Background:Osteosarcoma (OS) is a highly aggressive bone malignancy with limited treatment options and poor prognosis. This exploratory study aimed to identify molecular subtypes of early-stage, treatment-naive OS to guide precise therapeutic strategies.Methods:We analyzed RNA-seq data obtained from tumor tissues from 102 OS patients using a non-negative matrix factorization algorithm (NMF) to classify the tumors into three subtypes: S1, S2, and S3. Differential gene expression was evaluated using DESeq2, followed by functional enrichment analysis with clusterProfiler and CancerHallmarks. The tumor microenvironment was assessed through ESTIMATE and CIBERSORT, and drug sensitivity was predicted using OncoPredict. SAOS-2 and MG63 cells, representing the S1 subtype, were used in the viability essays to determine the effect of hesperidin, a natural phenolic compound noted for its anti-cancer potential, alone and in combination with doxorubicin and 5-fluorouracil.Results:This study revealed three OS subtypes: S1 was enriched in cell cycle regulation, vesicular transport, and RNA metabolism while S2 and S3 were enriched in pathways related to extracellular matrix organization and protein translation, respectively. S1 displayed high tumor purity, significant chemoresistance, and overexpression of KIF20 A, correlating with poor prognosis.AURKB, a hesperidin target, was implicated in S1 pathogenesis. In vitro, hesperidin significantly reduced the viability of SAOS-2 and MG63 cells and enhanced doxorubicin efficacy.Conclusions:Our findings support the molecular subclassification of OS, emphasizing subtype-specific mechanisms of tumor progression and chemoresistance, with hesperidin offering potential as a therapeutic adjunct for high-risk OS patients.
背景：骨肉瘤是一种高度侵袭性的骨恶性肿瘤，治疗手段有限且预后不良。本探索性研究旨在识别早期未接受治疗的骨肉瘤分子亚型，以指导精准治疗策略。 方法：我们利用非负矩阵分解算法对102例骨肉瘤患者肿瘤组织的RNA测序数据进行分析，将肿瘤分为S1、S2和S3三种亚型。采用DESeq2进行差异基因表达评估，随后通过clusterProfiler和CancerHallmarks进行功能富集分析。通过ESTIMATE和CIBERSORT评估肿瘤微环境，并利用OncoPredict预测药物敏感性。选用代表S1亚型的SAOS-2和MG63细胞进行活力实验，评估具有抗癌潜力的天然酚类化合物橙皮苷单用及与阿霉素和5-氟尿嘧啶联用的效果。 结果：本研究揭示了三种骨肉瘤亚型：S1亚型富集于细胞周期调控、囊泡运输和RNA代谢通路；S2和S3亚型分别富集于细胞外基质组织和蛋白质翻译相关通路。S1亚型表现出高肿瘤纯度、显著化疗耐药性及KIF20A过表达，这些特征与不良预后相关。橙皮苷的作用靶点AURKB与S1亚型的发病机制相关。体外实验表明，橙皮苷显著降低SAOS-2和MG63细胞活力，并增强阿霉素的疗效。 结论：我们的研究结果支持骨肉瘤的分子亚型分类，强调了肿瘤进展和化疗耐药性的亚型特异性机制，橙皮苷为高危骨肉瘤患者提供了潜在的辅助治疗选择。
肿瘤(癌症)患者之家