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      Nuclear ING2 expression is reduced in human cutaneous melanomas

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          Abstract

          Cutaneous malignant melanoma is a severe and sometimes life-threatening cancer. The molecular mechanism of melanomagenesis is incompletely understood. Deregulation of apoptosis is probably one of the key factors contributing to the progression of melanoma. The inhibitor of growth (ING) family proteins are candidate tumour suppressors which play important roles in apoptosis. Downregulated expression of ING proteins have been reported in several tumour types, including the loss of nuclear expression of p33ING1b in melanoma. As ING2 exhibits 58.9% homology with p33ING1b, we hypothesized that the aberrant expression of ING2 may be involved in melanomagenesis. Here, we used tissue microarray technology and immunohistochemistry to examine ING2 expression in human nevi and melanoma biopsies. Our data showed that nuclear ING2 expression was significantly reduced in radial growth phase (RGP), vertical growth phase (VGP), and metastatic melanomas compared with dysplastic nevi ( P<0.05). Our data also revealed that nuclear ING2 expression was not associated with patient's gender, age or tumour thickness, ulceration, American Joint Committee on Cancer (AJCC) stage, tumour subtype, location and 5-year survival ( P>0.05). Taken together, our results suggest that nuclear ING2 expression is significantly reduced in human melanomas and that reduced ING2 may be an important molecular event in the initiation of melanoma development.

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          Most cited references35

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          Control of apoptosis by p53.

          The p53 tumor suppressor acts to integrate multiple stress signals into a series of diverse antiproliferative responses. One of the most important p53 functions is its ability to activate apoptosis, and disruption of this process can promote tumor progression and chemoresistance. p53 apparently promotes apoptosis through transcription-dependent and -independent mechanisms that act in concert to ensure that the cell death program proceeds efficiently. Moreover, the apoptotic activity of p53 is tightly controlled, and is influenced by a series of quantitative and qualitative events that influence the outcome of p53 activation. Interestingly, other p53 family members can also promote apoptosis, either in parallel or in concert with p53. Although incomplete, our current understanding of p53 illustrates how apoptosis can be integrated into a larger tumor suppressor network controlled by different signals, environmental factors, and cell type. Understanding this network in more detail will provide insights into cancer and other diseases, and will identify strategies to improve their therapeutic treatment.
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            Identification of XAF1 as an antagonist of XIAP anti-Caspase activity.

            The inhibitors of apoptosis (IAPs) suppress apoptosis through the inhibition of the caspase cascade and thus are key proteins in the control of cell death. Here we have isolated the protein XIAP-associated factor 1 (XAF1) on the basis of its ability to bind XIAP, a member of the IAP family. XIAP suppresses caspase activation and cell death in vitro, and XAF1 antagonizes these XIAP activities. Expression of XAF1 triggers a redistribution of XIAP from the cytosol to the nucleus. XAF1 is ubiquitously expressed in normal tissues, but is present at low or undetectable levels in many different cancer cell lines. Loss of control over apoptotic signalling is now recognized as a critical event in the development of cancer. Our results indicate that XAF1 may be important in mediating the apoptosis resistance of cancer cells.
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              Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma.

              Frequent somatic mutation of v-raf murine sarcoma viral oncogene homolog B (BRAF), a downstream effector of the rat sarcoma oncogene (RAS) signaling pathway, is described in melanoma and other tumors. Our analysis of melanoma cell lines suggests that activating mutations in BRAF can occur simultaneously with inactivation of phosphatase and tensin homolog (PTEN), but neuroblastoma RAS (NRAS) mutations are not coincident. We determined the concurrent prevalence of mutations in BRAF and NRAS, and alteration of PTEN expression in 69 primary cutaneous melanomas. BRAF mutations were seen in 57% of cases. NRAS was mutated in 17% of samples, exclusively in exon 2. Two cases showed concurrent BRAF and NRAS mutations. Using immunohistochemistry, PTEN protein expression was lost or greatly reduced in 19% of tumors. Seven tumors with reduced PTEN yielded DNA amenable to sequencing, and three also showed mutation in BRAF but none in NRAS. In all, 11 (85%) of 13 tumors showing reduced PTEN expression were greater than 3.5 mm thick, and the association of increasing Breslow thickness and loss or reduction of PTEN expression was statistically significant (P<0.0001). Mutations in NRAS were not coincident with reduced PTEN expression, and the concurrent mutation of NRAS and BRAF was rare.
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                0007-0920
                1532-1827
                27 June 2006
                03 July 2006
                : 95
                : 1
                : 80-86
                Affiliations
                [1 ]Department of Dermatology and Skin Science, Jack Bell Research Centre , Vancouver, BC, Canada V6H 3Z6
                [2 ]Department of Pathology, Vancouver Coastal Health Research Institute, University of British Columbia , Vancouver, BC Canada V6H 3Z6
                Author notes
                [* ]Author for correspondence: gangli@ 123456interchange.ubc.ca
                Article
                6603205
                10.1038/sj.bjc.6603205
                2360493
                16755297
                1df6b3d6-68af-43ed-a384-04b8bfab73c3
                Copyright 2006, Cancer Research UK
                History
                : 09 December 2005
                : 23 March 2006
                : 11 May 2006
                Categories
                Molecular Diagnostics

                Oncology & Radiotherapy
                melanoma,gene expression,ing2,tissue microarray
                Oncology & Radiotherapy
                melanoma, gene expression, ing2, tissue microarray

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