USP34 regulates PIN1-cGAS-STING axis-dependent ferroptosis in cervical cancer via SUMOylation.

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-02-06 Epub Date: 2025-01-03 DOI:10.1016/j.intimp.2024.113968

Dan Liao, Yumeng Cui, Lijuan Shi, Saitian Zeng, Huali Wang

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引用次数: 0

Abstract

Background: Cervical cancer is a prevalent form of cancer in women, and the inhibition of ferroptosis has been shown to promote the progression of cervical cancer tumours. This study aimed to investigate the role of PIN1 in regulating ferroptosis in cervical cancer, focusing on its ability to modulate the cGAS-STING pathway and the potential involvement of USP34 as an upstream regulator of PIN1.

Methods: PIN1-overexpressing and PIN1-knockdown cell lines were constructed. In addition to activating p-STING via PIN1 knockdown and inhibiting p-STING via PIN1 overexpression, cell activity was evaluated via CCK8, EdU, transwell and flow cytometry assays. The expression of USP34, PIN1, cGAS, p-STING, and STING was analysed through qRT-PCR and immunofluorescence. Western blot analysis was used to detect the regulatory effects of USP34, PIN1, cGAS, p-STING, and STING, as well as SUMOylation. Ferroptosis was detected by ROS immunofluorescence, the mitochondrial membrane potential, and mitochondrial electron microscopy. Furthermore, PIN1-knockdown cells were used to construct xenograft tumours in BALB/c male nude mice, and the relevant verification experiments were performed in vivo.

Results: PIN1 can increase the proliferation and invasion of cervical cancer cells by significantly inhibiting ferroptosis. The mechanism by which PIN1 promotes cancer is inhibition of the cGAS-STING pathway. Additionally, we found that USP34 could increase the expression of PIN1 via SUMOylation in cervical cancer cells.

Conclusion: This study confirmed that USP34 could upregulate PIN1 expression and SUMOylation, thereby inhibiting ferroptosis by suppressing the cGAS-STING pathway and in turn promoting the progression of cervical cancer.

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USP34通过SUMOylation调控子宫颈癌中PIN1-cGAS-STING轴依赖性铁下垂。

背景：宫颈癌是一种常见的女性癌症形式，抑制铁下垂已被证明可促进宫颈癌肿瘤的进展。本研究旨在探讨PIN1在宫颈癌铁下垂中的调节作用，重点关注其调节cGAS-STING通路的能力以及USP34作为PIN1上游调节因子的潜在参与。方法：构建pin1过表达细胞系和pin1敲低细胞系。除了通过PIN1敲低激活p-STING和通过PIN1过表达抑制p-STING外，还通过CCK8、EdU、transwell和流式细胞术检测评估细胞活性。采用qRT-PCR和免疫荧光法分析USP34、PIN1、cGAS、p-STING、STING的表达情况。Western blot检测USP34、PIN1、cGAS、p-STING、STING以及SUMOylation的调控作用。采用ROS免疫荧光、线粒体膜电位、线粒体电镜检测铁下垂。利用pin1敲低细胞在BALB/c雄性裸鼠体内构建异种移植肿瘤，并进行体内验证实验。结果：PIN1可通过抑制铁下垂而促进宫颈癌细胞的增殖和侵袭。PIN1促进癌症的机制是抑制cGAS-STING通路。此外，我们发现USP34可以通过SUMOylation增加子宫颈癌细胞中PIN1的表达。结论：本研究证实USP34可上调PIN1表达和SUMOylation，从而通过抑制cGAS-STING通路抑制铁下垂，进而促进宫颈癌的进展。

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

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.