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Trim21 通过介导 CCT2 泛素化抑制乳腺癌的恶性进展并促进 CD4T 细胞活化。

Trim21-mediated CCT2 ubiquitination suppresses malignant progression and promotes CD4T cell activation in breast cancer.

机构信息

Department of Breast Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

Biological Resource Center, Qilu Hospital of Shandong University, Jinan, Shandong, China.

出版信息

Cell Death Dis. 2024 Jul 30;15(7):542. doi: 10.1038/s41419-024-06944-8.

DOI:10.1038/s41419-024-06944-8
PMID:39079960
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11289294/
Abstract

Breast cancer remains a significant global health challenge, and its mechanisms of progression and metastasis are still not fully understood. In this study, analysis of TCGA and GEO datasets revealed a significant increase in CCT2 expression in breast cancer tissues, which was associated with poor prognosis in breast cancer patients. Functional analysis revealed that CCT2 promoted breast cancer growth and metastasis through activation of the JAK2/STAT3 signaling pathway. Additionally, the E3 ubiquitin ligase Trim21 facilitated CCT2 ubiquitination and degradation, significantly reversing the protumor effects of CCT2. Most interestingly, we discovered that exosomal CCT2 derived from breast cancer cells suppressed the activation and proinflammatory cytokine secretion of CD4 T cell. Mechanistically, exosomal CCT2 constrained Ca-NFAT1 signaling, thereby reducing CD40L expression on CD4 T cell. These findings highlight CCT2 upregulation as a potential driver of breast cancer progression and immune evasion. Our study provides new insights into the molecular mechanisms underlying breast cancer progression, suggesting that CCT2 is a promising therapeutic target and prognostic predictor for breast cancer.

摘要

乳腺癌仍然是一个重大的全球健康挑战，其进展和转移的机制仍未完全阐明。在这项研究中，对 TCGA 和 GEO 数据集的分析显示，CCT2 在乳腺癌组织中的表达显著增加，这与乳腺癌患者的预后不良有关。功能分析显示，CCT2 通过激活 JAK2/STAT3 信号通路促进乳腺癌的生长和转移。此外，E3 泛素连接酶 Trim21 促进 CCT2 的泛素化和降解，显著逆转了 CCT2 的促肿瘤作用。最有趣的是，我们发现来自乳腺癌细胞的外泌体 CCT2 抑制了 CD4 T 细胞的激活和促炎细胞因子的分泌。从机制上讲，外泌体 CCT2 限制了 Ca-NFAT1 信号，从而降低了 CD4 T 细胞上的 CD40L 表达。这些发现强调了 CCT2 的上调是乳腺癌进展和免疫逃逸的潜在驱动因素。我们的研究为乳腺癌进展的分子机制提供了新的见解，表明 CCT2 是乳腺癌有前途的治疗靶点和预后预测因子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e528/11289294/d1b764a05109/41419_2024_6944_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e528/11289294/e9c6a5a59b46/41419_2024_6944_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e528/11289294/125fbf8339b9/41419_2024_6944_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e528/11289294/5048e6a3886a/41419_2024_6944_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e528/11289294/2a3f90465b13/41419_2024_6944_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e528/11289294/a6ce06e6d30a/41419_2024_6944_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e528/11289294/81d9c47564c8/41419_2024_6944_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e528/11289294/55dc35a8b2a9/41419_2024_6944_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e528/11289294/d1b764a05109/41419_2024_6944_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e528/11289294/e9c6a5a59b46/41419_2024_6944_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e528/11289294/125fbf8339b9/41419_2024_6944_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e528/11289294/5048e6a3886a/41419_2024_6944_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e528/11289294/2a3f90465b13/41419_2024_6944_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e528/11289294/a6ce06e6d30a/41419_2024_6944_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e528/11289294/81d9c47564c8/41419_2024_6944_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e528/11289294/55dc35a8b2a9/41419_2024_6944_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e528/11289294/d1b764a05109/41419_2024_6944_Fig8_HTML.jpg

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Trim21-mediated CCT2 ubiquitination suppresses malignant progression and promotes CD4T cell activation in breast cancer.

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引用本文的文献

[1]
Oxidative stress-related genes in uveal melanoma: the role of CALM1 in modulating oxidative stress and apoptosis and its prognostic significance.

Front Oncol. 2025-8-1

[2]
TRIM21: a multifaceted regulator in cancer.

Front Cell Dev Biol. 2025-7-15

[3]
"Small extracellular vesicles: messengers at the service of breast cancer agenda in the primary and distant microenvironments".

J Exp Clin Cancer Res. 2025-7-21

[4]
Post-Translational Modifications of RNA-Modifying Proteins in Cellular Dynamics and Disease Progression.

Adv Sci (Weinh). 2024-11

本文引用的文献

[1]
Ubiquitin E3 ligases assisted technologies in protein degradation: Sharing pathways in neurodegenerative disorders and cancer.

Ageing Res Rev. 2024-4

[2]
Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7.

Proc Natl Acad Sci U S A. 2024-3-19

[3]
The E3 ligase HUWE1 increases the sensitivity of CRC to oxaliplatin through TOMM20 degradation.

Oncogene. 2024-2

[4]
NNMT/1-MNA Promote Cell-Cycle Progression of Breast Cancer by Targeting UBC12/Cullin-1-Mediated Degradation of P27 Proteins.

Adv Sci (Weinh). 2024-3

[5]
PRMT6 methylation of STAT3 regulates tumor metastasis in breast cancer.

Cell Death Dis. 2023-10-9

[6]
Tumor-specific cholinergic CD4 T lymphocytes guide immunosurveillance of hepatocellular carcinoma.

Nat Cancer. 2023-10

[7]
Tat-CCT2 Protects the Neurons from Ischemic Damage by Reducing Oxidative Stress and Activating Autophagic Removal of Damaged Protein in the Gerbil Hippocampus.

Neurochem Res. 2023-12

[8]
HSPB1 facilitates chemoresistance through inhibiting ferroptotic cancer cell death and regulating NF-κB signaling pathway in breast cancer.

Cell Death Dis. 2023-7-15

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Cancer Cell. 2023-3-13

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Front Endocrinol (Lausanne). 2023

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