%0 Journal Article
%T Melanoma Development and Progression Are Associated with Rad6 Upregulation and ¦Â-Catenin Relocation to the Cell Membrane
%A Karli Rosner
%A Darius R. Mehregan
%A Evangelia Kirou
%A Judith Abrams
%A Seongho Kim
%A Michelle Campbell
%A Jillian Frieder
%A Kelsey Lawrence
%A Brittany Haynes
%A Malathy P. V. Shekhar
%J Journal of Skin Cancer
%D 2014
%I Hindawi Publishing Corporation
%R 10.1155/2014/439205
%X We have previously demonstrated that Rad6 and ¦Â-catenin enhance each other's expression through a positive feedback loop to promote breast cancer development/progression. While ¦Â-catenin has been implicated in melanoma pathogenesis, Rad6 function has not been investigated. Here, we examined the relationship between Rad6 and ¦Â-catenin in melanoma development and progression. Eighty-eight cutaneous tumors, 30 nevi, 29 primary melanoma, and 29 metastatic melanomas, were immunostained with anti-¦Â-catenin and anti-Rad6 antibodies. Strong expression of Rad6 was observed in only 27% of nevi as compared to 100% of primary and 96% of metastatic melanomas. ¦Â-Catenin was strongly expressed in 97% of primary and 93% of metastatic melanomas, and unlike Rad6, in 93% of nevi. None of the tumors expressed nuclear ¦Â-catenin. ¦Â-Catenin was exclusively localized on the cell membrane of 55% of primary, 62% of metastatic melanomas, and only 10% of nevi. Cytoplasmic ¦Â-catenin was detected in 90% of nevi, 17% of primary, and 8% of metastatic melanoma, whereas 28% of primary and 30% of metastatic melanomas exhibited ¦Â-catenin at both locations. These data suggest that melanoma development and progression are associated with Rad6 upregulation and membranous redistribution of ¦Â-catenin and that ¦Â-catenin and Rad6 play independent roles in melanoma development. 1. Introduction The Wnt/¦Â-catenin pathway has been implicated in the development and progression of melanoma and a wide range of cancer types, including colorectal cancer, breast cancer, esophageal carcinoma, and liver cancer [1¨C3]. Under normal conditions, intracellular ¦Â-catenin levels are kept low through a multiprotein system that mediates ¦Â-catenin degradation [4]. Increases in expression and binding of certain Wnt ligands to Frizzled receptor or mutations in specific components of the ¦Â-catenin degradation assembly deactivate this regulatory mechanism. Consequently, ¦Â-catenin accumulates in the cytoplasm and translocates to the nucleus. Nuclear ¦Â-catenin stimulates transcription of a large number of TCF/¦Â-catenin responsive genes that include cyclin D1, c-myc [5, 6], and the melanocyte-specific gene, microphthalmia-associated transcription factor MITF-M [7]. Thus, accumulation of nuclear ¦Â-catenin as observed in several cancer types is considered a marker of canonical Wnt/¦Â-catenin pathway deregulation and unfavorable prognosis [3, 8]. Previous studies have reported an association between nuclear ¦Â-catenin accumulation and melanoma progression and suggested nuclear ¦Â-catenin to be a marker of poor prognosis [1, 7].
%U http://www.hindawi.com/journals/jsc/2014/439205/