CA9-Positive Keloid Fibroblasts: Modulator of Local Inflammation Induced by the Hypoxic and Glycolysis-enhanced Microenvironment

Abstract

Background/aim: Hypoxic areas and a metabolic shift toward glycolysis are common features of keloids; however, the roles and underlying molecular mechanisms of these features in keloid pathogenesis remain largely unknown. The study aimed to investigate the role of proteins related to the hypoxia-glycolysis-acidosis sequence in keloid pathogenesis.

Materials and methods: Hypoxia-inducible factor (HIF)-1α, glucose transporter (Glut)-1, and carbonic anhydrase (CA) 9 expression were compared in five normal skin and 48 keloid tissue samples using immunohistochemistry. In vitro studies were performed using primary cultured keloid fibroblasts (KFs) obtained from two patients with keloids.

Results: HIF-1α, Glut-1, and CA9 expression were higher in keloid tissues than in normal skin tissue samples. A significant association was found between HIF-1α and Glut-1 and CA9 expression in keloid tissues. CA9 expression was associated with patients in proliferative phases or exhibiting symptoms. CA9-overexpressing KFs presented features of senescent cells, including increased senescence-associated β-galactosidase activity, senescent cell marker expression, decreased proliferation, and increased expression of inflammatory factors. Cytokine receptor interaction as well as cellular senescence were identified as significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways in oligonucleotide microarray analysis comparing CA9-overexpressing KFs and control cells.

Conclusion: Hypoxia, glycolysis, and acidosis sequencing may underlie keloid pathogenesis. CA9 may represent a mediator promoting local inflammation in keloids. This study provides insights into potential therapeutic molecular targets of keloids to effectively suppress prolonged inflammation and reduce the frequency of keloid recurrence.