Department of Orthopedics, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
Environ Toxicol. 2024 Feb;39(2):1001-1017. doi: 10.1002/tox.24011. Epub 2023 Nov 27.
Osteosarcoma (OS), notorious for its complex pathogenesis and formidable prognosis, represents a significant medical quandary. This research embarked on a quest to unravel the implications of lactylation-related genes (LRGs) in OS, offering a novel lens through which to interpret its intricacies. A meticulous evaluation of 329 LRGs within the TARGET dataset spotlighted 27 paramount genes, intricately intertwined with survival. These genes highlighted metabolic processes-particularly amino acid metabolism-as key players, as evidenced in both GO and KEGG analyses. Utilizing consensus clustering and principal component analysis, the 93 OS samples were segmented into two distinct groups, differing notably in overall and event-free survival. Cluster 2 demonstrated a heightened immune response, contrasting the other cluster. Machine learning techniques, like generalized boosted model, CoxBoost, and RSF, spotlighted MYC and GOT2 as critical genes. Using multivariate Cox regression, a risk model was developed, categorizing patients into high and low-risk groups, each displaying varied survival patterns. Additionally, a contrast was observed between MYC and GOT2's associations with HLA molecules, emphasizing their distinct roles in antigen presentation. Potential therapeutic avenues were identified for each risk group, with special attention to mutations in MYC, particularly amplifications, hinting at its role in tumor progression. Finally, delving deeper into the role of MYC, Western blot analyses exhibited amplified myc protein levels in OS cells U-2 and MG-63 when juxtaposed against human osteoblastic cells Hfob1.19. A focused knockdown of myc in OS cells subsequently confirmed its influence on cell proliferation and migration, with reduced myc expression resulting in inhibited cell activities. Furthermore, immunofluorescence assays corroborated myc's heightened expression in OS cells relative to normal osteoblastic cells. In summary, this study accentuates the vital role of LRGs and specifically MYC in OS, ushering in a horizon of tailored therapeutic strategies.
骨肉瘤（OS）以其复杂的发病机制和严峻的预后而臭名昭著，是一个重大的医学难题。本研究旨在揭示乳酰化相关基因（LRGs）在 OS 中的意义，为深入理解其复杂性提供新的视角。通过对 TARGET 数据集内的 329 个 LRGs 进行细致评估，确定了 27 个关键基因，这些基因与生存密切相关。GO 和 KEGG 分析均表明，这些基因与代谢过程，尤其是氨基酸代谢密切相关。通过共识聚类和主成分分析，93 个 OS 样本被分为两个截然不同的群组，在总生存期和无事件生存期方面存在显著差异。群组 2表现出更强的免疫反应，与另一群组形成鲜明对比。广义提升模型、CoxBoost 和随机森林等机器学习技术，突显了 MYC 和 GOT2 是关键基因。通过多变量 Cox 回归，建立了一个风险模型，将患者分为高风险和低风险组，每组的生存模式各不相同。此外，还观察到 MYC 和 GOT2 与 HLA 分子的关联存在差异，这表明它们在抗原呈递方面发挥着不同的作用。为每个风险组确定了潜在的治疗途径，特别关注 MYC 的突变，尤其是扩增，这表明其在肿瘤进展中的作用。最后，深入研究 MYC 的作用，Western blot 分析表明，在与人类成骨细胞 Hfob1.19 相比时，OS 细胞 U-2 和 MG-63 中的 myc 蛋白水平升高。OS 细胞中 myc 的特异性敲低进一步证实了其对细胞增殖和迁移的影响，降低 myc 表达导致细胞活性受到抑制。此外，免疫荧光分析也证实了 myc 在 OS 细胞中的表达高于正常成骨细胞。综上所述，本研究强调了 LRGs，特别是 MYC 在 OS 中的重要作用，为制定针对性的治疗策略开辟了新的前景。
