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

Oncotarget. 2017 Feb 21;8(8):13730-13746. doi: 10.18632/oncotarget.14629.

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.

Keywords: ISCU; hypoxia inducible factor; lactate/H+ transporters; miR-210; oropharyngeal squamous cell carcinoma.

MeSH terms

  • Carbonic Anhydrase IX / metabolism*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism*
  • Cell Line, Tumor
  • Female
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Iron-Sulfur Proteins / metabolism*
  • Male
  • MicroRNAs / metabolism*
  • Middle Aged
  • Monocarboxylic Acid Transporters / metabolism*
  • Muscle Proteins / metabolism*
  • Oropharyngeal Neoplasms / genetics
  • Oropharyngeal Neoplasms / metabolism*
  • Signal Transduction
  • Squamous Cell Carcinoma of Head and Neck
  • Symporters / metabolism*
  • Up-Regulation

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • ISCU protein, human
  • Iron-Sulfur Proteins
  • MIRN210 microRNA, human
  • MicroRNAs
  • Monocarboxylic Acid Transporters
  • Muscle Proteins
  • SLC16A4 protein, human
  • Symporters
  • monocarboxylate transport protein 1
  • Carbonic Anhydrase IX