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IF 6.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Apoptosis Pub Date : 2025-02-04 DOI:10.1007/s10495-025-02084-2

Zhaoran Su, Menglan Liu, Mathias Krohn, Sandra Schwarz, Michael Linnebacher

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引用次数: 0

摘要

背景：结肠直肠癌（CRC）是全球健康的重大负担，化疗耐药性是有效治疗面临的重大挑战。SEC23A是COPII囊泡转运系统的核心成分，对蛋白质转运和细胞平衡至关重要。然而，它在 CRC 进展和化疗耐药性中的功能仍不确定。本研究调查了SEC23A的表达与对5-氟尿嘧啶（5-FU）（一种广泛使用的化疗药物）的敏感性之间的相关性，尤其侧重于ER应激诱导的细胞凋亡：方法：通过生物信息学分析评估 SEC23A 在 CRC 中的表达及其与患者预后的关系。利用GDSC数据预测了化疗敏感性，并通过实验验证了SEC23A表达的CRC细胞系。为了探索SEC23A在获得性耐药性中的作用，研究人员采用了患者异种移植（PDX）模型和5-FU耐药细胞系。研究人员进行了细胞凋亡测定、细胞周期分析和ER应激调节实验，以阐明其潜在机制：结果：与正常组织相比，SEC23A在CRC样本中的表达明显减少。结果：与正常组织相比，SEC23A 在 CRC 样本中的表达明显减少，这种减少与较差的预后有关，包括总生存率和疾病特异性生存率。生物信息学预测和体外实验都证明，SEC23A的低表达与对5-FU的耐药性增加之间存在相关性。在PDX模型中，与原发肿瘤相比，转移灶在接受5-FU治疗后SEC23A的表达有所下降。在对5-FU耐药的细胞系中过表达SEC23A可恢复对药物的敏感性并增加细胞凋亡。生物信息学和实验分析表明，SEC23A与ER应激相关的细胞凋亡通路密切相关。据观察，SEC23A表达的升高促进了错误折叠蛋白在5-FU处理后的积累，进而导致ER应激和细胞凋亡的增加：结论：SEC23A通过调节ER应激诱导的细胞凋亡，在调节CRC细胞对5-FU的敏感性方面起着至关重要的作用。结论：SEC23A通过调节ER应激诱导的细胞凋亡，在调节CRC细胞对5-FU的敏感性方面起着至关重要的作用，其下调会导致化疗耐药，这表明SEC23A可作为CRC的预后标志物和治疗靶点。旨在上调SEC23A或增强ER应激的策略可能会为克服化疗耐药性和改善CRC患者的治疗效果提供新的途径。

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The impact of SEC23A on 5-FU chemotherapy sensitivity and its involvement in endoplasmic reticulum stress-induced apoptosis in colorectal cancer.

Background: Colorectal cancer (CRC) represents a significant global health burden, with chemotherapy resistance representing a significant challenge to effective treatment. SEC23A, a core component of the COPII vesicle trafficking system, is of critical importance with regard to protein transport and cellular homeostasis. Nevertheless, its function in CRC progression and chemoresistance remains uncertain. The present study investigates the correlation between SEC23A expression and sensitivity to 5-fluorouracil (5-FU), a widely used chemotherapeutic agent, with particular emphasis on ER stress-induced apoptosis.

Methods: A bioinformatic analysis was conducted to evaluate SEC23A expression in CRC and its association with patient prognosis. Chemotherapy sensitivity was predicted using GDSC data and validated experimentally using CRC cell lines with manipulated SEC23A expression. In order to explore the role of SEC23A in acquired drug resistance, patient-derived xenograft (PDX) models and 5-FU-resistant cell lines were employed. Apoptosis assays, cell cycle analysis, and ER stress modulation experiments were performed to elucidate the underlying mechanisms.

Results: SEC23A expression was significantly reduced in CRC samples compared to normal tissues. This reduction was linked to a poorer prognosis, including both overall and disease-specific survival. A correlation was observed between low SEC23A expression and increased resistance to 5-FU, as evidenced by both bioinformatic predictions and in vitro experiments. In PDX models, metastatic lesions exhibited decreased SEC23A expression following 5-FU treatment in comparison to primary tumors. Overexpression of SEC23A in 5-FU-resistant cell lines restored sensitivity to the drug and increased apoptosis. Bioinformatic and experimental analyses revealed a robust correlation between SEC23A and ER stress-related apoptotic pathways. Elevated expression of SEC23A was observed to facilitate the accumulation of misfolded proteins in response to 5-FU treatment, which in turn resulted in increased ER stress and apoptosis.

Conclusions: SEC23A plays a crucial role in modulating the sensitivity of CRC cells to 5-FU by regulating ER stress-induced apoptosis. Its downregulation contributes to chemoresistance, indicating that SEC23A may serve as a prognostic marker and therapeutic target in CRC. Strategies aimed at upregulating SEC23A or enhancing ER stress may provide new avenues for overcoming chemoresistance and improving treatment outcomes for CRC patients.

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来源期刊

Apoptosis 生物-生化与分子生物学

CiteScore

9.10

自引率

4.20%

发文量

审稿时长

1 months

期刊介绍： Apoptosis, a monthly international peer-reviewed journal, focuses on the rapid publication of innovative investigations into programmed cell death. The journal aims to stimulate research on the mechanisms and role of apoptosis in various human diseases, such as cancer, autoimmune disease, viral infection, AIDS, cardiovascular disease, neurodegenerative disorders, osteoporosis, and aging. The Editor-In-Chief acknowledges the importance of advancing clinical therapies for apoptosis-related diseases. Apoptosis considers Original Articles, Reviews, Short Communications, Letters to the Editor, and Book Reviews for publication.