钙蛋白酶 2 通过调节肿瘤微环境中钙蛋白酶 1 的表达来调节 IL-1α 的分泌并抑制肿瘤的发展。

IF 6.5 2区 医学 Q1 IMMUNOLOGY
Oncoimmunology Pub Date : 2025-12-01 Epub Date: 2025-01-13 DOI:10.1080/2162402X.2025.2451444
Zuhairah Binte Hanafi, Yu Mei, Huey Yee Teo, Ying Zhu, Chew Chin Yong Lionel, Jing Wen Chiu, Jinhua Lu, Haiyan Liu
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引用次数: 0

摘要

促肿瘤炎症显著影响癌症进展,靶向炎性细胞因子已成为临床试验中有前景的治疗方法。白细胞介素(IL)-1α是IL-1细胞因子家族的一员,在炎症和癌变中都起着至关重要的作用。IL-1α是如何在肿瘤微环境中分泌的还不清楚,我们之前的研究表明,calpain 1切割IL-1α前体以促进成熟IL-1α的分泌,从而通过招募髓源性抑制细胞加剧肝细胞癌。在这项研究中,我们报道calpain 2也调节IL-1α的分泌。值得注意的是,在富含il -1α的肿瘤微环境中,钙蛋白酶2的缺乏导致肝细胞癌的发展增强。进一步的研究表明,缺乏钙蛋白酶2会增加钙蛋白酶1的表达,这意味着两种钙蛋白酶之间存在一种代偿机制。机制上,calpain2缺乏导致FoxO3表达增加,FoxO3是一种促进calpain1表达的叉头转录因子。综上所述,这些结果表明calpain 2通过诱导FoxO3调节calpain 1的表达,从而调节IL-1α的分泌,为癌症治疗提供了新的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Calpain 2 regulates IL-1α secretion and inhibits tumor development via modulating calpain 1 expression in the tumor microenvironment.

Tumor-promoting inflammation significantly impacts cancer progression, and targeting inflammatory cytokines has emerged as a promising therapeutic approach in clinical trials. Interleukin (IL)-1α, a member of the IL-1 cytokine family, plays a crucial role in both inflammation and carcinogenesis. How IL-1α is secreted in the tumor microenvironment has been poorly understood, and we previously showed that calpain 1 cleaves pro-IL-1α for mature IL-1α secretion, which exacerbates hepatocellular carcinoma by recruiting myeloid-derived suppressor cells. In this study, we report that calpain 2 also modulates IL-1α secretion. Notably, a deficiency in calpain 2 resulted in enhanced hepatocellular carcinoma development within an IL-1α-enriched tumor microenvironment. Further investigations revealed that calpain 2 deficiency increased calpain 1 expression, implying a compensatory mechanism between the two calpains. Mechanistically, calpain 2 deficiency led to increased expression of FoxO3, which is a forkhead transcription factor that promotes calpain 1 expression. Collectively, these results suggest that calpain 2 modulates calpain 1 expression, and therefore IL-1α secretion through the induction of FoxO3, offering novel potential therapeutic targets for cancer treatment.

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来源期刊
Oncoimmunology
Oncoimmunology ONCOLOGYIMMUNOLOGY-IMMUNOLOGY
CiteScore
12.50
自引率
2.80%
发文量
276
审稿时长
24 weeks
期刊介绍: OncoImmunology is a dynamic, high-profile, open access journal that comprehensively covers tumor immunology and immunotherapy. As cancer immunotherapy advances, OncoImmunology is committed to publishing top-tier research encompassing all facets of basic and applied tumor immunology. The journal covers a wide range of topics, including: -Basic and translational studies in immunology of both solid and hematological malignancies -Inflammation, innate and acquired immune responses against cancer -Mechanisms of cancer immunoediting and immune evasion -Modern immunotherapies, including immunomodulators, immune checkpoint inhibitors, T-cell, NK-cell, and macrophage engagers, and CAR T cells -Immunological effects of conventional anticancer therapies.
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