Alterations of p14ARF and p16INK4a in Gliomas

60 - 80%的恶性胶质瘤中p16 INK 4a的表达由于纯合缺失、点突变或DNA甲基化而改变。作者试图阐明另一种INK 4a基因产物p14 ARF在恶性胶质瘤中的改变。p14 ARF直接与MDM 2结合，阻止泛素对p53的消化。在恶性胶质瘤中，p14 ARF的改变可能通过负调节p53而促进肿瘤的进展。应用免疫组织化学方法检测了93例恶性胶质瘤（39例间变性星形细胞瘤（AA），54例胶质母细胞瘤（GB））中p16 INK 4a、p14 ARF、MDM 2和p53的表达。对其中的病例进行Southern杂交分析和INK 4a基因测序。p16 INK 4a在AA和GB中的表达分别为23/39（59.0%）和27/54（50.0%）。所有p16 INK 4a缺陷病例同时也存在p14 ARF缺陷。细胞质内积累的p！5/39（12.8%）例AA和17/54（31.5%）例GB中检测到6 INK 4a，2例胞浆p16 INK 4a点突变。22例p16 INK 4a阳性者，2例p14 ARF阳性，20例p14 ARF缺失。p16 INK 4a和p14 ARF在11/39（28.2%）的AA和10/54（18.5%）的GB细胞核中表达。恶性胶质瘤中INK 4a基因的改变导致p16 INK 4a和p14 ARF基因缺陷。在恶性胶质瘤中，除INK 4a基因纯合性缺失外，p16 INK 4a可能存在另一种负调控机制，INK 4a基因点突变引起的细胞内积聚可能是p16 INK 4a和p14 ARF失活的另一种机制。

The expression of p16INK4a is altered in 60 - 80 % of malignant gliomas due to homozygous deletion, point mutation or DNA methylation. The authors tried to elucidate the alteration of another INK4a gene products, p14ARF, in malignant gliomas. p14ARF binds directly to MDM2, preventing the digestion of p53 by ubiquitine. The alteration of p14ARF is supposed to promote tumor progression through negative regulation of p53 in malignant gliomas. The expression of p16INK4a, p14ARF, MDM2 and p53 was examined by immunohistochemistry in 93 malignant gliomas [39 anaplastic astrocytomas (AA), 54 glioblastomas (GB)]. Southern blot analysis and DNA sequence of INK4a gene were performed for selected cases. p16INK4a expression was deficient in 23/39 (59.0 %) AAs and 27/54 (50.0 %) GBs, respectively. All of p16INK4a deficient cases were also deficient for p14ARF. Cytoplasmic accumulation of p!6INK4a was detected in 5/39 (12.8 %) AAs and 17/54 (31.5 %) GBs.Point mutation was detected in 2 cases with cytoplasmic p16INK4a. Among 22 cases with cytoplasmic p16INK4a, p14ARF was also accumulated in cytoplasm of 2 cases, but deficient 20 cases. p16INK4a and p14ARF ware positive in nuclei of 11/39 (28.2 %) AAs and 10/54 (18.5 %) GBs. Alteration of INK4a gene caused both p16INK4a and p14ARF deficiency in malignant gliomas. Besides homozygous deletion of INK4a gene, alternative negative regulating mechanism of p16INK4a might be present.Cytoplasmic accumulation due to point mutation of INK4a gene could be one of the alternative mechanisms for inactivation of p16INK4a and p14ARF in malignant gliomas.