Zhou Shufeng, Hassan Amani, Kungyal Tenzin, Tabariès Sebastien, Luna José Luis Ramírez García, Siegel Peter M, Philip Anie
Departments of Surgery and Medicine, Division of Plastic Surgery, the Research Institute of the McGill University Health Center, McGill University, Montreal, QC H3G 1A4, Canada.
The Goodman Cancer Institute, Faculty of Medicine, McGill University, Montreal, QC H3A 1A3, Canada.
Cancers (Basel). 2022 Jul 28;14(15):3672. doi: 10.3390/cancers14153672.
(1) Background: Squamous cell carcinoma (SCC) is one of the leading causes of cancer-related deaths worldwide. CD109 is overexpressed in many cancers including SCC. Although a pro-tumorigenic role for CD109 has been shown in non-SCC cancers, and in one type of SCC, the mechanisms and signaling pathways reported are discrepant. (2) Methods: The CD109-EGFR interaction and CD109-mediated regulation of EGFR expression, signaling, and stemness were studied using microarray, immunoblot, immunoprecipitation, qPCR, immunofluorescence, and/or spheroid formation assays. The role of CD109 in tumor progression and metastasis was studied using xenograft tumor growth and metastatic models. (3) Results: We establish the in vivo tumorigenicity of CD109 in vulvar SCC cells and demonstrate that CD109 is an essential regulator of EGFR expression at the mRNA and protein levels and of EGFR/AKT signaling in vulvar and hypopharyngeal SCC cells. Furthermore, we show that the mechanism involves EGFR-CD109 heteromerization and colocalization, leading to the stabilization of EGFR levels. Additionally, we demonstrate that the maintenance of epithelial morphology and in vitro tumorigenicity of SCC cells require CD109 localization to the cell surface. (4) Conclusions: Our study identifies an essential role for CD109 in vulvar SCC progression. We demonstrate that CD109 regulates SCC cellular stemness and epithelial morphology via a cell-surface CD109-EGFR interaction, stabilization of EGFR levels and EGFR/AKT signaling.
(1) 背景：鳞状细胞癌（SCC）是全球癌症相关死亡的主要原因之一。CD109在包括SCC在内的多种癌症中过度表达。尽管已在非SCC癌症以及一种类型的SCC中显示出CD-109的促肿瘤发生作用，但所报道的机制和信号通路存在差异。(2) 方法：使用微阵列、免疫印迹、免疫沉淀、qPCR、免疫荧光和/或球体形成试验研究CD109-EGFR相互作用以及CD109介导的EGFR表达、信号传导和干性调节。使用异种移植肿瘤生长和转移模型研究CD109在肿瘤进展和转移中的作用。(3) 结果：我们确定了CD109在外阴SCC细胞中的体内致瘤性，并证明CD109是外阴和下咽SCC细胞中EGFR表达在mRNA和蛋白质水平以及EGFR/AKT信号传导的关键调节因子。此外，我们表明该机制涉及EGFR-CD109异源二聚化和共定位，导致EGFR水平的稳定。此外，我们证明SCC细胞上皮形态的维持和体外致瘤性需要CD109定位于细胞表面。(4) 结论：我们的研究确定了CD109在外阴SCC进展中的关键作用。我们证明CD109通过细胞表面CD109-EGFR相互作用、EGFR水平的稳定和EGFR/AKT信号传导来调节SCC细胞的干性和上皮形态。
