Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA.
Sci Rep. 2024 Nov 27;14(1):29517. doi: 10.1038/s41598-024-80921-1.
The goal of this study is to develop a non-invasive approach for early detection of oral squamous cell carcinoma (OSCC) using our established mouse model that faithfully recapitulates the human disease. We present for the first time a comparative metabolomic profiling of saliva samples of the tobacco smoke constituent, dibenzo[def, p]pyrene, (DB[a, l]P) vs. DMSO (control)-treated mice using an established and highly sensitive LC-MS/MS approach. DB[a, l]P was administered by topical application into the mouse oral cavity (25 µmol, 3x week for 6 weeks) and saliva was collected 24 h after the last dose of carcinogen administration. Using an untargeted metabolomics approach (negative and positive modes), we found that DB[a, l]P differentially altered several metabolites known to be involved in the carcinogenesis process when compared to DMSO. Of particular significance, we found that DB[a, l]P significantly enriched the levels of phosphatidic acid, known to bind and activate mTORC which can enhance proliferation and promote carcinogenesis. Pathway enrichment analysis revealed that DB[a, l]P altered two major lipid metabolism pathways (phospholipid biosynthesis and glycerolipid metabolism). Collectively, our results using saliva as a safe and non-invasive approach, provide additional mechanistic insights on DB[a, l]P-induced OSCC and potential biomarkers for early detection and an opportunity for cancer interception via reprogramming lipid metabolism.
本研究旨在开发一种非侵入性方法，通过我们建立的能真实再现人类疾病的小鼠模型，用于早期检测口腔鳞状细胞癌（OSCC）。我们首次提出了一种使用已建立的、高度敏感的 LC-MS/MS 方法，对烟草烟雾成分二苯并[a，l]蒽（DB[a，l]P）与 DMSO（对照）处理的小鼠的唾液样本进行比较代谢组学分析。DB[a，l]P 通过局部应用于小鼠口腔（25µmol，每周 3 次，共 6 周），在最后一次致癌物给药后 24 小时收集唾液。使用非靶向代谢组学方法（正负模式），我们发现与 DMSO 相比，DB[a，l]P 可使几种已知参与致癌过程的代谢物发生差异变化。特别重要的是，我们发现 DB[a，l]P 显著增加了已知与 mTORC 结合并激活的磷脂酸水平，这可以增强增殖并促进致癌作用。途径富集分析显示，DB[a，l]P 改变了两个主要的脂质代谢途径（磷脂生物合成和甘油酯代谢）。总之，我们使用唾液作为一种安全、非侵入性的方法的结果，为 DB[a，l]P 诱导的 OSCC 提供了额外的机制见解，并为早期检测和通过重新编程脂质代谢来拦截癌症提供了潜在的生物标志物。
