Purpose

Epithelial to mesenchymal transition (EMT) is pivotal in embryonic development and wound healing, whereas in cancer it inflicts malignancy and drug resistance. The recognition of an EMT-like process in glioma is relatively new and its clinical and therapeutic significance has, as yet, not been fully elucidated. Here, we aimed to delineate the clinical significance of the EMT-like process in glioma and its therapeutic relevance to rabeprazole.

Methods

We investigated the expression profiles of EMT-associated proteins in primary glioma biopsies through Western blotting and immunohistochemistry, and correlated them with various clinicopathological features and data listed in the cancer genome atlas (TCGA). In addition, the anticancer efficacy of rabeprazole and its therapeutic relevance to EMT along with temozolomide chemo-sensitization were assessed using multiple cell-based assays, Western blotting and confocal imaging. For in vivo assessment, we used a stereotaxic C6-rat glioma model.

Results

Expression analysis of EMT-associated proteins in glioma biopsies, in conjunction with clinicopathological and TCGA dataset analyses, revealed non-canonical expression of E/N-cadherin and upregulation of GFAP, vimentin and β-catenin. The increased expression of EMT-associated proteins may attribute to glioma malignancy and a poor patient prognosis. Subsequent in vitro studies revealed that rabeprazole treatment attenuated glioma cell growth and migration, and induced apoptosis. Rabeprazole suppressed EMT by impeding AKT/GSK3β phosphorylation and/or NF-κB signaling and sensitized temozolomide resistance. Additional in vivo studies showed restricted tumor growth and inhibited expression of EMT-associated proteins after rabeprazole treatment.

Conclusions

Our data revealed (i) a clinical association of the EMT-like process with glioma malignancy and a poor survival and (ii) an anticancer and temozolomide sensitizing effect of rabeprazole by repressing EMT.

Graphical abstract

中文翻译：

---

雷贝拉唑本身具有疗效，并通过 EMT 抑制降低胶质瘤对替莫唑胺的耐药性

目的

上皮间质转化 (EMT) 在胚胎发育和伤口愈合中至关重要，而在癌症中它会导致恶性肿瘤和耐药性。在胶质瘤中识别 EMT 样过程相对较新，其临床和治疗意义尚未完全阐明。在这里，我们旨在描述 EMT 样过程在胶质瘤中的临床意义及其与雷贝拉唑的治疗相关性。

方法

我们通过蛋白质印迹和免疫组织化学研究了原发性胶质瘤活检中 EMT 相关蛋白的表达谱，并将它们与癌症基因组图谱 (TCGA) 中列出的各种临床病理学特征和数据相关联。此外，雷贝拉唑的抗癌功效及其与 EMT 的治疗相关性以及替莫唑胺化学增敏作用通过多种基于细胞的测定、蛋白质印迹和共聚焦成像进行了评估。对于体内评估，我们使用立体定向 C6 大鼠神经胶质瘤模型。

结果

胶质瘤活检中 EMT 相关蛋白的表达分析，结合临床病理学和 TCGA 数据集分析，揭示了 E/N-钙粘蛋白的非典型表达以及 GFAP、波形蛋白和 β-连环蛋白的上调。EMT 相关蛋白的表达增加可能是胶质瘤恶性肿瘤和患者预后不良的原因。随后的体外研究表明，雷贝拉唑治疗减弱了胶质瘤细胞的生长和迁移，并诱导了细胞凋亡。雷贝拉唑通过阻止 AKT/GSK3β 磷酸化和/或 NF-κB 信号传导和致敏替莫唑胺耐药性来抑制 EMT。其他体内研究显示，在雷贝拉唑治疗后，肿瘤生长受到限制，EMT 相关蛋白的表达受到抑制。

结论

我们的数据揭示了（i）EMT 样过程与胶质瘤恶性肿瘤和较差的存活率的临床关联，以及（ii）雷贝拉唑通过抑制 EMT 的抗癌和替莫唑胺增敏作用。

图形概要