DAZAP1通过诱导线粒体自噬维持胃癌的干性。

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Peiling Zhang, Wei Wang, Hong Xiang, Yun Zhou, Qian Peng, Guolong Liu, Zhi-Xiang Xu, Lin Lu
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引用次数: 0

摘要

干细胞在胃癌(GC)的恶性行为中起关键作用,使其治疗和预后复杂化。然而,GC干细胞(GCSCs)的调控机制仍然知之甚少。DAZAP1是一种与多种恶性肿瘤相关的剪接调节因子,在胃癌中的作用尚不清楚。本研究探讨了DAZAP1对GC干性的影响及其机制。球体形成试验和干性标记分析显示,DAZAP1促进GCSCs的肿瘤进展。功能富集分析表明,DAZAP1通过促进氧化磷酸化(OXPHOS)增强肿瘤干性,通过海马实验和线粒体电位测量证实了这一点。透射电镜和免疫荧光分析表明,DAZAP1促进有丝分裂。RNA免疫沉淀和PCR分析显示,DAZAP1通过无义介导的mRNA衰变调节有丝分裂相关基因ULK1的剪接和表达。救援实验表明,ULK1的过表达逆转了DAZAP1沉默诱导的GC干性和OXPHOS水平的抑制。我们的研究结果表明,DAZAP1减少ULK1衰变,从而激活有丝分裂,增强OXPHOS,以满足癌症干细胞的代谢需求。这些发现突出了DAZAP1作为治疗GC的靶点的治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
DAZAP1 maintains gastric cancer stemness by inducing mitophagy.

Stem cells play a pivotal role in the malignant behavior of gastric cancer (GC), complicating its treatment and prognosis. However, the regulatory mechanisms of GC stem cells (GCSCs) remain poorly understood. DAZ-associated protein 1 (DAZAP1), a splicing regulator linked to various malignancies, has an unclear role in GC. This study investigated DAZAP1's impact on GC stemness and its mechanisms. DAZAP1 promoted tumor progression in GCSCs, as shown by sphere formation assays and stemness marker analysis. Functional enrichment analysis suggested that DAZAP1 enhanced tumor stemness by promoting oxidative phosphorylation (OXPHOS), which was validated through Seahorse assays and measurements of mitochondrial potential. Transmission electron microscopy and immunofluorescence analyses demonstrated that DAZAP1 promoted mitophagy. RNA immunoprecipitation and PCR analysis revealed that DAZAP1 regulated the splicing and expression of the mitophagy-related gene ULK1 through nonsense-mediated mRNA decay. Rescue experiments showed that overexpression of ULK1 reversed the suppression of GC stemness and OXPHOS levels induced by DAZAP1 silencing. Our findings indicate that DAZAP1 reduces ULK1 decay, thereby activating mitophagy and enhancing OXPHOS to fulfill the metabolic demands of cancer stem cells. These findings highlight the therapeutic potential of DAZAP1 as a target for treating GC.

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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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