Kumamoto Hiroyuki, Izutsu Takashi, Ohki Kousuke, Takahashi Nobuhiro, Ooya Kiyoshi
Department of Oral Medicine and Surgery, Tohoku University Graduate School of Dentistry, Sendai, Japan.
J Oral Pathol Med. 2004 May;33(5):292-9. doi: 10.1111/j.0904-2512.2004.00044.x.
To clarify the roles of the p53-MDM2-p14(ARF) cell cycle regulation system in oncogenesis and cytodifferentiation of odontogenic tumors, p53 gene status and expression of p53, MDM2, and p14(ARF) proteins was analyzed in ameloblastomas as well as tooth germs.
Paraffin sections of 16 tooth germs and 46 benign and 5 malignant ameloblastomas were examined immunohistochemically for the expression of p53, MDM2, and p14(ARF) proteins. Frozen tissue samples of 10 benign ameloblastomas and 1 malignant (metastasizing) ameloblastoma were analyzed by direct DNA sequencing to detect p53 gene alteration.
Immunohistochemical reactivity for p53 was detected in 2 of 13 tooth germs, 13 of 29 ameloblastomas, and 5 of 5 malignant ameloblastomas, and the expression ratio of p53 in tooth germs was significantly lower than those in benign and malignant ameloblastomas. Direct DNA sequencing showed no alteration of p53 gene exons 5-8 in any sample of 10 benign ameloblastomas and 1 metastasizing ameloblastoma. Expression of MDM2 and p14(ARF) was detected in all samples of normal and neoplastic odontogenic epithelium, and the expression ratios in tooth germs tended to be lower than those in benign and malignant ameloblastomas. In ameloblastomas, expression of p53, MDM2, and p14(ARF) was significantly higher in plexiform cases than in follicular cases. Markedly decreased reactivity for p53, MDM2, and p14(ARF) was detected in keratinizing and granular cells in ameloblastoma subtypes. Basal cell ameloblastoma showed slightly higher reactivity for p53, MDM2, and p14(ARF) as compared with other subtypes.
Elevated expression of p53, MDM2, and p14(ARF) in benign and malignant ameloblastomas suggests that alteration of the p53-MDM2-p14(ARF) cascade is involved in oncogenesis and/of malignant transformation of odontogenic epithelium. p53 gene status implied that p53 mutation might play a minor role in neoplastic changes of odontogenic epithelium. Immunoreactivity for p53, MDM2, and p14(ARF) in ameloblastoma variants suggests that these factors might be associated with tissue structuring and cytodifferentiation of ameloblastomas.
为阐明p53-MDM2-p14(ARF)细胞周期调控系统在牙源性肿瘤发生和细胞分化中的作用，对成釉细胞瘤以及牙胚中的p53基因状态和p53、MDM2及p14(ARF)蛋白的表达进行了分析。
采用免疫组织化学方法检测16个牙胚、46例良性和5例恶性成釉细胞瘤石蜡切片中p53、MDM2及p14(ARF)蛋白的表达。采用直接DNA测序法分析10例良性成釉细胞瘤和1例恶性（转移性）成釉细胞瘤冷冻组织样本，以检测p53基因改变。
在13个牙胚中的2个、29例成釉细胞瘤中的13例以及5例恶性成釉细胞瘤中的5例检测到p53免疫组织化学反应性，牙胚中p53的表达率显著低于良性和恶性成釉细胞瘤。直接DNA测序显示，10例良性成釉细胞瘤和1例转移性成釉细胞瘤的任何样本中p53基因外显子5-至8均无改变。在所有正常和肿瘤性牙源性上皮样本中均检测到MDM2和p14(ARF)表达，牙胚中的表达率往往低于良性和恶性成釉细胞瘤。在成釉细胞瘤中，丛状型病例中p53、MDM2和p14(ARF)的表达显著高于滤泡型病例。在成釉细胞瘤亚型的角化细胞和颗粒细胞中检测到p53、MDM2和p14(ARF)的反应性明显降低。基底细胞型成釉细胞瘤与其他亚型相比，p53、MDM2和p14(ARF)的反应性略高。
良性和恶性成釉细胞瘤中p53、MDM2和p14(ARF)表达升高表明，p53-MDM2-p14(ARF)级联改变参与牙源性上皮的发生和/或恶性转化。p53基因状态表明p53突变可能在牙源性上皮的肿瘤性改变中起次要作用。成釉细胞瘤变体中p53、MDM2和p14(ARF)的免疫反应性表明，这些因素可能与成釉细胞瘤的组织结构和细胞分化有关。
