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Pathophysiological significance of altered kerakin expression in oral cancer

口腔癌中角蛋白表达改变的病理生理学意义

基本信息

批准号：
21592320
负责人：
SAKAMOTO Kei
金额：
$ 2.83万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21592320/
关键词：
口腔病理学口腔癌前癌病変 Notch ケラチン扁平上皮癌上皮異形成 Notch1

项目摘要

We clarified basal-cell dominant expression of NOTCH1 in squamous epithelium. NOTCH1 was downregulated in squamous neoplasms of oral mucosa, esophagus and uterine cervix, compared to the normal basal cells, although the expression tended to be retained in cervical lesions. NOTCH1 downregulation was observed even in precancers, and there was little difference between cancers and high-grade precancerous lesions, suggesting its minor contribution to cancer-specific events such as invasion. In culture experiments, reduction of NOTCH1 expression resulted in downregulation of keratin 13 and keratin 15, and upregulation of keratin 17, and NOTCH1 knockdown cells formed a dysplastic stratified epithelium mimicking a precancerous lesion. The NOTCH1 downregulation and the concomitant alterations of those keratin expressions were confirmed in the squamous neoplasms both by immunohistochemical and cDNA microarray analyses. Our data indicate that reduction of NOTCH1 expression directs the basal cells to cease terminal differentiation and to form an immature epithelium, thereby playing a major role in the histopathogenesis of epithelial dysplasia. Furthermore, downregulation of NOTCH1 expression seems to be an inherent mechanism for switching the epithelium from a normal and mature state to an activated and immature state, suggesting its essential role in maintaining the epithelial integrity.

我们阐明了NOTCH 1在鳞状上皮中的基底细胞优势表达。与正常基底细胞相比，口腔粘膜、食管和子宫颈鳞状细胞肿瘤中NOTCH 1表达下调，尽管其表达倾向于保留在子宫颈病变中。即使在癌前病变中也观察到NOTCH1下调，并且癌症和高级别癌前病变之间几乎没有差异，这表明其对癌症特异性事件如侵袭的贡献很小。在培养实验中，NOTCH 1表达的减少导致角蛋白13和角蛋白15的下调，角蛋白17的上调，并且NOTCH 1敲低的细胞形成模仿癌前病变的发育不良的复层上皮。通过免疫组化和cDNA微阵列分析证实了鳞状细胞肿瘤中NOTCH 1的下调和伴随的角蛋白表达的改变。我们的数据表明，NOTCH 1表达的减少指导基底细胞停止终末分化并形成不成熟的上皮，从而在上皮发育不良的组织发生中发挥重要作用。此外，NOTCH 1表达的下调似乎是将上皮从正常和成熟状态转换为活化和未成熟状态的内在机制，表明其在维持上皮完整性中的重要作用。