Gliomas, the most common CNS (central nerve system) tumors, face poor survival due to severe chemoresistance exacerbated by hypoxia. However, studies on whether altered hypoxic conditions benefit for chemo-sensitivity and how gliomas react to increased oxygen stimulation are limited. In this study, we demonstrated that increased oxygen stimulation promotes glioma growth and chemoresistance. Mechanically, increased oxygen stimulation upregulates miR-1290 levels. miR-1290, in turn, downregulates PLCB1, while PLCB1 facilitates the proteasomal degradation of β-catenin and active-β-catenin by increasing the proportion of ubiquitinated β-catenin in a destruction complex-independent mechanism. This process inhibits PLCB1 expression, leads to the accumulation of active-β-catenin, boosting Wnt signaling through an independent mechanism and ultimately promoting chemoresistance in glioma cells. Pharmacological inhibition of Wnt by WNT974 could partially inhibit glioma volume growth and prolong the shortened survival caused by increased oxygen stimulation in a glioma-bearing mouse model. Moreover, PLCB1, a key molecule regulated by increased oxygen stimulation, shows promising predictive power in survival analysis and has great potential to be a biomarker for grading and prognosis in glioma patients. These results provide preliminary insights into clinical scenarios associated with altered hypoxic conditions in gliomas, and introduce a novel perspective on the role of the hypoxic microenvironment in glioma progression. Furthermore, the outcomes reveal the potential risks of utilizing hyperbaric oxygen treatment (HBOT) in glioma patients, particularly when considering HBOT as a standalone option to ameliorate neuro-dysfunctions or when combining HBOT with a single chemotherapy agent without radiotherapy.

中文翻译：

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增加氧刺激可通过 PLCB1 促进神经胶质瘤的化疗耐药和表型转变


神经胶质瘤是最常见的 CNS（中枢神经系统）肿瘤，由于缺氧加剧了严重的化疗耐药性，因此面临着较差的生存率。然而，关于改变缺氧条件是否有益于化疗敏感性以及神经胶质瘤如何对增加的氧刺激做出反应的研究有限。在这项研究中，我们证明增加氧刺激可促进神经胶质瘤生长和化疗耐药性。从机械角度来看，增加氧刺激会上调 miR-1290 水平。 miR-1290反过来下调PLCB1，而PLCB1通过在破坏复合物独立机制中增加泛素化β-连环蛋白的比例，促进β-连环蛋白和活性β-连环蛋白的蛋白酶体降解。该过程抑制 PLCB1 表达，导致活性 β-catenin 积累，通过独立机制增强 Wnt 信号传导，最终促进神经胶质瘤细胞的化疗耐药性。 WNT974 对 Wnt 的药理抑制可以部分抑制神经胶质瘤体积的生长，并延长神经胶质瘤小鼠模型中因氧刺激增加而缩短的生存期。此外，PLCB1是一种受增加氧刺激调节的关键分子，在生存分析中显示出有希望的预测能力，并且具有成为神经胶质瘤患者分级和预后的生物标志物的巨大潜力。这些结果为与神经胶质瘤缺氧条件改变相关的临床情况提供了初步见解，并提出了关于缺氧微环境在神经胶质瘤进展中的作用的新视角。 此外，结果揭示了在神经胶质瘤患者中使用高压氧治疗 (HBOT) 的潜在风险，特别是当考虑将 HBOT 作为改善神经功能障碍的独立选择或将 HBOT 与单一化疗药物联合而不进行放疗时。