pablo, Bernaldo-de-Quirós, Sandra, Rodrigo, Juan Pablo, Astudillo, Aurora, Chiara, María-Dolores
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355133/
https://www.ncbi.nlm.nih.gov/pubmed/28099149
http://dx.doi.org/10.18632/oncotarget.14629
_version_ 1782515475431817216
author Sáenz-de-Santa-María, Inés
Bernardo-Castiñeira, Cristóbal
Secades, Pablo
Bernaldo-de-Quirós, Sandra
Rodrigo, Juan Pablo
Astudillo, Aurora
Chiara, María-Dolores
author_facet Sáenz-de-Santa-María, Inés
Bernardo-Castiñeira, Cristóbal
Secades, Pablo
Bernaldo-de-Quirós, Sandra
Rodrigo, Juan Pablo
Astudillo, Aurora
Chiara, María-Dolores
author_sort Sáenz-de-Santa-María, Inés
collection PubMed
description Metabolic reprogramming is a very heterogeneous phenomenon in cancer. It mostly consists on increased glycolysis, lactic acid formation and extracellular acidification. These events have been associated to increased activity of the hypoxia inducible factor, HIF-1α. This study aimed at defining the metabolic program activated by HIF-1α in oropharyngeal squamous cell carcinomas (SCC) and assessing its clinical impact. Global gene/miRNA expression was analyzed in SCC-derived cells exposed to hypoxia. Expression of HIF-1α, the carbonic anhydrase CAIX, and the lactate/H(+) transporters MCT1 and MCT4 were analyzed by immunohistochemistry in 246 SCCs. Cell-based analysis revealed that HIF-1α-driven metabolic program includes over-expression of glycolytic enzymes and the microRNA miR-210 coupled to down-regulation of its target, the iron-sulfur cluster assembly protein, ISCU. pH-regulator program entailed over-expression of CAIX, but not MCT1 or MCT4. Accordingly, significant overlapping exists between over-expression of HIF-1α and CAIX, but not HIF-1α and MCT1 or MCT4, in tumor cells. Increased miR-210 and concomitant decreased ISCU RNA levels were found in ~40% of tumors and this was significantly associated with HIF-1α and CAIX, but not MCT1 or MCT4, over-expression. HIF-1α and/or CAIX over-expression was associated with high recurrence rate and low overall survival of surgically treated patients. By contrast, clinically significant correlations were not found in tumors with MCT1 or MCT4 over-expression. This is the first study that provides in vivo evidences of coordinated activation of HIF-1α, CAIX, miR-210 and ISCU in carcinoma and association with poor prognosis, a finding with important implications for the development of metabolic-targeting therapies against hypoxia.
format Online
Article
Text
id pubmed-5355133
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-53551332017-04-15 Clinically relevant HIF-1α-dependent metabolic reprogramming in oropharyngeal squamous cell carcinomas includes coordinated activation of CAIX and the miR-210/ISCU signaling axis, but not MCT1 and MCT4 upregulation Sáenz-de-Santa-María, Inés Bernardo-Castiñeira, Cristóbal Secades, Pablo Bernaldo-de-Quirós, Sandra Rodrigo, Juan Pablo Astudillo, Aurora Chiara, María-Dolores Oncotarget Research Paper Metabolic reprogramming is a very heterogeneous phenomenon in cancer. It mostly consists on increased glycolysis, lactic acid formation and extracellular acidification. These events have been associated to increased activity of the hypoxia inducible factor, HIF-1α. This study aimed at defining the metabolic program activated by HIF-1α in oropharyngeal squamous cell carcinomas (SCC) and assessing its clinical impact. Global gene/miRNA expression was analyzed in SCC-derived cells exposed to hypoxia. Expression of HIF-1α, the carbonic anhydrase CAIX, and the lactate/H(+) transporters MCT1 and MCT4 were analyzed by immunohistochemistry in 246 SCCs. Cell-based analysis revealed that HIF-1α-driven metabolic program includes over-expression of glycolytic enzymes and the microRNA miR-210 coupled to down-regulation of its target, the iron-sulfur cluster assembly protein, ISCU. pH-regulator program entailed over-expression of CAIX, but not MCT1 or MCT4. Accordingly, significant overlapping exists between over-expression of HIF-1α and CAIX, but not HIF-1α and MCT1 or MCT4, in tumor cells. Increased miR-210 and concomitant decreased ISCU RNA levels were found in ~40% of tumors and this was significantly associated with HIF-1α and CAIX, but not MCT1 or MCT4, over-expression. HIF-1α and/or CAIX over-expression was associated with high recurrence rate and low overall survival of surgically treated patients. By contrast, clinically significant correlations were not found in tumors with MCT1 or MCT4 over-expression. This is the first study that provides in vivo evidences of coordinated activation of HIF-1α, CAIX, miR-210 and ISCU in carcinoma and association with poor prognosis, a finding with important implications for the development of metabolic-targeting therapies against hypoxia. Impact Journals LLC 2017-01-13 /pmc/articles/PMC5355133/ /pubmed/28099149 http://dx.doi.org/10.18632/oncotarget.14629 Text en Copyright: © 2017 Sáenz-de-Santa-María et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Sáenz-de-Santa-María, Inés
Bernardo-Castiñeira, Cristóbal
Secades, Pablo
Bernaldo-de-Quirós, Sandra
Rodrigo, Juan Pablo
Astudillo, Aurora
Chiara, María-Dolores
Clinically relevant HIF-1α-dependent metabolic reprogramming in oropharyngeal squamous cell carcinomas includes coordinated activation of CAIX and the miR-210/ISCU signaling axis, but not MCT1 and MCT4 upregulation
title Clinically relevant HIF-1α-dependent metabolic reprogramming in oropharyngeal squamous cell carcinomas includes coordinated activation of CAIX and the miR-210/ISCU signaling axis, but not MCT1 and MCT4 upregulation
title_full Clinically relevant HIF-1α-dependent metabolic reprogramming in oropharyngeal squamous cell carcinomas includes coordinated activation of CAIX and the miR-210/ISCU signaling axis, but not MCT1 and MCT4 upregulation
title_fullStr Clinically relevant HIF-1α-dependent metabolic reprogramming in oropharyngeal squamous cell carcinomas includes coordinated activation of CAIX and the miR-210/ISCU signaling axis, but not MCT1 and MCT4 upregulation
title_full_unstemmed Clinically relevant HIF-1α-dependent metabolic reprogramming in oropharyngeal squamous cell carcinomas includes coordinated activation of CAIX and the miR-210/ISCU signaling axis, but not MCT1 and MCT4 upregulation
title_short Clinically relevant HIF-1α-dependent metabolic reprogramming in oropharyngeal squamous cell carcinomas includes coordinated activation of CAIX and the miR-210/ISCU signaling axis, but not MCT1 and MCT4 upregulation
title_sort clinically relevant hif-1α-dependent metabolic reprogramming in oropharyngeal squamous cell carcinomas includes coordinated activation of caix and the mir-210/iscu signaling axis, but not mct1 and mct4 upregulation
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355133/
https://www.ncbi.nlm.nih.gov/pubmed/28099149
http://dx.doi.org/10.18632/oncotarget.14629
work_keys_str_mv AT saenzdesantamariaines clinicallyrelevanthif1adependentmetabolicreprogramminginoropharyngealsquamouscellcarcinomasincludescoordinatedactivationofcaixandthemir210iscusignalingaxisbutnotmct1andmct4upregulation
AT bernardocastineiracristobal clinicallyrelevanthif1adependentmetabolicreprogramminginoropharyngealsquamouscellcarcinomasincludescoordinatedactivationofcaixandthemir210iscusignalingaxisbutnotmct1andmct4upregulation
AT secadespablo clinicallyrelevanthif1adependentmetabolicreprogramminginoropharyngealsquamouscellcarcinomasincludescoordinatedactivationofcaixandthemir210iscusignalingaxisbutnotmct1andmct4upregulation
AT bernaldodequirossandra clinicallyrelevanthif1adependentmetabolicreprogramminginoropharyngealsquamouscellcarcinomasincludescoordinatedactivationofcaixandthemir210iscusignalingaxisbutnotmct1andmct4upregulation
AT rodrigojuanpablo clinicallyrelevanthif1adependentmetabolicreprogramminginoropharyngealsquamouscellcarcinomasincludescoordinatedactivationofcaixandthemir210iscusignalingaxisbutnotmct1andmct4upregulation
AT astudilloaurora clinicallyrelevanthif1adependentmetabolicreprogramminginoropharyngealsquamouscellcarcinomasincludescoordinatedactivationofcaixandthemir210iscusignalingaxisbutnotmct1andmct4upregulation
AT chiaramariadolores clinicallyrelevanthif1adependentmetabolicreprogramminginoropharyngealsquamouscellcarcinomasincludescoordinatedactivationofcaixandthemir210iscusignalingaxisbutnotmct1andmct4upregulation