P53 in human melanoma fails to regulate target genes associated with apoptosis and the cell cycle and may contribute to proliferation

BMC Cancer

Research Article

Rodney J Scott¹  Carla F Kairupan¹  Nikola A Bowden¹  Bente A Talseth-Palmer¹  Katie A Ashton¹  Kelly A Avery-Kiejda²  Peter Hersey²  Amanda J Croft²  Xu D Zhang²  Lyndee L Scurr³  Helen Rizos³ 

[1] Discipline of Medical Genetics, School of Biomedical Sciences, Faculty of Health, University of Newcastle at the Hunter Medical Research Institute, Newcastle, NSW, Australia;Oncology and Immunology, Calvary Mater Newcastle Hospital, University of Newcastle, Newcastle, NSW, Australia;Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, NSW, Australia;

关键词: Melanoma;    Melanoma Cell;    Metastatic Melanoma;    Melanoma Cell Line;    Control shRNA;   

DOI  :  10.1186/1471-2407-11-203

 received in 2010-10-19, accepted in 2011-05-27,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundMetastatic melanoma represents a major clinical problem. Its incidence continues to rise in western countries and there are currently no curative treatments. While mutation of the P53 tumour suppressor gene is a common feature of many types of cancer, mutational inactivation of P53 in melanoma is uncommon; however, its function often appears abnormal.MethodsIn this study whole genome bead arrays were used to examine the transcript expression of P53 target genes in extracts from 82 melanoma metastases and 6 melanoma cell lines, to provide a global assessment of aberrant P53 function. The expression of these genes was also examined in extracts derived from diploid human melanocytes and fibroblasts.ResultsThe results indicated that P53 target transcripts involved in apoptosis were under-expressed in melanoma metastases and melanoma cell lines, while those involved in the cell cycle were over-expressed in melanoma cell lines. There was little difference in the transcript expression of P53 target genes between cell lines with null/mutant P53 compared to those with wild-type P53, suggesting that altered expression in melanoma was not related to P53 status. Similarly, down-regulation of P53 by short-hairpin RNA (shRNA) had limited effect on P53 target gene expression in melanoma cells, whereas there were a large number of P53 target genes whose mRNA expression was significantly altered by P53 inhibition in melanocytes. Analysis of whole genome gene expression profiles indicated that the ability of P53 to regulate genes involved in the cell cycle was significantly reduced in melanoma cells. Moreover, inhibition of P53 in melanocytes induced changes in gene expression profiles that were characteristic of melanoma cells and resulted in increased proliferation. Conversely, knockdown of P53 in melanoma cells resulted in decreased proliferation.ConclusionsThese results indicate that P53 target genes involved in apoptosis and cell cycle regulation are aberrantly expressed in melanoma and that this aberrant functional activity of P53 may contribute to the proliferation of melanoma.

【 授权许可】

Unknown   
© Avery-Kiejda et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.