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.
abstract: 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.
authors.affiliation: Servicio de Otorrinolaringología, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias and CIBERONC, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: Sáenz-de-Santa-María
authors.affiliation: Servicio de Otorrinolaringología, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias and CIBERONC, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Cristóbal
authors.initials: C
authors.lastname: Bernardo-Castiñeira
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, CX, Amsterdam, The Netherlands.
authors.forename: Pablo
authors.initials: P
authors.lastname: Secades
authors.affiliation: Servicio de Otorrinolaringología, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias and CIBERONC, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Bernaldo-de-Quirós
authors.affiliation: Servicio de Otorrinolaringología, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias and CIBERONC, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Rodrigo
authors.affiliation: Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Aurora
authors.initials: A
authors.lastname: Astudillo
authors.affiliation: Servicio de Otorrinolaringología, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias and CIBERONC, Universidad de Oviedo, Oviedo, Spain.
authors.forename: María-Dolores
authors.initials: MD
authors.lastname: Chiara
mesh_terms: D000071231:Carbonic Anhydrase IX / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D009959:Oropharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D027981:Symporters / Q000378:metabolism*; D015854:Up-Regulation; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000071231:Carbonic Anhydrase IX; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007506:Iron-Sulfur Proteins; D035683:MicroRNAs; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C506160:ISCU protein, human; C543800:MIRN210 microRNA, human; C406962:SLC16A4 protein, human
keywords: ISCU; hypoxia inducible factor; lactate/H+ transporters; miR-210; oropharyngeal squamous cell carcinoma