Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China.
Int J Mol Sci. 2024 Jan 29;25(3):1643. doi: 10.3390/ijms25031643.
Sarcomas are heterogeneous connective tissue malignancies that have been historically categorized into soft tissue and bone cancers. Although multimodal therapies are implemented, many sarcoma subtypes are still difficult to treat. Lipids play vital roles in cellular activities; however, ectopic levels of lipid metabolites have an impact on tumor recurrence, metastasis, and drug resistance. Thus, precision therapies targeting lipid metabolism in sarcoma need to be explored. In this study, we performed a comprehensive analysis of molecular stratification based on lipid metabolism-associated genes (LMAGs) using both public datasets and the data of patients in our cohort and constructed a novel prognostic model consisting of squalene epoxidase (SQLE) and tumor necrosis factor (TNF). We first integrated information on gene expression profile and survival outcomes to divide TCGA sarcoma patients into high- and low-risk subgroups and further revealed the prognosis value of the metabolic signature and immune infiltration of patients in both groups, thus proposing various therapeutic recommendations for sarcoma. We observed that the low-risk sarcoma patients in the TCGA-SARC cohort were characterized by high proportions of immune cells and increased expression of immune checkpoint genes. Subsequently, this lipid metabolic signature was validated in four external independent sarcoma datasets including the CHCAMS cohort. Notably, SQLE, a rate-limiting enzyme in cholesterol biosynthesis, was identified as a potential therapeutic target for sarcoma. Knockdown of SQLE substantially inhibited cell proliferation and colony formation while promoting the apoptosis of sarcoma cells. Terbinafine, an inhibitor of SQLE, displayed similar tumor suppression capacity in vitro. The prognostic predictive model and the potential drug target SQLE might serve as valuable hints for further in-depth biological, diagnostic, and therapeutic exploration of sarcoma.
肉瘤是异质性结缔组织恶性肿瘤，历史上分为软组织癌和骨癌。尽管采用了多模态治疗，但许多肉瘤亚型仍然难以治疗。脂质在细胞活动中起着至关重要的作用；然而，脂质代谢物的异位水平会影响肿瘤的复发、转移和耐药性。因此，需要探索针对肉瘤脂质代谢的精准治疗方法。在这项研究中，我们使用公共数据集和我们队列中的患者数据，对基于脂质代谢相关基因（LMAGs）的分子分层进行了全面分析，并构建了一个由角鲨烯环氧化酶（SQLE）和肿瘤坏死因子（TNF）组成的新型预后模型。我们首先整合了基因表达谱和生存结果信息，将 TCGA 肉瘤患者分为高风险和低风险亚组，进一步揭示了两组患者代谢特征和免疫浸润的预后价值，从而为肉瘤提出了各种治疗建议。我们观察到 TCGA-SARC 队列中的低风险肉瘤患者具有较高比例的免疫细胞和免疫检查点基因的高表达。随后，该脂质代谢特征在包括 CHCAMS 队列在内的四个外部独立肉瘤数据集得到验证。值得注意的是，胆固醇生物合成的限速酶 SQLE 被鉴定为肉瘤的潜在治疗靶点。SQLE 的敲低显著抑制了肉瘤细胞的增殖和集落形成，同时促进了细胞凋亡。SQLE 的抑制剂特比萘芬在体外也表现出类似的肿瘤抑制能力。预后预测模型和潜在的药物靶点 SQLE 可能为肉瘤的进一步深入生物学、诊断和治疗探索提供有价值的线索。
