Downregulation of apoptosis-related genes in keloid tissues

Background. Physiologically programmed cell death or apoptosis occurs durin g the natural balance between cellular proliferation and demise. Materials and Methods. We compared the expression of 64 apoptosis-related g enes in keloids and normal scars to investigate the potential role of apopt osis in keloid formation. Two sets of mRNA were isolated from keloids excis ed from four previously untreated patients and four normal scar patients se parately. Human cDNA arrayed hybridization was performed to compare the apo ptosis-related gene expression between these two groups. In addition, TUNEL assays were performed to evaluate the percentage of apoptotic cells in kel oids (center and periphery) versus normal scars. Results. Eight of the sixty-four apoptosis-related genes studied were signi ficantly underexpressed in keloid tissue. The underexpressed genes and thei r relative expression compared with normal scar were defender against cell death 1 (DAD-1) (34.1% of normal scar); nucleoside diphosphate kinase B (c- myc transcription factor) (24.7%); glutathione S-transferase (17.9%); gluta thione S-transferase microsomal (28.1%); glutathione peroxidase (47.2%); tu mor necrosis factor receptor 1-associated protein (TRADD) (51.0%); 19-kDa i nteracting protein 3 (NIP3) (36.0%); and cytoplasmic dynein light chain 1 ( HDLC1) (47.7%), Spatial analysis of apoptosis using TUNEL assays revealed a poptosis indices of 0.83 for keloid periphery and 0.63 for keloid center. Conclusions. In this study we demonstrated underexpression of apoptosis-rel ated genes in human keloid tissue and decreased apoptotic activity in fibro blasts derived from keloids versus normal scars. We hypothesized that keloi d fibroblasts fail to undergo physiologically programmed cell death and, th us, continue to produce and secrete connective tissue beyond the period exp ected in normal scar formation, accounting for the progressive and hypertro phic nature of keloids, This mechanism leads to new possibilities for treat ment of keloids through induction of apoptosis, (C) 1999 Academic Press.