Papadimitrakopoulou V A, Izzo J, Mao L, Keck J, Hamilton D, Shin D M, El-Naggar A, den Hollander P, Liu D, Hittelman W N, Hong W K
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1500 Holcombe Boulevard, Houston, TX 77030, USA.
Clin Cancer Res. 2001 Oct;7(10):3127-34.
To better understand the role of G(1)-S transition regulator abnormalities in the pathogenesis of advanced premalignant lesions of the upper aerodigestive tract and the biological effects of chemoprevention, we studied biopsies obtained sequentially from participants in a prospective trial using 13-cis retinoic acid, IFN-alpha, and alpha-tocopherol for 12 months.
Cyclin D1 and p16 expression were analyzed by immunohistochemistry, loss of heterozygosity by polymerase chain reacting amplification, and then electrophoretic separation of the products, methylation of the p16 promoter by methylation-specific polymerase chain reacting, and cyclin D1 gene amplification by fluorescence in situ hybridization.
Baseline dysregulation of cyclin D1 expression was found in 50% (14 of 28) and was reversed in 6 of 14 cases, whereas p16 expression was lost in 46% (13 of 28) and regained in 2 of 13 cases. Loss of heterozygosity at 9p21 occurred in 68% and p16(INK4a) promoter methylation occurred in 75% of cases, with increasing frequency from mild to severe dysplasia. Cyclin D1 gene amplification was identified in two cases. Cyclin D1 protein dysregulation at last follow-up alone and in combination with p16 loss was associated with histological progression and cancer development (P < 0.01).
Additional study of these alterations in a larger sample and exploration of the upstream signaling partners of these cell cycle regulators in vivo is warranted to identify cancer risk profiles that would be meaningful targets for chemopreventive intervention.
为了更好地理解G(1)-S转换调节异常在上消化道晚期癌前病变发病机制中的作用以及化学预防的生物学效应，我们对一项前瞻性试验的参与者进行了研究，这些参与者连续12个月使用13-顺式维甲酸、干扰素-α和α-生育酚，并对其活检样本进行分析。
通过免疫组织化学分析细胞周期蛋白D1和p16的表达，通过聚合酶链反应扩增检测杂合性缺失，然后对产物进行电泳分离，通过甲基化特异性聚合酶链反应检测p16启动子的甲基化，通过荧光原位杂交检测细胞周期蛋白D1基因扩增。
在50%（28例中的14例）患者中发现细胞周期蛋白D1表达的基线失调，其中14例中有6例得到逆转；而46%（28例中的13例）患者的p16表达缺失，13例中有2例恢复。9p21杂合性缺失发生在68%的病例中，p16(INK4a)启动子甲基化发生在75%的病例中，且从轻度发育异常到重度发育异常频率增加。在两例中鉴定出细胞周期蛋白D1基因扩增。仅在最后一次随访时细胞周期蛋白D1蛋白失调以及与p16缺失共同出现与组织学进展和癌症发生相关（P < 0.01）。
有必要在更大样本中对这些改变进行进一步研究，并在体内探索这些细胞周期调节因子的上游信号伙伴，以确定癌症风险特征，这些特征将是化学预防干预的有意义靶点。
