Ho Kuo-Hao, Hsu Shao-Yuan, Chen Peng-Hsu, Cheng Chia-Hsiung, Liu Ann-Jeng, Chien Ming-Hsien, Chen Ku-Chung
Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Department of Neurosurgery, Taipei City Hospital Ren-Ai Branch, Taipei, Taiwan.
Biochim Biophys Acta Mol Cell Res. 2025 Feb;1872(2):119885. doi: 10.1016/j.bbamcr.2024.119885. Epub 2024 Dec 2.
Glioblastoma multiforme (GBM) is an aggressive type of brain tumor known for its hypoxic microenvironment. Understanding the dysregulated mechanisms in hypoxic GBM is crucial for its effective treatment. Through data mining of The Cancer Genome Atlas (TCGA) with hypoxia enrichment scores and in vitro experiments, miR-128-3p was negatively correlated with hypoxia signaling and the epithelial-mesenchymal transition (EMT). Additionally, lower miR-128-3p levels existed in hypoxic GBM, leading to desensitizing temozolomide (TMZ)'s efficacy, a first-line therapeutic drug for GBM. Overexpressing miR-128-3p enhanced both the in vitro and in vivo sensitivity of hypoxic gliomas to TMZ treatment. Mechanistically, HIF-1α suppressed miR-128-3p expression in hypoxic GBM. Through establishing miR-128-3p-mediated transcriptomic profiles and data mining, interleukin (IL)-8 was selected. IL-8 respectively showed positive and negative correlations with hypoxia and miR-128-3p, and was associated with poor TMZ therapeutic results in GBM. Elevated miR-128-3p, which targets both the 3'-untranslated region (UTR) and 5'UTR of IL-8, resulted in suppression of IL-8 expression. Moreover, IL-8 was validated to be involved in HIF-1α/miR-128-3p-regulated TMZ sensitivity and the EMT in hypoxic GBM cells. Collectively, the HIF-1α/miR-128-3p/IL-8 signaling pathway plays a critical role in promoting the progression of hypoxic GBM. Targeting this signaling pathway holds promise as a potential therapeutic strategy.
多形性胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，以其缺氧微环境而闻名。了解缺氧GBM中的失调机制对其有效治疗至关重要。通过利用缺氧富集评分对癌症基因组图谱（TCGA）进行数据挖掘和体外实验，发现miR-128-3p与缺氧信号传导和上皮-间质转化（EMT）呈负相关。此外，缺氧GBM中miR-128-3p水平较低，导致一线治疗药物替莫唑胺（TMZ）的疗效降低。过表达miR-128-3p可增强缺氧胶质瘤对TMZ治疗的体外和体内敏感性。从机制上讲，HIF-1α抑制缺氧GBM中miR-128-3p的表达。通过建立miR-128-3p介导的转录组图谱和数据挖掘，选择了白细胞介素（IL）-8。IL-8分别与缺氧和miR-128-3p呈正相关和负相关，并且与GBM中TMZ治疗效果不佳有关。升高的miR-128-3p靶向IL-8的3'-非翻译区（UTR）和5'UTR，导致IL-8表达受到抑制。此外，IL-8被证实参与了缺氧GBM细胞中HIF-1α/miR-128-3p调节的TMZ敏感性和EMT。总的来说，HIF-1α/miR-128-3p/IL-8信号通路在促进缺氧GBM的进展中起关键作用。靶向该信号通路有望成为一种潜在的治疗策略。
