Chen Ying, Wang Zhao-Yan, Wu Hao
Department of Otolaryngology, Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Kongjiang Road #1665, Shanghai, 200092, China.
Eur Arch Otorhinolaryngol. 2015 Sep;272(9):2227-34. doi: 10.1007/s00405-014-3135-y. Epub 2014 Jun 26.
Recent studies have shed considerable light into schwannomas. To date, only merlin has been identified as a hallmark or pathogenesis of both sporadic and NF2-related schwannomas. Here, we show, by immunoblot and immunohistochemical analyses of 58 sporadic vestibular schwannomas, that upregulation of p53 was observed in 90 % of tumors examined. No p53 mutations were found in 12 % tumors analyzed. Expression of p14ARF was negative in 95 % of tumors, while overexpression of MDM2 was found in all specimens. Aberrant DNA hypermethylation of the p14ARF promoter was observed in three of seven tumors examined (43 %), associated with remarkably decreased mRNA levels. The very high degree of concordance in the aberrations of the p14ARF/MDM2/p53 pathway in this tumor may be considered to be a new player in the pathogenesis of sporadic vestibular schwannomas. Moreover, expression of p21 (waf1) was negative in all tumors, suggesting that the aberration of this pathway is associated with greater attenuation of p21-mediated signals that are critical for growth inhibition. These data are in agreement with the model in RT-4 rat schwannoma cells: i.e., overexpression of ARF was associated with accumulation of p21 expression both at protein and mRNA levels. ShRNA knock-down of p53 expression attenuated p21-mediated increase in cellular arrest in the G1-phase, suggesting that p14ARF regulates p21 protein levels through a p53-dependent pathway. Thus, this study reveals a high degree of concordance in the aberrations of the p14ARF/MDM2/p53 pathway with the development of sporadic vestibular schwannomas.
近期的研究为神经鞘瘤带来了诸多启示。迄今为止，仅发现默林是散发性和与神经纤维瘤病2型（NF2）相关的神经鞘瘤的一个标志或发病机制。在此，我们通过对58例散发性前庭神经鞘瘤进行免疫印迹和免疫组化分析表明，在所检测的90%的肿瘤中观察到p53上调。在分析的12%的肿瘤中未发现p53突变。95%的肿瘤中p14ARF表达为阴性，而在所有标本中均发现MDM2过表达。在所检测的7例肿瘤中有3例（43%）观察到p14ARF启动子异常DNA高甲基化，这与mRNA水平显著降低相关。该肿瘤中p14ARF/MDM2/p53通路异常的高度一致性可能被视为散发性前庭神经鞘瘤发病机制中的一个新因素。此外，所有肿瘤中p21（waf1）表达均为阴性，这表明该通路的异常与对生长抑制至关重要的p21介导信号的更大程度减弱相关。这些数据与RT - 4大鼠神经鞘瘤细胞中的模型一致，即ARF过表达与p21在蛋白和mRNA水平的表达积累相关。p53表达的短发夹RNA（shRNA）敲低减弱了p21介导的细胞在G1期停滞的增加，这表明p14ARF通过p53依赖途径调节p21蛋白水平。因此，本研究揭示了p14ARF/MDM2/p53通路异常与散发性前庭神经鞘瘤发生发展的高度一致性。
