The multi-step process of human skin carcinogenesis:: A role for p53, cyclin D1, hTERT, p16, and TSP-1
The multi-step process of human skin carcinogenesis:: A role for p53, cyclin D1, hTERT, p16, and TSP-1
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DOI：
10.1016/j.ejcb.2006.11.002
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发表时间：
2007-12-01
影响因子：
6.6
通讯作者：
Boukamp, Petra
中科院分区：
文献类型：
--
作者：
Burnworth, Bettina;Arendt, Susanne;Boukamp, Petra
正如Hanahan和温伯格（2000. Cell 100，57-70）致癌作用需要关键事件，例如（1）基因组不稳定性，（11）细胞周期失调，（iii）诱导端粒长度维持机制，和（iv）血管生成开关。通过比较p53、细胞周期蛋白D1、p16、hTERT和TSP-1在作为早期瘤形成范例的自发消退的角化棘皮瘤（KA）中的表达，以及作为晚期肿瘤发展范例的恶性浸润性皮肤鳞状细胞癌（SCC），我们现在能够将这些蛋白质表达的变化分配到特定的阶段，并将它们分配到多个皮肤癌发生是一个多步骤的过程。我们发现，突变失活的p53基因，并与基因组不稳定的发病是最早的事件。单个p53;在“正常”皮肤中已经看到p53阳性细胞，并且3/5的光化性角化病（AK）、5/22的KA和13/23的SCC含有p53阳性斑块。细胞周期调节因子cyclin D1的过度表达以及细胞周期抑制因子p16的丢失表明细胞周期失调。有趣的是，在80%的KA和SCC中分别观察到细胞周期蛋白D1的过表达，在裸鼠的HaCaT细胞移植中显示出细胞周期独立的功能。细胞周期蛋白D1过度表达与大量炎症反应相关，最终导致组织破坏。另一方面，细胞周期抑制剂p16的缺失与SCC相关。因此，这是诱人的建议，细胞周期蛋白D I的过度表达是一个早期的变化，除了生长刺激导致改变上皮-间充质相互作用，而功能p16能够控制这种失调的生长，需要消除恶性进展。不受控制的生长的另一个要求是通过上调端粒酶活性来抑制端粒侵蚀。如通过hTERT蛋白表达所测量的，所研究的所有KA和SCC均为阳性，在两组中具有类似的蛋白质分布和类似于正常表皮的表达模式。因此，端粒酶可能不需要在皮肤癌中显着增加。最后，我们发现血管生成抑制剂TSP-1在大多数KA中强烈表达，并且主要由肿瘤细胞表达，而在SCC中，通常弱表达仅限于肿瘤间质。此外，我们提供的证据表明，15号染色体的一个拷贝的丢失是负责减少TSP-1的表达，从而这种畸变有助于肿瘤血管形成（即血管生成开关）所需的恶性生长。(c)2006年Elsevier GmbH。All rights reserved.
As proposed by Hanahan and Weinberg (2000. Cell 100, 57-70) carcinogenesis requires crucial events such as (1) genomic instability, (11) cell cycle deregulation, (iii) induction of a telomere length maintenance mechanism, and (iv) an angiogenic switch. By comparing the expression of p53, cyclin D1, p16, hTERT, and TSP-1 in spontaneously regressing keratoacanthoma (KA) as a paradigm of early neoplasia, with malignant invasive cutaneous squamous cell carcinoma (SCC) as a paradigm of advanced tumour development, we are now able to assign the changes in the expression of these proteins to specific stages and allocate them to defined roles in the multi-step process of skin carcinogenesis. We show that mutational inactivation of the p53 gene, and with that the onset of genomic instability is the earliest event. Individual p53;-positive cells are already seen in "normal" skin, and 3/5 actinic keratoses (AKs), 5/22 KAs, and 13/23 SCCs contain p53-positive patches. Cell cycle deregulation was indicated by the overexpression of the cell cycle regulator cyclin D1, as well as by the loss of the cell cycle inhibitor p16. Interestingly, overexpression of cyclin D1 - observed in 80% of KAs and SCCs, respectively - showed a cell cycle-independent function in HaCaT cell transplants on nude mice. Cyclin D1 overexpression was associated with a massive inflammatory response, finally leading to tissue destruction. Loss of the cell cycle inhibitor p16, on the other hand, correlated with SCCs. Thus, it is tempting to suggest that overexpression of cyclin D I is an early change that in addition to growth stimulation leads to an altered epithelial-mesenchymal interaction, while functional p16 is able to control this deregulated growth and needs to be eliminated for malignant progression. Another requirement for uncontrolled growth is the inhibition of telomere erosion by up-regulating telomerase activity. As measured by hTERT protein expression, all of the KAs and SCCs studied were positive, with a similar distribution of the protein in both groups and an expression pattern resembling that of normal epidermis. Thus, telomerase may not need to be increased significantly in skin carcinomas. Finally, we show that the angiogenesis)genesis inhibitor TSP-1 is strongly expressed in most KAs, and mainly by the tumour cells, while in SCCs the generally weak expression is restricted to the tumour-stroma. Furthermore, we provide evidence that the loss of a copy of chromosome 15 is responsible for reduced TSP-1 expression and thereby this aberration contributes to tumour vascularisation (i.e. the angiogenic switch) required for malignant growth. (c) 2006 Elsevier GmbH. All rights reserved.