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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.
Highlights
Malignant cell transformation requires metabolic reprogramming to support anabolic cell growth
And 1B, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway involved in glycolysis/ gluconeogenesis was found as the most significantly enriched in hypoxic versus normoxic cells. This includes TPI, HK, LDHA, PGK, PGAM genes which are known hypoxia inducible factor-1α (HIF-1α) target genes. These genes were not found up-regulated by hypoxia when SCC38 cells were treated with HIF-1α-directed siRNAs (Figure 1C)
This study provides in vivo evidences supporting that HIF-1α, CAIX, miR-210 and iron-sulfur cluster assembly protein (ISCU) are coordinately activated in oropharyngeal squamous cell carcinomas (SCC)
Summary
Malignant cell transformation requires metabolic reprogramming to support anabolic cell growth. The glucose-derived pyruvate generated in cancer cells, rather than being oxidized in mitochondria, is transformed into lactate in the cytosol and is subsequently exported to the micro-environment. This metabolic shift with production of lactate even in the presence of sufficient oxygen is known as the Warburg effect [2] which is a highly regulated metabolic state that diverts glycolytic intermediates into branching pathways that allow the generation of biosynthetic precursors [3]. HCO3− anions can be recaptured by the tumour cells through HCO3− transporters to assist with intracellularpH buffering [11, 12] These proteins, coupled with other modifiers of the intracellular pH, actively contribute to the development of tumor cells that have a more alkaline intracellular pH than normal cells, despite being surrounded by an acidic stromal microenvironment. The generation of this unique pH gradient likely represents a key factor in promoting the capacity of the tumor to invade and metastasize [13]
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