COPB2 facilitates EDEM3-mediated mannose trimming to sustain ER homeostasis in ovarian cancer.

IF 4.8 2区医学 Q1 Medicine

Cellular Oncology Pub Date : 2025-07-30 DOI:10.1007/s13402-025-01089-y

Dong-Xue Li, Ni Yang, Lan-Yu Hua, Jun-Jie Wang, Dilinazi Abudujilile, Zhi-Gang Zhang, Peng-Feng Zhu, Ting-Yan Shi, Rong Zhang

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引用次数: 0

Abstract

Background: Ovarian cancer (OC) is a lethal gynecologic malignancy with limited therapeutic success due to late diagnosis and therapy resistance. Endoplasmic reticulum (ER) stress and ER-associated degradation (ERAD) are key to tumor adaptation, yet the mechanisms sustaining ER homeostasis in OC remain poorly defined.

Methods: We combined multi-omics analyses, tissue microarrays, and in vitro and in vivo models. Functional assays involved COPB2 knockdown or overexpression in OC cells, xenografts in nude mice, and mechanistic studies including protein interaction and glycoproteomic analyses.

Results: COPB2 was significantly upregulated in OC and associated with poor prognosis. It promoted cell proliferation and survival by alleviating ER stress and suppressing apoptosis. Mechanistically, COPB2 interacted with EDEM3, a key ERAD enzyme, enhancing its ER localization and mannose-trimming function. COPB2 depletion impaired EDEM3 activity, resulting in glycan processing defects and ER stress accumulation. In vivo, COPB2 overexpression accelerated tumor growth.

Conclusions: This study identifies a novel COPB2-EDEM3 axis that maintains ER homeostasis and drives OC progression. Targeting this axis may offer new opportunities for therapeutic intervention and biomarker development.

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COPB2促进edem3介导的甘露糖修剪以维持卵巢癌内质网稳态。

背景：卵巢癌（OC）是一种致命的妇科恶性肿瘤，由于诊断较晚和治疗耐药，治疗成功率有限。内质网（ER）应激和内质网相关降解（ERAD）是肿瘤适应的关键，但在OC中维持内质网稳态的机制尚不清楚。方法：采用多组学分析、组织微阵列、体外和体内模型相结合的方法。功能分析包括在OC细胞中敲除或过表达COPB2，裸鼠异种移植，以及包括蛋白质相互作用和糖蛋白组学分析在内的机制研究。结果：COPB2在OC中显著上调，且与预后不良相关。它通过减轻内质网应激和抑制细胞凋亡促进细胞增殖和存活。在机制上，COPB2与ERAD关键酶EDEM3相互作用，增强其内质网定位和甘露糖修剪功能。COPB2缺失损害了EDEM3活性，导致多糖加工缺陷和内质网胁迫积累。在体内，COPB2过表达加速了肿瘤的生长。结论：本研究确定了一种新的COPB2-EDEM3轴，该轴维持内质网稳态并驱动OC进展。靶向这一轴可能为治疗干预和生物标志物的开发提供新的机会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cellular Oncology Biochemistry, Genetics and Molecular Biology-Cancer Research

CiteScore

10.40

自引率

1.50%

发文量

审稿时长

16 weeks

期刊介绍： The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.