Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Department of Neurosurgery, Taipei City Hospital Ren-Ai Branch, Taipei, Taiwan.
Pharmacol Res. 2019 Sep;147:104390. doi: 10.1016/j.phrs.2019.104390. Epub 2019 Aug 6.
Temozolomide (TMZ) is a first-line chemotherapeutic agent used against glioblastoma multiforme (GBM), but this disease exhibits recurrence and high lethality. Therefore, it is critical to explore biomarkers which involve in drug resistance and can be represented as different therapeutic effects after a diagnosis. We attempted to investigate the underlying variably expressed genes that contribute to the formation of resistance to TMZ. We analyzed gene and microRNA (miR) data from GBM patients in The Cancer Genome Atlas (TCGA) database to identify genetic factors associated with poor TMZ efficacy. By conducting a gene set enrichment analysis (GSEA), the epithelial-to-mesenchymal transition (EMT) was associated with poor TMZ responses. To identify roles of microRNAs in regulating TMZ resistance, a differential microRNA analysis was performed in TMZ-treated GBM patients. Downregulation of miR-140 was significantly correlated with poor survival. By integrating TCGA transcriptomic data and genomics of drug sensitivity in cancer (GDSC), cathepsin B (CTSB) was inversely associated with miR-140 expression and poor TMZ efficacy. By a pan-cancer analysis, both miR-140 and CTSB were found to be prognostic factors in other cancer types. We also identified that CTSB was a direct target gene of miR-140. Overexpression of miR-140 reduced CTSB levels, enhanced TMZ cytotoxicity, suppressed the mesenchymal transition, and influenced CTSB-regulated tumor sphere formation and stemness marker expression. In contrast, overexpression of CTSB decreased TMZ-induced glioma cell death, promoted the mesenchymal transition, and attenuated miR-140-increased TMZ cytotoxicity. These findings provide novel targets to increase the therapeutic efficacy of TMZ against GBM.
替莫唑胺（TMZ）是一种用于治疗多形性胶质母细胞瘤（GBM）的一线化疗药物，但这种疾病表现出复发和高致死率。因此，探索参与耐药性的生物标志物并能在诊断后表现出不同的治疗效果至关重要。我们试图研究导致 TMZ 耐药的潜在差异表达基因。我们分析了癌症基因组图谱（TCGA）数据库中 GBM 患者的基因和 microRNA（miR）数据，以确定与 TMZ 疗效差相关的遗传因素。通过进行基因集富集分析（GSEA），上皮-间充质转化（EMT）与 TMZ 反应不良相关。为了确定 microRNAs 在调节 TMZ 耐药性中的作用，对 TMZ 治疗的 GBM 患者进行了差异 microRNA 分析。miR-140 的下调与较差的生存显著相关。通过整合 TCGA 转录组数据和癌症药物敏感性基因组学（GDSC），组织蛋白酶 B（CTSB）与 miR-140 表达和 TMZ 疗效差呈负相关。通过泛癌分析，miR-140 和 CTSB 均被发现是其他癌症类型的预后因素。我们还确定 CTSB 是 miR-140 的直接靶基因。miR-140 的过表达降低了 CTSB 水平，增强了 TMZ 的细胞毒性，抑制了间充质转化，并影响了 CTSB 调节的肿瘤球体形成和干性标志物表达。相反，CTSB 的过表达降低了 TMZ 诱导的神经胶质瘤细胞死亡，促进了间充质转化，并减弱了 miR-140 增加的 TMZ 细胞毒性。这些发现为提高 TMZ 治疗 GBM 的疗效提供了新的靶点。
