P53 in human melanoma fails to regulate target genes associated with apoptosis and the cell cycle and may contribute to proliferation.
P53 in human melanoma fails to regulate target genes associated with apoptosis and the cell cycle and may contribute to proliferation.
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DOI：
10.1186/1471-2407-11-203
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发表时间：
2011-05-27
期刊：
影响因子：
3.8
通讯作者：
Hersey P
中科院分区：
文献类型：
--
作者：
Avery-Kiejda KA;Bowden NA;Croft AJ;Scurr LL;Kairupan CF;Ashton KA;Talseth-Palmer BA;Rizos H;Zhang XD;Scott RJ;Hersey P
转移性黑色素瘤是一个主要的临床问题。它在西方国家的发病率继续上升，目前还没有根治的方法。虽然P53肿瘤抑制基因突变是许多类型癌症的共同特征，但P53突变失活在黑色素瘤中并不常见；然而，其功能经常出现异常。本研究利用全基因组珠阵列技术检测了82例黑色素瘤转移瘤细胞和6株黑色素瘤细胞株提取液中P53靶基因的转录表达，以期对异常的P53功能进行整体评估。从二倍体人类黑素细胞和成纤维细胞中提取的提取物中也检测到了这些基因的表达。结果表明，在黑色素瘤转移瘤和黑色素瘤细胞系中，参与细胞凋亡的P53靶向转录本低表达，而在黑色素瘤细胞系中，参与细胞周期的P53靶向转录本高表达。P53基因缺失/突变的细胞株与野生型P53基因表达差异无统计学意义，提示黑色素瘤中P53基因的表达改变与P53状态无关。同样，短发夹状RNA(ShRNA)下调P53对黑色素瘤细胞中P53靶基因表达的影响有限，而在黑色素瘤细胞中存在大量的P53靶基因，其mRNA表达被P53抑制显著改变。全基因组基因表达谱分析表明，在黑色素瘤细胞中，p53调控细胞周期相关基因的能力显著降低。此外，抑制黑素细胞中的p53会导致黑色素瘤细胞特有的基因表达谱发生变化，并导致细胞增殖增加。相反，黑色素瘤细胞中P53基因的敲除会导致细胞增殖减少。这些结果表明，参与细胞凋亡和细胞周期调控的P53靶基因在黑色素瘤中异常表达，这种异常的功能活性可能与黑色素瘤的增殖有关。
Metastatic 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. In 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. The 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. These 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.
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影响因子：
64.5
作者：
Cawley, S;Bekiranov, S;Gingeras, TR
通讯作者：
Gingeras, TR
影响因子：
8
作者：
Kichina, JV;Rauth, S;Gudkov, AV
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Gudkov, AV
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5.4
作者：
Dull, T;Zufferey, R;Naldini, L
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Naldini, L
影响因子：
8.8
作者：
Mhaidat, N. M.;Zhang, X. D.;Allen, J.;Avery-Kiejda, K. A.;Scott, R. J.;Hersey, P.
通讯作者：
Hersey, P.
影响因子：
11.5
作者：
Avery-Kiejda, Kelly A.;Zhang, Xu Dong;Hersey, Peter
通讯作者：
Hersey, Peter