Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, Indianapolis, Indiana, USA.
Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, Indiana, USA.
J Cell Mol Med. 2023 May;27(9):1290-1295. doi: 10.1111/jcmm.17722. Epub 2023 Apr 5.
The maintenance of diminished acid ceramidase (ASAH1) gene expression leading to the accumulation of antiproliferative intracellular ceramides in oral squamous cell carcinoma (OSCC) has emerged as a prospective oral cancer therapeutic regimen. Our published study demonstrated that the key periodontal pathogen Porphyromonas gingivalis downregulates the expression patterns of ASAH1 mRNA in normal epithelial cells in vitro. Therefore, P. gingivalis may also beneficially diminish the expression of ASAH1 in OSCC. Because a uniquely structured P. gingivalis-derived phosphoethanolamine dihydroceramide (PEDHC) inhibits the proliferation of normal human fibroblasts, this study aimed to test the effect of PEDHC on the survival of human oral squamous OECM-1 cells in vitro. We demonstrated that the P. gingivalis dihydroceramide-null (ΔPG1780) strain upregulates the expression of ASAH1 mRNA and promotes aggressive proliferation and migration of OECM-1 cells compared to the parent P. gingivalis-W83 strain. In addition, the intracellular concentration of ceramides was dramatically elevated in OECM-1 cells exposed to PEDHC in vitro. Furthermore, PEDHC inhibited expression patterns of ASAH1 mRNA as well as some genes associated with degradation of the basement membranes and extracellular matrix, for example, MMP-2, ADAM-17 and IL-6, in OECM-1 cells. Altogether, these data indicated that PEDHC produced by P. gingivalis inhibits acid ceramidase expression, promotes intracellular ceramide accumulation and suppresses the survival and migration of OSCC cells in vitro. Further studies are needed to determine molecular mechanisms of PEDHC-mediated inhibitory effect(s) on OSCC using in vivo models of oral cancer.
酸 ceramidase（ASAH1）基因表达的维持导致口腔鳞状细胞癌（OSCC）中增殖抑制性细胞内 ceramides 的积累，这已成为一种有前途的口腔癌治疗方案。我们的研究表明，主要的牙周病原体牙龈卟啉单胞菌（Porphyromonas gingivalis）在体外下调正常上皮细胞中 ASAH1 mRNA 的表达模式。因此，牙龈卟啉单胞菌也可能有益于减少 OSCC 中 ASAH1 的表达。由于具有独特结构的牙龈卟啉单胞菌衍生的磷酸乙醇胺二氢神经酰胺（PEDHC）抑制正常人类成纤维细胞的增殖，本研究旨在测试 PEDHC 对体外人口腔鳞状 OECM-1 细胞存活的影响。我们证明，与亲本牙龈卟啉单胞菌-W83 株相比，牙龈卟啉单胞菌二氢神经酰胺缺失（ΔPG1780）株上调 ASAH1 mRNA 的表达，并促进 OECM-1 细胞的侵袭性增殖和迁移。此外，在体外暴露于 PEDHC 的 OECM-1 细胞中，细胞内 ceramides 浓度显著升高。此外，PEDHC 抑制了 ASAH1 mRNA 以及与基底膜和细胞外基质降解相关的一些基因的表达模式，例如 MMP-2、ADAM-17 和 IL-6。总之，这些数据表明，牙龈卟啉单胞菌产生的 PEDHC 抑制酸 ceramidase 表达，促进细胞内 ceramides 积累，并抑制 OSCC 细胞的存活和迁移。需要进一步研究以确定使用口腔癌体内模型研究 PEDHC 介导的对 OSCC 的抑制作用的分子机制。
