Number of acquired melanocytic nevi in patients with melanoma and control subjects in Japan: Nevus count is a significant risk factor for nonacral melanoma but not for acral melanoma.

BACKGROUND: Epidemiologic studies have suggested that number of acquired melanocytic nevi is a risk factor for melanoma development in Japanese as it is in white populations. However, there are only a few population-based studies on acquired nevi in Asian populations, and no epidemiologic study on relationship between number of acquired nevi and melanoma in Japanese populations has been reported. OBJECTIVE: The purpose of this study was to assess number, size, and distribution of acquired melanocytic nevi in a Japanese population. Particular attention was paid to evaluation of relationship between number of acquired nevi and development of nonacral or acral malignant melanoma. METHODS: In all, 82 patients with malignant melanoma and 600 control subjects were included in this study. All participants were Japanese. The number of acquired melanocytic nevi, 2 mm or larger in diameter, on the whole body except the scalp and genital areas was counted by experienced dermatologists. The participants were divided into 5 age categories (0-19, 20-39, 40-59, 60-79, and >80 years old) for the statistical analyses. This categorization adjusted the age and sex distribution between patients with melanomas and control subjects in 40- to 59-, 60- to 79-, and over 80-year-old groups. RESULTS: In the control Japanese population, the number of acquired melanocytic nevi on the whole body increased with age in 0- to 19-year-old age group and reached the highest number, 6.7 +/- 8.1/person, in 20- to 39-year-old group. In patients with nonacral melanoma, the number of acquired nevi on the whole body in 40- to 59- and 60- to 79-year-old groups was significantly higher than that of the corresponding control group. In contrast, the rate of individuals who had acquired nevi on soles, palms, and nail apparatus was not significantly different between acral melanoma group and the control group in 40- to 59- and 60- to 79-year-old groups. CONCLUSION: This study has revealed that a large number of acquired melanocytic nevi is a risk factor for the development of nonacral melanoma in Japanese and white populations. However, acquired nevi on soles, palms, and nail apparatus do not seem to be a risk factor for acral melanoma in Japanese populations.

ASC/TMS1, a caspase-1 activating adaptor, is downregulated by aberrant methylation in human melanoma.

ASC/TMS1 is an adaptor protein activating caspase-1 that stimulates processing of proIL-1beta and proIL-18. ASC was reported to be aberrantly methylated and silenced in human breast cancers. In our present study, ASC expression was examined in 12 melanoma cell lines by Western blot analysis and in 18 benign melanocytic nevi and 32 melanoma tissues by immunohistochemical staining. ASC expression was absent or reduced in 7 of 12 (58.3%) cell lines and in 20 of 32 (62.5%) melanoma tissues, whereas all 18 benign melanocytic nevi showed intensive ASC expression. To investigate whether ASC silencing in melanoma is involved in aberrant methylation, methylation specific PCR was carried out. Five of ten (50%) melanoma tissues exhibited methylation in CpG island of ASC companied with reduced ASC expression. Six of twelve (50%) melanoma cell lines showed aberrant methylation in the ASC gene, and 4 of the 6 (66.7%) methylation positive cell lines exhibited reduced ASC expression. We characterized methylation patterns in melanoma cell lines by using bisulfite genomic sequencing, and found that the degree of aberrant methylation correlated with the level of reductive ASC expression. Treatment with demethylating agent 5-aza-2'-deoxycytidine resulted in both demethylation of the ASC gene and the upregulation of ASC expression in the methylation positive melanoma cell lines. Our study shows that ASC is downregulated in melanoma, and that its suppression is partially mediated by aberrant methylation.

Calponin h1 suppresses tumor growth of Src-induced transformed 3Y1 cells in association with a decrease in angiogenesis.

Calponin h1 (CNh1) is a basic actin-binding protein that is abundantly expressed in smooth muscle cells and involved in smooth muscle contraction by inhibiting actomyosin MgATPase. In recent studies, CNh1 was noted to suppress cell proliferation and tumorigenicity in leiomyosarcoma and tumor growth in fibrosarcoma cell lines. To further investigate the function of CNh1 as a tumor suppressor, we transfected the human CNh1 gene into a v-src-transformed rat fibroblast cell line SR-3Y1. The volume of the tumors derived from one randomly selected CNh1-transfectant (C1) in nude mice was reduced to 34.1% of that from a randomly selected vector transfectant (V1). A similar tendency was observed in another independent pair (C2, V2). Pathological analysis showed a significant decrease in the number of mitotic cells in the CNh1-transfectants. Further, a marked reduction in the number of vessels in the CNh1-transfectant was observed. DNA synthesis under conditions without serum was significantly reduced in the CNh1-transfectant (C1) compared with the control transfectant (V1), while no significant difference was seen in the cellular growth in the presence of 10% serum. A slight but significant reduction in in vitro cellular motility in the CNh1-transfectant was also observed. While the suppression of growth potential and cell motility by CNh1 transfer was significant but partial, a marked reduction in vascular endothelial growth factor (VEGF) mRNA and the secretion of VEGF protein was observed in the CNh1-transfectant. These results suggest that CNh1 plays a role as tumor suppressor in SR-3Y1 mainly by decreasing VEGF expression and angiogenesis in vivo and partially through reducing cellular proliferative potential and cell motility.