Notch3 is frequently downregulated in oral cancer

• Published in: Journal of oral and maxillofacial surgery, medicine, and pathology medicine, and pathology, 2017-11, Vol.29 (6), p.504-510
• Main Authors: Ichimura, Norihisa, Yamamoto, Noriyuki, Nishikawa, Masaya, Furue, Hiroki, Kondo, Yutaka, Hibi, Hideharu
• Format: Article
• Language: English
• Subjects: DNA methylation; Notch3; Oral squamous cell carcinoma
• ISSN: 2212-5558; 2212-5566
• DOI: 10.1016/j.ajoms.2017.06.006

Members of the Notch family are frequently dysregulated in various types of cancers, and these alterations can lead to oncogenesis or tumor suppression depending on the context. The aim of this study was to elucidate the relationship between members of the Notch family and oral squamous cell carcinoma (OSCC) tumorigenesis, with a focus on epigenetic alteration, especially DNA methylation. We analyzed the expression and DNA methylation of members of the Notch family in six OSCC cell lines. Additionally, we evaluated the DNA methylation level and the frequency of Notch3 methylation in clinical samples and compared the results between tumor and normal tissues using The Cancer Genome Atlas (TCGA) dataset. Further, we comprehensively evaluated DNA methylation and gene mutation of Notch3 in tumor tissues. Notch1, Notch2, and Notch4 were substantially expressed in all the OSCC cells, whereas Notch3 expression was not detected; moreover, Notch3 was highly methylated at the promoter region in one of the six cell lines. In the OSCC clinical samples, Notch3 methylation was significantly higher in tumor than in normal tissues (P=0.04). Intriguingly, DNA methylation and loss of function mutation of Notch3 tended to be mutually exclusive. Our data indicate that Notch3 is downregulated by multiple mechanisms during OSCC tumorigenesis, mainly due to DNA methylation.