Hypoxia and HIF-1 alpha Regulate Collagen Production in Keloids

Abstract

Keloids are reactive or spontaneous fibroproliferative dermal tumors characterized by the exaggerated and uncontrolled accumulation of extracellular collagen. Current approaches to mitigate keloidogenesis are largely procedural in nature. However, a better understanding of its biological drivers may lead to novel targeted treatments for keloids. Through whole-genome expression analysis, we found that an HIF-1 alpha transcriptional footprint is preferentially upregulated (activation score = 2.024; P = 1.05E-19) in keloid fibroblasts compared with normal dermal fibroblasts. We verified that HIF-1 alpha protein is more strongly expressed in keloid specimens compared with normal skin (P = 0.035) and that hypoxia (1% O-2) leads to increased collagen, especially in the extracellular compartment. Collagen levels were reduced uniformly by selective HIF-1 alpha inhibitor CAY10585. Our results indicate that collagen secretion may be intimately linked to a hypoxic microenvironment within keloid tumors and that HIF-1 alpha blockade could be a novel avenue of treatment for these tumors.