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Background: Vascular endothelial growth factor A (VEGFA), a critical mediator of tumor angiogenesis, is a well-characterized target of hypoxia-inducible factor 1 (HIF-1). Murine arrest-defective protein 1A (mARD1A(225)) acetylates HIF-1alpha, triggering its degradation, and thus may play a role in decreased expression of VEGFA.Methods: We generated Apc(Min/+)/mARD1A(225) transgenic mice and quantified growth of intestinal polyps. Human gastric MKN74 and murine melanoma B16F10 cells overexpressing mARD1A(225) were injected into mice, and tumor growth and metastasis were measured. VEGFA expression and microvessel density in tumors were assessed using immunohistochemistry. To evaluate the role of mARD1A(225) acetylation of Lys532 in HIF-1alpha, we injected B16F10-mARD1A(225) cell lines stably expressing mutant HIF-1alpha/K532R into mice and measured metastasis. All statistical tests were two-sided, and P values less than .05 were considered statistically significant.Results: Apc(Min/+)/mARD1A(225) transgenic mice (n = 25) had statistically significantly fewer intestinal polyps than Apc(Min/+) mice (n = 21) (number of intestinal polyps per mouse: Apc(Min/+) mice vs Apc(Min/+)/mARD1A(225) transgenic mice, mean = 83.4 vs 38.0 polyps, difference = 45.4 polyps, 95% confidence interval [CI] = 41.8 to 48.6; P < .001). The growth and metastases of transplanted tumors were also statistically significantly reduced in mice injected with mARD1A(225)-overexpressing cells than in mice injected with control cells (P < .01). Moreover, overexpression of mARD1A(225) decreased VEGFA expression and microvessel density in tumor xenografts (P < .04) and Apc(Min/+) intestinal polyps (P = .001). Mutation of lysine 532 of HIF-1alpha in B16F10-mARD1A(225) cells prevented HIF-1alpha degradation and inhibited the antimetastatic effect of mARD1A(225) (P < .001).Conclusion: mARD1A(225) may be a novel upstream target that blocks VEGFA expression and tumor-related angiogenesis. [ABSTRACT FROM AUTHOR]

Abstract Background Though acral lentiginous melanoma (ALM) is a major type of malignant melanoma, no immunohistochemical study on this type of melanoma has been reported. Objective The purpose of this study is to analysis the immunohistochemical findings of ALM using routinely used immune markers. Methods An immunohistochemical study was performed on paraffin sections of 20 ALMs using S-100 protein, HMB-45, MART-1, vimentin, epithelial membrane antigen (EMA) and CAM 5.2. Results S-100 protein (95%) was found to be a more sensitive marker than either HMB-45 (80%) or MART-1 (70%) for recognizing ALM. Melanin bleaching was useful for recognizing heavily pigmented ALM using both S-100 protein and HMB-45. The intensity of HMB-45 correlated well with the melanin content. However, there was no significant correlation between the intensity of S-100 protein and the melanin content. One and two out of 20 cases stained focally with EMA and CAM5.2, respectively, but these cases stained also with HMB-45 and/or S-100 protein. Conclusions S-100 protein and HMB-45 were relatively sensitive markers for recognizing ALM. Despite the occasional positivity for the epithelial markers in ALM, all epithelial marker-positive cases stained also with HMB-45 and/or S-100 protein. Therefore, we recommend that the panel of antibodies used for recognizing ALM should contain at least S-100 protein and HMB-45. [ABSTRACT FROM AUTHOR]