Expression patterns of cell cycle components in sporadic and neurofibromatosis type 1-related malignant peripheral nerve sheath tumors
Expression patterns of cell cycle components in sporadic and neurofibromatosis type 1-related malignant peripheral nerve sheath tumors
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DOI：
10.1093/jnen/64.1.74
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发表时间：
2005-01-01
影响因子：
3.2
通讯作者：
Lothe, RA
中科院分区：
文献类型：
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作者：
Agesen, TH;Florenes, VA;Lothe, RA
高度恶性外周神经鞘瘤（MPNSTs）的分子生物学基础的发展仍然是未知的。在本研究中，10个选定的细胞周期成分的表达模式进行了研究，在一系列的15 MPNST患者（n = 9）或（n = 5）神经纤维瘤病1型（NF 1）。13例肿瘤不表达细胞周期蛋白依赖性激酶抑制剂p16（INK4A），这一观察结果与3例肿瘤的纯合子基因缺失、5例肿瘤的杂合子基因缺失和5例肿瘤的基因重排有关。具有一个看似完整等位基因的肿瘤中蛋白表达的缺失不是由p16（INK4A）或p14（ARF）启动子高甲基化引起的。所有肿瘤样品均表达正常大小的RB1、细胞周期蛋白D3、CDK2、CDK4、p21（CIP1）和p27（KIP1）蛋白，只有单个肿瘤显示这些蛋白之一p21（CIP1）的异常蛋白条带。4个肿瘤中没有细胞周期蛋白D1，除1个肿瘤外，所有肿瘤均表达TP53蛋白，9个MPNST中有3个表达正常大小的MDM2。总之，这项研究表明，绝大多数MPNST具有p16（INK4A）基因的总体重排，解释了在相同肿瘤中编码蛋白的缺失。表达水平在家族性（NF 1）和散发性病例之间均匀分布，但应注意的是，2例p16（INK4A）表达病例是散发性的。这些数据表明，p16（INK4A）的完全缺乏是足以激活大多数MPNST的细胞周期，因此，它是没有必要的肿瘤增殖，以进一步刺激通过改变其他中心组件的周期。
The molecular biology underlying the development of highly malignant peripheral nerve sheath tumors (MPNSTs) remains mostly unknown. In the present study, the expression pattern of 10 selected cell cycle components is investigated in a series of 15 MPNSTs from patients with (n = 9) or without (n = 5) neurofibromatosis type 1 (NF1). Thirteen tumors did not express the cyclin-dependent kinase inhibitor, p16(INK4A), an observation that was related to homozygote gene deletions in three tumors, heterozygote deletions in five, and gross gene rearrangements in five. The absence of protein expression in the tumors with one seemingly intact allele was not caused by promoter hypermethylation of p16(INK4A) or p14(ARF). All tumor samples expressed normal sized RB1, cyclin D3, CDK2, CDK4, p21(CIP1), and p27(KIP1) proteins, and only a single tumor showed an aberrant protein band for one of these proteins, p21(CIP1). Cyclin D1 was absent in four tumors; all except one tumor showed expression of TP53 protein, and three of nine MPNSTs had expression of normal-sized MDM2. In conclusion, this study shows that the vast majority of MPNSTs had gross rearrangements of the p16(INK4A) gene, explaining the absence of the encoded protein in the same tumors. The level of expression was equally distributed between the familial (NF1) and sporadic cases, although it should be noted that the 2 cases with p16(INK4A) expression were sporadic. The data imply that the complete absence of p16(INK4A) is sufficient for activation of the cell cycle in most MPNSTs; thus, it is not necessary for tumor proliferation to further stimulate the cycle through alteration of other central components.