Orosomucoid 2 upregulation mediates liver injury-induced colorectal cancer liver metastasis by promoting EMT and cell migration.

IF 5.7 2区 医学 Q1 Medicine Cancer Science Pub Date : 2024-03-12 DOI:10.1111/cas.16131
Xundong Wei, Lei Wang, Bing Yang, Yuanyuan Ma, Wei Yuan, Jie Ma
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Abstract

The relationship between drug-induced liver injury and liver metastasis of colorectal cancer and the underlying mechanisms are not well understood. In this study, we used carbon tetrachloride to construct a classic mouse liver injury model and injected CT26 colorectal cancer cells into the mouse spleen to simulate the natural route of colorectal cancer liver metastasis. Liver injury significantly increased the number of colorectal cancer liver metastases. Transcriptome sequencing and data-independent acquisition protein quantification identified proteins that were significantly differentially expressed in injured livers, and orosomucoid (ORM) 2 was identified as a target protein for tumor liver metastasis. In vitro experiments showed that exogenous ORM2 protein increased the expression of EMT markers such as Twist, Zeb1, Vim, Snail1 and Snail2 and chemokine ligands to promote CT26 cell migration. In addition, liver-specific overexpression of the ORM2 protein in the mouse model significantly promoted tumor cell liver metastasis without inducing liver injury. Our results indicate that drug-induced liver injury can promote colorectal cancer liver metastasis and that ORM2 can promote cell migration by inducing EMT in tumor cells.

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Orosomucoid 2上调通过促进EMT和细胞迁移介导肝损伤诱导的结直肠癌肝转移。
药物诱导的肝损伤与结直肠癌肝转移之间的关系及其内在机制尚不十分清楚。在本研究中,我们用四氯化碳构建了经典的小鼠肝损伤模型,并将 CT26 大肠癌细胞注入小鼠脾脏以模拟大肠癌肝转移的自然途径。肝损伤明显增加了结直肠癌肝转移的数量。转录组测序和数据独立获取蛋白定量鉴定出了在损伤肝脏中显著差异表达的蛋白,并确定了orosomucoid(ORM)2是肿瘤肝转移的靶蛋白。体外实验表明,外源性ORM2蛋白可增加Twist、Zeb1、Vim、Snail1和Snail2等EMT标记物以及趋化因子配体的表达,从而促进CT26细胞迁移。此外,在小鼠模型中肝特异性过表达ORM2蛋白可显著促进肿瘤细胞的肝转移,而不会引起肝损伤。我们的研究结果表明,药物诱导的肝损伤可促进结直肠癌肝转移,而ORM2可通过诱导肿瘤细胞的EMT促进细胞迁移。
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来源期刊
Cancer Science
Cancer Science ONCOLOGY-
CiteScore
9.90
自引率
3.50%
发文量
406
审稿时长
17 weeks
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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