State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, Zhejiang, China.
Oral Dis. 2022 Apr;28(3):621-630. doi: 10.1111/odi.13791. Epub 2021 Feb 16.
Primary cilia, evolutionally conserved organelles involving multiple cell functions, are frequently lost in various cancers. However, little is known about the role of primary cilia in oral squamous cell carcinoma (OSCC).
Immunofluorescence staining was applied to detect primary cilia in normal, oral leukoplakia (OLK) and OSCC tissues. Differentially expressed ciliary genes of OSCC were screened from the TCGA database. Immunohistochemical analysis was used for validating the correlation between the expression of interested proteins and primary cilia, and their regulatory effect on primary cilia was further proved in vitro and in vivo.
A significant decrease in cilia ratio was found in OLK, especially in OSCC. Multiple ciliary genes were abnormally expressed in OSCC and epidermal growth factor receptor (EGFR)-Aurora A signaling was chosen for further study. A parallel increase of EGFR-Aurora A was observed in OLK and OSCC tissues. Moreover, EGFR activation induced obvious cilia absorption by phosphorylating Aurora A. Besides, Aurora A silencing significantly restored ciliary expression and decreased tumor growth in vivo.
The abnormal activation of EGFR-Aurora A leads to the gradual loss of primary cilia in oral mucosa carcinogenesis. Primary cilia have the potential to be new biomarkers and therapeutic targets of oral cancer.
初级纤毛是参与多种细胞功能的进化上保守的细胞器，在各种癌症中经常丢失。然而，初级纤毛在口腔鳞状细胞癌（OSCC）中的作用知之甚少。
应用免疫荧光染色检测正常、口腔白斑（OLK）和 OSCC 组织中的初级纤毛。从 TCGA 数据库中筛选出 OSCC 的差异表达纤毛基因。免疫组织化学分析用于验证感兴趣蛋白的表达与初级纤毛之间的相关性，并在体外和体内进一步证明它们对初级纤毛的调节作用。
在 OLK 中，特别是在 OSCC 中，纤毛比例明显下降。在 OSCC 中多个纤毛基因异常表达，选择表皮生长因子受体（EGFR）-Aurora A 信号通路进行进一步研究。在 OLK 和 OSCC 组织中观察到 EGFR-Aurora A 的平行增加。此外，EGFR 激活通过磷酸化 Aurora A 引起明显的纤毛吸收。此外，Aurora A 沉默显著恢复纤毛表达并减少体内肿瘤生长。
EGFR-Aurora A 的异常激活导致口腔黏膜癌变中初级纤毛逐渐丢失。初级纤毛有可能成为口腔癌的新生物标志物和治疗靶点。
