Sialylated IgG-activated integrin β4-Src-Erk axis stabilizes c-Myc in a p300 lysine acetyltransferase-dependent manner to promote colorectal cancer liver metastasis

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia Pub Date : 2025-02-25 DOI:10.1016/j.neo.2025.101140

Jing Chen , Shenghua Zhang , Xinmei Huang , Qianqian Wang , Weiyan Xu , Jing Huang , Yuming Su , Qinkun Sun , Xiaojuan Du , Baocai Xing , Xiaoyan Qiu

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引用次数: 0

Abstract

Background

Liver metastasis is a leading cause of colorectal cancer mortality. Therefore, the underlying mechanism and potential therapeutic target of colorectal cancer liver metastasis urge to be found. Mounting evidence indicates that cancer-derived sialylated IgG promotes tumor formation and progression. However, the role of sialylated IgG in colorectal cancer liver metastasis remains undefined.

Materials and methods

Analysis of sialylated IgG in paired tumor tissues and adjacent normal tissues from 65 colorectal cancer patients was performed using immunohistochemical staining. Functional assays of sialylated IgG were explored in vitro and in vivo. The downstream target of sialylated IgG was investigated by performing gene-set enrichment analysis, ubiquitination assay, cycloheximide chase assay, acetylation assay and co-immunoprecipitation.

Results

Here, our investigation reveals that sialylated IgG is significantly upregulated in colorectal cancer and that the increase of IgG is positively associated with liver metastasis and poor overall survival in colorectal cancer patients. Sialylated IgG promotes colorectal cancer cell migration, invasion and liver metastasis. Notably, anti-sialylated IgG antibody effectively blocks colorectal cancer liver metastasis in mouse models. Mechanistically, sialylated IgG upregulates c-Myc protein level by decreasing c-Myc ubiquitination. Moreover, we find that p300/CBP can stabilize c-Myc by reducing c-Myc ubiquitination. Overexpression of p300/CBP protects c-Myc protein level from sialylated IgG-knockdown in a lysine acetyltransferase activity-dependent manner. Furthermore, sialylated IgG upregulates p300 protein level through integrin β4-FAK-Src-Erk signaling.

Conclusion

Collectively, these results indicate that a novel sialylated IgG-integrin β4-FAK-Src-Erk-p300-c-Myc signaling pathway promotes colorectal cancer liver metastasis, thus providing potential therapeutic targets for colorectal cancer liver metastasis.

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背景肝转移是结直肠癌死亡的主要原因。因此，结直肠癌肝转移的潜在机制和治疗靶点亟待找到。越来越多的证据表明，癌症衍生的硅氨酰化 IgG 会促进肿瘤的形成和发展。材料与方法采用免疫组化染色法分析了 65 例结直肠癌患者的配对肿瘤组织和邻近正常组织中的硅氨酰化 IgG。在体外和体内探索了硅氨酰化 IgG 的功能测试。通过基因组富集分析、泛素化检测、环己亚胺追逐检测、乙酰化检测和共免疫沉淀等方法研究了硅氨酰化 IgG 的下游靶点。结果我们的研究发现，硅氨酰化 IgG 在结直肠癌中显著上调，IgG 的增加与结直肠癌患者的肝转移和总生存率低呈正相关。硅氨酰化 IgG 促进结直肠癌细胞迁移、侵袭和肝转移。值得注意的是，在小鼠模型中抗硅氨酰化 IgG 抗体能有效阻止结直肠癌肝转移。从机理上讲，硅氨酰化 IgG 通过减少 c-Myc 泛素化来上调 c-Myc 蛋白水平。此外，我们还发现 p300/CBP 可以通过减少 c-Myc 泛素化来稳定 c-Myc。过量表达 p300/CBP 可保护 c-Myc 蛋白水平不受 sialylated IgG 敲除的影响，这种保护是以赖氨酸乙酰转移酶活性依赖的方式进行的。总之，这些结果表明，一种新型的硅氨酰化IgG-整合素β4-FAK-Src-Erk-p300-c-Myc信号通路促进了结直肠癌肝转移，从而为结直肠癌肝转移提供了潜在的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neoplasia 医学-肿瘤学

CiteScore

9.20

自引率

2.10%

发文量

审稿时长

26 days

期刊介绍： Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.