Abstract

Emerging evidence indicates that the Warburg effect (aerobic glycolysis) is a marker of malignancy in pancreatic cancer (PC). Receptor expression–enhancing protein 3 (REEP3) is dysregulated in various cancers; however, no studies have addressed whether REEP3 is involved in regulating PC malignancy, particularly with respect to the Warburg effect. Herein, we identified a new diagnostic marker of PC, which may be useful for developing drugs to treat PC and providing insight into the molecular pathology of PC. The microarray dataset GSE183795 was retrieved from the Gene Expression Omnibus database and the differentially expressed genes were analyzed. REEP3 expression was examined in PC cell lines and normal pancreatic ductal epithelial cells. Following REEP3 knockdown or overexpression in PC cells, cell invasion, migration, glucose uptake, lactate production, ATP levels, and epidermal growth factor receptor (EGFR)/extracellular regulated kinase (ERK) pathway protein expression were assessed via scratch, Transwell, glucose, and lactate assays and western blot analysis. A database analysis revealed that REEP3 was highly expressed in PC tumor tissues from 179 patients. In addition, patients with high REEP3 tumor expression exhibited poor overall and disease-free survival. Our results suggest that REEP3 is upregulated in multiple PC cell lines. Moreover, cell viability indicators, such as proliferation, invasion, migration, glycolytic activity, and EGFR/ERK pathway protein expression were conspicuously restrained on REEP3 disruption in PC cells. Overall, these findings suggest that REEP3 assists PC cell proliferation, invasion, and migration by facilitating the Warburg effect through the activation of the EGFR/ERK signaling pathway.

中文翻译：

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REEP3 作为一种新型癌基因通过激活 EGFR/ERK 通路促进胰腺癌细胞的 Warburg 效应

摘要

新的证据表明，瓦尔堡效应（有氧糖酵解）是胰腺癌 (PC) 恶性肿瘤的标志。受体表达增强蛋白 3 ( REEP3 ) 在多种癌症中失调；然而，尚无研究探讨REEP3是否参与调节 PC 恶性肿瘤，特别是 Warburg 效应。在此，我们发现了一种新的 PC 诊断标志物，它可能有助于开发治疗 PC 的药物并提供对 PC 分子病理学的深入了解。从Gene Expression Omnibus数据库检索微阵列数据集GSE183795，并对差异表达基因进行分析。在 PC 细胞系和正常胰腺导管上皮细胞中检查REEP3表达。PC 细胞中REEP3敲低或过表达后，通过划痕、Transwell、葡萄糖、以及乳酸测定和蛋白质印迹分析。数据库分析显示REEP3在179名患者的PC肿瘤组织中高表达。此外，REEP3肿瘤高表达的患者总体生存率和无病生存率较差。我们的结果表明REEP3在多种 PC 细胞系中表达上调。此外，细胞活力指标，如增殖、侵袭、迁移、糖酵解活性和 EGFR/ERK 通路蛋白表达，在 PC 细胞中明显抑制REEP3破坏。总的来说，这些发现表明REEP3通过激活 EGFR/ERK 信号通路促进 Warburg 效应，从而协助 PC 细胞增殖、侵袭和迁移。