Cellular senescence in naevi and immortalisation in melanoma: a role for p16?
Cellular senescence in naevi and immortalisation in melanoma: a role for p16?
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Naevi中的细胞衰老和黑色素瘤中的永生化：P16的作用？
DOI：
10.1038/sj.bjc.6603283
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发表时间：
2006-08-21
影响因子：
8.8
通讯作者：
Bennett, D C
中科院分区：
文献类型：
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作者：
Gray-Schopfer, V C;Cheong, S C;Chong, H;Chow, J;Moss, T;Abdel-Malek, Z A;Marais, R;Wynford-Thomas, D;Bennett, D C
细胞衰老，即体细胞在有限次数的分裂后出现的不可逆的增殖停滞，被认为是癌症的关键障碍，但直到最近才在体内证明这一点的直接证据。人类细胞衰老最著名的形式归因于端粒缩短以及通过 p53 和 p21 的 DNA 损伤反应。还有一种更快速的衰老形式，依赖于 p16-视网膜母细胞瘤途径。 p16 (CDKN2A) 是已知的黑色素瘤易感基因。在这里，我们使用逆转录病毒介导的基因转移来确认培养的人类黑色素细胞的正常衰老形式涉及p16，因为需要破坏p16/视网膜母细胞瘤途径以及端粒酶激活才能永生化。黑素细胞病变中衰老介质和标记物的表达（免疫染色）模式提供了强有力的证据，表明细胞衰老发生在体内良性黑素细胞痣（痣）中，并且不涉及 p53 或 p21 上调，尽管 p16 广泛表达。相比之下，发育不良痣和早期（径向生长期，RGP）黑色素瘤显示较少的 p16 和一些 p53 和 p21 免疫染色。所有 RGP 黑色素瘤均表达 p21，表明存在 p53 介导的衰老区域，而大多数晚期（垂直生长期）黑色素瘤区域同时缺乏 p16 和 p21，这意味着逃避了两种形式的衰老（永生化）。此外，致癌性 BRAF 可以在人类黑素细胞中诱导核 p16 表达，但不能诱导 p21 表达，这一点在大约 80% 的痣中发现。我们得出的结论是，细胞衰老可以形成黑色素瘤发展的障碍。这也为 p16 为何是黑色素瘤抑制基因提供了可能的解释。
Cellular senescence, the irreversible proliferative arrest seen in somatic cells after a limited number of divisions, is considered a crucial barrier to cancer, but direct evidence for this in vivo was lacking until recently. The best-known form of human cell senescence is attributed to telomere shortening and a DNA-damage response through p53 and p21. There is also a more rapid form of senescence, dependent on the p16-retinoblastoma pathway. p16 (CDKN2A) is a known melanoma susceptibility gene. Here, we use retrovirally mediated gene transfer to confirm that the normal form of senescence in cultured human melanocytes involves p16, since disruption of the p16/retinoblastoma pathway is required as well as telomerase activation for immortalisation. Expression (immunostaining) patterns of senescence mediators and markers in melanocytic lesions provide strong evidence that cell senescence occurs in benign melanocytic naevi (moles) in vivo and does not involve p53 or p21 upregulation, although p16 is widely expressed. In comparison, dysplastic naevi and early (radial growth-phase, RGP) melanomas show less p16 and some p53 and p21 immunostaining. All RGP melanomas expressed p21, suggesting areas of p53-mediated senescence, while most areas of advanced (vertical growth-phase) melanomas lacked both p16 and p21, implying escape from both forms of senescence (immortalisation). Moreover, nuclear p16 but not p21 expression can be induced in human melanocytes by oncogenic BRAF, as found in around 80% of naevi. We conclude that cell senescence can form a barrier to melanoma development. This also provides a potential explanation of why p16 is a melanoma suppressor gene.