Abstract：
Odontogenic tumors (OGTs), which originate from cells of odontogenic apparatus and their remnants, are rare entities. Primary intraosseous carcinoma NOS (PIOC), is one of the OGTs, but it is even rarer and has a worse prognosis. The precise characteristics of PIOC, especially in immunohistochemical features and its pathogenesis, remain unclear. We characterized a case of PIOC arising from the left mandible, in which histopathological findings showed a transition from the odontogenic keratocyst to the carcinoma. Remarkably, the tumor lesion of this PIOC prominently exhibits malignant attributes, including invasive growth of carcinoma cell infiltration into the bone tissue, an elevated Ki-67 index, and lower signal for CK13 and higher signal for CK17 compared with the non-tumor region, histopathologically and immunohistopathologically. Further immunohistochemical analyses demonstrated increased expression of ADP-ribosylation factor (ARF)-like 4c (ARL4C) (accompanying expression of β-catenin in the nucleus) and yes-associated protein (YAP) in the tumor lesion. On the other hand, YAP was expressed and the expression of ARL4C was hardly detected in the non-tumor region. In addition, quantitative RT-PCR analysis using RNAs and dot blot analysis using genomic DNA showed the activation of Wnt/β-catenin signaling and epigenetic alterations, such as an increase of 5mC levels and a decrease of 5hmC levels, in the tumor lesion. A DNA microarray and a gene set enrichment analysis demonstrated that various types of intracellular signaling would be activated and several kinds of cellular functions would be altered in the pathogenesis of PIOC. Experiments with the GSK-3 inhibitor revealed that β-catenin pathway increased not only mRNA levels of ankyrin repeat domain1 (ANKRD1) but also protein levels of YAP and transcriptional co-activator with PDZ-binding motif (TAZ) in oral squamous cell carcinoma cell lines. These results suggested that further activation of YAP signaling by Wnt/β-catenin signaling may be associated with the pathogenesis of PIOC deriving from odontogenic keratocyst in which YAP signaling is activated.
摘要：
牙源性肿瘤（OGTs），起源于牙源性器官的细胞及其残留物，是稀有实体。原发性骨内癌NOS(PIOC),是OGTs之一，但更罕见，预后更差。PIOC的精确特性，特别是在免疫组织化学特征及其发病机制方面，仍然不清楚。我们描述了一个由左下颌骨引起的PIOC病例，其中组织病理学发现显示从牙源性角化囊肿转变为癌。值得注意的是,该PIOC的肿瘤病变突出表现出恶性属性，包括癌细胞浸润到骨组织的侵袭性生长，Ki-67指数升高,与非肿瘤区域相比，CK13的信号较低，CK17的信号较高，组织病理学和免疫组织病理学。进一步的免疫组织化学分析表明，ADP-核糖基化因子（ARF）样4c（ARL4C）（伴随核中β-连环蛋白的表达）和YE相关蛋白（YAP）在肿瘤病变中的表达增加。另一方面,在非肿瘤区域表达YAP且几乎检测不到ARL4C的表达。此外,使用RNA的定量RT-PCR分析和使用基因组DNA的斑点印迹分析显示Wnt/β-catenin信号的激活和表观遗传改变，例如5mC水平的增加和5hmC水平的降低，在肿瘤病变中。DNA微阵列和基因集富集分析表明，在PIOC的发病机理中，各种类型的细胞内信号将被激活，几种细胞功能将被改变。使用GSK-3抑制剂的实验表明，β-catenin途径不仅增加了口腔鳞状细胞癌细胞系中锚蛋白重复域1（ANKRD1）的mRNA水平，而且还增加了YAP和与PDZ结合基序（TAZ）的转录共激活因子的蛋白水平。这些结果表明，通过Wnt/β-catenin信号传导进一步激活YAP信号可能与源自牙源性角化囊肿的PIOC的发病机理有关，其中YAP信号被激活。
