BACKGROUND Recent studies have implicated a role for perioperative medications in determining patient outcomes after surgery for malignant tumours, including relapse and metastasis. METHODS A combined approach spanned molecular, cellular, and organismal levels, including bioinformatics, immunohistochemical staining of clinical and animal samples, RNA sequencing of glioblastoma multiforme (GBM) cells with Ingenuity Pathway Analysis, lentiviral-mediated gene expression modulation, in vitro cell experiments, and in vivo orthotopic tumour transplantation. RESULTS We observed a significant correlation between increased kappa opioid receptor (KOP receptor) expression and better prognosis in patients with glioma. Exogenous KOP receptor overexpression in GBM cells in vitro induced cell cycle arrest, suppressed cell growth, and promoted apoptosis. Conversely, reducing KOP receptor expression in GBM cells reduced the proportion of cells in S and G2/M phases, accelerating cell growth. KOP receptor overexpression inhibited glioma cell growth and prolonged survival in mice in vivo, while KOP receptor knockdown had the opposite effect. Mechanistically, internalised KOP receptors were found to bind cytoplasmic p38, facilitating its nuclear translocation and phosphorylation, which influences downstream gene expression. The selective KOP receptor agonist TRK-820 triggered KOP receptor internalisation, activated the p38 pathway, and diminished glioma cell viability in vitro. CONCLUSIONS This combined molecular, cellular, and in vivo approach supports use of KOP receptor agonists as potential adjuvant therapeutics for glioma.

中文翻译：

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Kappa 阿片受体内化诱导的 p38 核易位抑制神经胶质瘤进展。


背景 最近的研究表明，围手术期药物在确定患者术后恶性肿瘤（包括复发和转移）预后方面的作用。方法 一种跨越分子、细胞和生物体水平的组合方法，包括生物信息学、临床和动物样本的免疫组织化学染色、多形性胶质母细胞瘤 （GBM） 细胞的 RNA 测序与独创性通路分析、慢病毒介导的基因表达调节、体外细胞实验和体内原位肿瘤移植。结果我们观察到 kappa 阿片受体 （KOP 受体） 表达增加与神经胶质瘤患者更好的预后之间存在显着相关性。GBM 细胞体外外源性 KOP 受体过表达诱导细胞周期停滞，抑制细胞生长，促进细胞凋亡。相反，降低 GBM 细胞中 KOP 受体的表达会降低 S 和 G2/M 期细胞的比例，从而加速细胞生长。KOP 受体过表达抑制胶质瘤细胞生长并延长小鼠体内存活，而 KOP 受体敲除则具有相反的作用。从机制上讲，发现内化的 KOP 受体结合细胞质 p38，促进其核易位和磷酸化，从而影响下游基因表达。选择性 KOP 受体激动剂 TRK-820 在体外触发 KOP 受体内化，激活 p38 通路，并降低神经胶质瘤细胞活力。结论这种分子、细胞和体内相结合的方法支持使用 KOP 受体激动剂作为神经胶质瘤的潜在辅助治疗。