Olasz Judit, Juhász Alíz, Remenár Eva, Engi Helga, Bak Mihály, Csuka Orsolya, Kásler Miklós
Department of Pathogenetics, National Institute of Oncology, 1122 Budapest, Hungary.
Oncol Rep. 2007 Jul;18(1):105-12.
Retinoids as important growth and differentiation regulating agents have a potential role in the chemoprevention of head and neck squamous cell carcinoma (HNSCC). Despite the promising preclinical and early clinical findings, limitations of application are raised by intrinsic resistance acquired during carcinogenesis. Retinoic acid receptor beta2 (RAR beta2) is one of the proximate mediators of retinoid signalling and its expression is often diminished in early stages of head and neck carcinogenesis. One form of retinoid resistance has been associated with the methylation-induced silencing of the RAR beta gene. We studied primary HNSCC samples of different anatomical sites in respect of methylation, expression and allelic loss of RAR beta gene. A strong correlation (p<0.01) was found between hyper-methylation and reduced expression of RAR beta2, however the allelic loss at 3p24, the locus of RAR beta, did not considerably influence its mRNA level. Hypopharynx tumors showed significantly lower hypermethylation (p<0.05) and higher mRNA expression levels of RAR beta2 compared to the tumors located at other sites of the head and neck. We could also provide evidence that poorly differentiated grade 3 tumors had significantly higher RAR beta2 expression and lower methylation levels (p<0.05) than better differentiated grade 1 and grade 2 tumors. In addition, we found a good correlation between the methylation degree of the RAR beta2 promoter and the ages of patients. Collectively, our results suggest that evaluation of several factors such as tumor location, age, histology and methylation state of the RAR beta gene might contribute to the selection of patients for retinoid-based chemoprevention.
维甲酸作为重要的生长和分化调节因子，在头颈部鳞状细胞癌（HNSCC）的化学预防中具有潜在作用。尽管临床前和早期临床研究结果令人鼓舞，但致癌过程中获得的内在抗性限制了其应用。维甲酸受体β2（RARβ2）是维甲酸信号传导的直接介质之一，其表达在头颈部致癌早期阶段常降低。一种维甲酸抗性形式与RARβ基因的甲基化诱导沉默有关。我们研究了不同解剖部位的原发性HNSCC样本中RARβ基因的甲基化、表达和等位基因缺失情况。发现RARβ2的高甲基化与表达降低之间存在强相关性（p<0.01），然而，RARβ基因座3p24处的等位基因缺失对其mRNA水平没有显著影响。与位于头颈部其他部位的肿瘤相比，下咽肿瘤的RARβ2高甲基化显著降低（p<0.05），mRNA表达水平更高。我们还可以证明，低分化3级肿瘤的RARβ2表达明显高于高分化1级和2级肿瘤，甲基化水平更低（p<0.05）。此外，我们发现RARβ2启动子的甲基化程度与患者年龄之间存在良好的相关性。总体而言，我们的结果表明，评估肿瘤位置、年龄、组织学和RARβ基因的甲基化状态等多个因素可能有助于选择基于维甲酸的化学预防患者。
