Analysis of HOX gene expression and the effects of HOXA9 overexpression in fibroblasts derived from keloid lesions and normal skin

Keloids are fibroproliferative lesions resulting from an abnormal wound healing process due to pathological mechanisms that remain incompletely understood. Keloids tend to occur more frequently in anterior versus posterior body regions (e.g., ears, face, upper torso); this has been attributed to higher skin tension in those areas, although this has not yet been conclusively proven. Previous studies reported reduced expression of multiple homeobox (HOX) genes in keloid versus normal fibroblasts, suggesting a role for HOX genes in keloid pathology. However, HOX genes are differentially expressed along the anterior-posterior axis. Hypothetically, differential HOX expression may be due to differences in body sites, as matched donor sites are often unavailable for keloids and normal skin. To better understand the basis for differential HOX gene expression in cells from keloids compared with normal skin, we compared HOXA7, HOXA9, HOXC8 and HOXC11 expression in keloid and normal skin-derived fibroblasts from various body sites. When keloid (N = 20) and normal (N = 12) fibroblast cell strains were evaluated, expression of HOXA7, HOXA9 and HOXC8 was significantly lower in keloid versus normal fibroblasts. However, HOX gene expression was lower in fibroblasts from more anterior versus posterior body sites. When keloid and normal cells from similar body sites were compared, differential HOX expression was not observed. To investigate the phenotypic relevance of HOX expression, HOXA9 was overexpressed in keloid and normal fibroblasts. HOXA9 overexpression did not affect proliferation but significantly reduced fibroblast migration and altered gene expression. The results suggest that differential HOX expression may be due to differences in positional identity between keloid and normal fibroblasts. However, HOX genes can potentially regulate fibroblast phenotype, suggesting that differential HOX gene expression may play a role in keloid development in anterior body sites.