Laboratory of Cancer Genetics, School of Medical Sciences, University of Campinas, 50 Vital Brasil Street, Barão Geraldo, Campinas, São Paulo, 13083-888, Brazil.
Laboratory of Nerve Regeneration, Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil.
Sci Rep. 2024 Oct 27;14(1):25681. doi: 10.1038/s41598-024-76210-6.
ERP29 gene encodes a chaperone protein critical for protein folding and secretion. Previous study linked ERP29 inhibition to an elevated risk of pharynx squamous cell carcinoma (PSCC) and reduced patients' survival. However, ERP29 role in PSCC progression remains unknown. Here, we investigated ERP29 impact on PSCC progression in cisplatin (CDDP)-sensitive (FaDu and LAU-2063), CDDP-treated (FaDu-CDDP), and CDDP-resistant (FaDu-R) cells. ERP29 silencing decreased necrosis and increased migration in CDDP-sensitive, treated, and resistant cells; and reduced E-cadherin and increased vimentin immunoexpression in CDDP-sensitive 3D-spheroids. During CDDP treatment, ERP29 silencing enhanced proliferation. In CDDP-sensitive cells, ERP29 silencing upregulated genes associated with WNT, MAPK, and PI3K/AKT signaling pathways while downregulating CASP9 expression. During CDDP treatment, ERP29 silencing downregulated MDM2 and CASP9 expression. In CDDP-resistant cells, ERP29 silencing upregulated SOS1, MAPK1, AKT1, ITGAV, and CCNE1, while downregulating KRAS, JUN, MDM2, and CASP9 expression. In addition, inhibition of microRNA miR-4421 increased ERP29 expression and decreased MAPK1, AKT1, and JUN expression in CDDP-sensitive cells, as well as SOS1, MAPK1, AKT1, and ITGAV in CDDP-resistant cells. Lower ERP29 and higher miR-4421 expressions were predictive of poor survival, suggesting a potential therapeutic use for miR-4421 inhibitors. Upon validation, these findings may contribute to targeted therapies for PSCC based on ensuring ERP29 expression.
ERP29 基因编码一种伴侣蛋白，对于蛋白质折叠和分泌至关重要。先前的研究将 ERP29 的抑制与咽部鳞状细胞癌 (PSCC) 的风险升高和患者生存率降低联系起来。然而，ERP29 在 PSCC 进展中的作用仍不清楚。在这里，我们研究了 ERP29 在顺铂 (CDDP) 敏感 (FaDu 和 LAU-2063)、CDDP 处理 (FaDu-CDDP) 和 CDDP 耐药 (FaDu-R) 细胞中对 PSCC 进展的影响。ERP29 沉默降低了 CDDP 敏感、处理和耐药细胞中的坏死并增加了迁移；并降低了 E-钙粘蛋白并增加了 CDDP 敏感 3D 球体中的波形蛋白免疫表达。在 CDDP 治疗期间，ERP29 沉默增强了增殖。在 CDDP 敏感细胞中，ERP29 沉默上调了与 WNT、MAPK 和 PI3K/AKT 信号通路相关的基因，同时下调了 CASP9 表达。在 CDDP 处理期间，ERP29 沉默下调了 MDM2 和 CASP9 表达。在 CDDP 耐药细胞中，ERP29 沉默上调了 SOS1、MAPK1、AKT1、ITGAV 和 CCNE1，同时下调了 KRAS、JUN、MDM2 和 CASP9 表达。此外，抑制 microRNA miR-4421 增加了 CDDP 敏感细胞中 ERP29 的表达并降低了 MAPK1、AKT1 和 JUN 的表达，以及 CDDP 耐药细胞中 SOS1、MAPK1、AKT1 和 ITGAV 的表达。较低的 ERP29 和较高的 miR-4421 表达预示着预后不良，这表明 miR-4421 抑制剂具有潜在的治疗用途。经验证，这些发现可能有助于基于确保 ERP29 表达的 PSCC 靶向治疗。
