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TRIM21 介导的 Sohlh2 泛素化抑制 M2 巨噬细胞极化和三阴性乳腺癌的进展。

TRIM21-mediated Sohlh2 ubiquitination suppresses M2 macrophage polarization and progression of triple-negative breast cancer.

机构信息

Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong, 250012, China.

Department of Human Anatomy and Neurobiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong, China.

出版信息

Cell Death Dis. 2023 Dec 20;14(12):850. doi: 10.1038/s41419-023-06383-x.

DOI:10.1038/s41419-023-06383-x
PMID:38123542
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10733312/
Abstract

Lung metastasis is the major cause of death in patients with triple-negative breast cancer (TNBC). Tumor-associated macrophages (TAMs) represent the M2-like phenotype with potent immunosuppressive activity, and play a pro-tumor role in TNBC lung metastasis. Sohlh2 belongs to the basic helix-loop-helix transcription factor family. However, its role in macrophages polarization remains unknown, especially in TNBC progression. Here we demonstrated that Sohlh2 overexpression promoted M2 macrophage polarization. Moreover, high expression of Sohlh2 in M2-like macrophage enhanced TNBC cell growth, migration and lung metastasis in vivo and in vitro. Mechanistically, we revealed that Sohlh2 functioned through up-regulating LXRα, ABCA1, ABCG1 expression and disturbing the lipid homeostasis on the membrane of macrophages. Sohlh2 could directly bind to the promoter of LXRα and promote its transcription activity. E3 ubiquitin ligase TRIM21 promoted Sohlh2 ubiquitination and degradation, and suppressed M2 macrophage polarization and TNBC progression. Collectively, our findings suggested that Sohlh2 in macrophage could be a novel therapeutic target for TNBC metastatic treatment.

摘要

肺转移是三阴性乳腺癌（TNBC）患者死亡的主要原因。肿瘤相关巨噬细胞（TAMs）表现出 M2 样表型，具有强大的免疫抑制活性，并在 TNBC 肺转移中发挥促肿瘤作用。Sohlh2 属于碱性螺旋-环-螺旋转录因子家族。然而，其在巨噬细胞极化中的作用尚不清楚，特别是在 TNBC 进展中。在这里，我们证明了 Sohlh2 的过表达促进了 M2 巨噬细胞的极化。此外，M2 样巨噬细胞中 Sohlh2 的高表达增强了 TNBC 细胞在体内和体外的生长、迁移和肺转移。从机制上讲，我们揭示了 Sohlh2 通过上调 LXRα、ABCA1、ABCG1 的表达和扰乱巨噬细胞膜上的脂质稳态来发挥作用。Sohlh2 可以直接结合 LXRα 的启动子并促进其转录活性。E3 泛素连接酶 TRIM21 促进 Sohlh2 的泛素化和降解，抑制 M2 巨噬细胞极化和 TNBC 进展。总之，我们的研究结果表明，巨噬细胞中的 Sohlh2 可能是治疗 TNBC 转移的新靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c65/10733312/70c827961a97/41419_2023_6383_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c65/10733312/257729a18c28/41419_2023_6383_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c65/10733312/f915480c5360/41419_2023_6383_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c65/10733312/75b18d8eb7c1/41419_2023_6383_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c65/10733312/7ea7acb61057/41419_2023_6383_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c65/10733312/7fe0eb766a67/41419_2023_6383_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c65/10733312/385ed0d2ad6a/41419_2023_6383_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c65/10733312/589be243fe89/41419_2023_6383_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c65/10733312/70c827961a97/41419_2023_6383_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c65/10733312/257729a18c28/41419_2023_6383_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c65/10733312/f915480c5360/41419_2023_6383_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c65/10733312/75b18d8eb7c1/41419_2023_6383_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c65/10733312/7ea7acb61057/41419_2023_6383_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c65/10733312/7fe0eb766a67/41419_2023_6383_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c65/10733312/385ed0d2ad6a/41419_2023_6383_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c65/10733312/589be243fe89/41419_2023_6383_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c65/10733312/70c827961a97/41419_2023_6383_Fig8_HTML.jpg

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