Photocarcinogenesis and inhibition of intercellular adhesion molecule 1 expression in cells of DNA-repair-defective individuals

Abstract

Cells from patients with xeroderma pigmentosum complementation group D (XP-D) and most patients with trichothiodystrophy (TTD) are deficient in excision repair of ultraviolet (UV) radiation-induced DNA damage. Although in both syndromes this defect is based on mutations in the same gene, XPD, only XP-D, not TTD, individuals have an increased risk of skin cancer. Since the reduction in DNA repair capacity is similar in XP-D and TTD patients, it cannot account for the difference in skin cancer risk. The features of XP-D and TTD might therefore be attributable to differences in the immune response following UV-irradiation, a factor which is presumed to be important for photocarcinogenesis. Sunlight-induced skin cancer represents the most prevalent malignancy in the Caucasian population, and its incidence is increasing (1). The pathogenesis of photocarcinogenesis is complex and only partially understood. Sunlight is a complete carcinogen, and it is generally accepted that ultraviolet B (UVB; 290-320 nm) radiation-induced DNA mutations constitute the initiation event for the generation of malignant skin cells (2). Studies in animals, however, provide evidence for a second mechanism for the development of clinically apparent skin cancer following UVB radiation exposure. In these studies, UVB radiation at subcarcinogenic doses was found to inhibit the surveillance function of the skin immune system directed against UVB radiation-induced skin tumors (3, 4). The importance of this second mechanism for photocarcinogenesis was demonstrated in tumor transplantation studies in mice, which cannot be carried out in humans. The evidence for a role of UVB radiation-induced immunosuppression in human skin cancer is therefore inevitably circumstantial and includes the observation that immunosuppressed humans who have received renal transplants have an increased frequency of sunlight-induced skin cancers (5-8).Here we take advantage of two human syndromes associated with defects in excision repair of UV-induced DNA lesions, namely xeroderma pigmentosum complementation group D (XP-D) and trichothiodystrophy (TTD) (9-11). Cells derived from XP-D and the majority of TTD patients have a defect in nucleotide excision repair (12, 13), which results from mutations in the same gene (XPD) (refs. 14-16 and unpublished results of B. C. Broughton and A.R.L.). Despite this similarity and a similar frequency of UV-induced mutations (17), only XP-D patients have an increased risk of developing skin cancer (10, 11). Since the increased risk of skin cancer in XP-D, as compared with TTD patients, cannot be explained simply by differences in DNA repair capacity, we hypothesized that XP-D and TTD cells might differ in some aspect of the immune response after UVB radiation.To test this hypothesis, the capacity of UVB radiation to suppress transcriptional expression of the intercellular adhesion molecule 1 (ICAM-1) was assessed in comparative studies employing XP-D and TTD cells. ICAM-1 serves as a ligand for leukocyte function-associated antige...

Enzyme plus light therapy to repair DNA damage in ultraviolet-B-irradiated human skin

“…In previous studies, the induction of ICAM-1 expression in human cells, including keratinocytes, has been shown to be suppressed upon exposure to sublethal doses of UVB radiation (22). This immunosuppressive effect of UVB irradiation was found to be dose-dependent, and this assay system has therefore been used as a photoimmunological endpoint to assess the susceptibility of human skin cells toward UVB radiation-induced immunosuppression (23). The present study demonstrated that, similar to the in vitro situation, UVB radiation is capable of suppressing IFN-␥-induced ICAM-1 expression in vivo as well.…”

Activation of p70 Ribosomal Protein S6 Kinase Is an Essential Step in the DNA Damage-dependent Signaling Pathway Responsible for the Ultraviolet B-mediated Increase in Interstitial Collagenase (MMP-1) and Stromelysin-1 (MMP-3) Protein Levels in Human Dermal Fibroblasts

“…A possible clue why the DNA repair inhibitor aphidicolin results in almost complete suppression of the UVB-induced MMP-1 and MMP-3 transcription, may come from the dual role of certain proteins in repair and transcription (86). The importance of this dual function in the regulation of distinct genes, such as ICAM-1, has recently been reported (87). Whether a similar mechanism may be active in aphidicolin suppression of the UVB-induced transcription of MMP-1 and MMP-3 genes remains to be resolved.…”

Mitochondrial Cytochrome c Release Mediates Ceramide-induced Activator Protein 2 Activation and Gene Expression in Keratinocytes

“…Expression of ICAM-1 was measured by differential reverse transcriptase-PCR using the RT-PCR core kit (Applied Biosystems, Darmstadt, Germany) and a specific primer pair for ICAM-1 (5Ј-TGACCAGCCCAAGTTGTTGG-3Ј, 5Ј-ATCTCTCC-TCACCAGCACCG-3Ј). Semiquantitative analysis of the RT-PCR products was done using ion exchange chromatography connected to an on-line UV spectrophotometer (absorption at 260 nm) (22,24). Gene expression was assessed in cells treated with 10 M C6-ceramide or 1000 units/ml IFN-␥.…”

“…Osteosarcoma cells depleted for mitochondrial DNA (Rho 0 cells) served as controls (21). Human dermal fibroblasts prepared from neonatal foreskin were cultured as described (22). HeLa cells were obtained from ATCC and cultured as described (23).…”