Wang Y, Becker D
Department of Medicine, University of Pittsburgh, Pennsylvania 15213, USA.
Oncogene. 1996 Mar 7;12(5):1069-75.
To determine whether loss or inactivation of the putative tumor-suppressor gene, p16, represents an initiating or a secondary event in the progression of human melanoma, we evaluated the status of this gene in early and advanced-stage melanomas of sporadic origin. The results of this analysis revealed p16 deletions in 4/6 primary and 6/14 metastatic melanoma cell lines but not in 3/3 metastatic melanoma specimens. Surprisingly, p16 deletions were also detected in 8/8 benign compound nevi and in 1/3 normal human melanocyte isolates. To investigate whether these deletions in benign and malignant stages of the human melanocytic system were specific for p16, we analysed the same specimens and cell lines for expression of p21, another cyclin-dependent kinase inhibitor and potential tumor suppressor. In contrast to p16, expression of p21 was detected in 3/3 melanocytes, in 3/3 benign nevi, and in greater than 50% of malignant melanoma cell lines and specimens. Finally, because of the recently documented inverse relationship between expression of p16 and pRb protein in a variety of tumor cell lines, we analysed some of the p16-positive and negative melanoma cell lines for the presence of pRb protein. The results demonstrated pRb protein in each of these cell lines. Taken together, although this study revealed deletions of the p16 gene in a significant number of sporadic primary and metastatic melanoma cell lines, they were also detected in benign nevus specimens and in some normal human melanocyte isolates. Thus, these findings cast some doubt on the role of this gene as being causal to the onset and progression of human melanoma, in particular, sporadic melanoma.
为了确定假定的肿瘤抑制基因p16的缺失或失活是人类黑色素瘤进展过程中的起始事件还是继发事件，我们评估了散发性起源的早期和晚期黑色素瘤中该基因的状态。分析结果显示，在4/6的原发性和6/14的转移性黑色素瘤细胞系中存在p16缺失，但在3/3的转移性黑色素瘤标本中未检测到。令人惊讶的是，在8/8的良性复合痣和1/3的正常人黑素细胞分离物中也检测到了p16缺失。为了研究人类黑素细胞系统良性和恶性阶段的这些缺失是否对p16具有特异性，我们分析了相同的标本和细胞系中另一种细胞周期蛋白依赖性激酶抑制剂及潜在肿瘤抑制因子p21的表达情况。与p16不同，在3/3的黑素细胞、3/3的良性痣以及超过50%的恶性黑色素瘤细胞系和标本中检测到了p21的表达。最后，由于最近记录的多种肿瘤细胞系中p16和pRb蛋白表达之间的负相关关系，我们分析了一些p16阳性和阴性的黑色素瘤细胞系中pRb蛋白的存在情况。结果显示这些细胞系中均存在pRb蛋白。综上所述，尽管本研究揭示了大量散发性原发性和转移性黑色素瘤细胞系中存在p16基因缺失，但在良性痣标本和一些正常人黑素细胞分离物中也检测到了该缺失。因此，这些发现对该基因在人类黑色素瘤尤其是散发性黑色素瘤的发生和进展中所起的因果作用提出了一些质疑。
