Suprabasin promotes gastric cancer liver metastasis via hepatic stellate cells-mediated EGF/CCL2/JAK2 intercellular signaling pathways.

IF 6.9 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Oncogene Pub Date : 2025-04-03 DOI:10.1038/s41388-025-03370-8

Difeng Li, Zhiqing Gao, Zhuojun Zhang, Han Chen, Ruiming Tang, Lihuan Zhou, Yingmin Ye, Jiaqian Lin, Ping Zhou, Chanjuan Wang, Xiaoli Feng, Yaoming He, Zijie Meng, Mingzhu Zheng, Wenjie Lu, Zhengfu Feng, Lan Wang, Yuanyuan Pei, Jianan Yang, Tianyu Tao, Xin Zhang, Lili Jiang

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引用次数: 0

Abstract

Gastric cancer is among the most prevalent gastrointestinal tumors, with liver metastasis significantly worsening patient outcomes. While hepatic stellate cell activation is crucial in hepatocellular carcinoma progression and liver metastasis, its role in gastric cancer liver metastasis is not well understood. In this study, we identified Suprabasin (SBSN) as a key oncogene driving gastric cancer liver metastasis. SBSN was upregulated in gastric cancer tissues and further elevated in liver metastasis, correlating with poor prognosis. Mechanistically, SBSN promoted proliferation, migration, and invasion of gastric cancer cells by activating the STAT3 signaling pathway, as shown in vitro and in vivo. Using a co-culture model of gastric cancer cells and hepatic stellate cell line LX-2, we found that increased SBSN expression in gastric cancer cells triggered EGF secretion, activating LX-2 cells through the EGF/EGFR axis. Activated LX-2 cells then secreted CCL2, initiating the CCL2/CCR2/JAK2 signaling pathway in gastric cancer cells, facilitating their migration to the liver and promoting colonization and growth. Our findings highlight the prognostic significance of SBSN in gastric cancer and liver metastasis, suggesting it as a potential biomarker for disease progression. The SBSN-mediated EGF/EGFR and CCL2/CCR2/JAK2 signaling axes are critical for LX-2 activation and gastric cancer cell migration, offering a rationale for targeting SBSN in treating gastric cancer liver metastasis.

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Suprabasin通过肝星状细胞介导的EGF/CCL2/JAK2细胞间信号通路促进胃癌肝转移。

胃癌是发病率最高的消化道肿瘤之一，肝转移会严重恶化患者的预后。虽然肝星状细胞活化在肝细胞癌进展和肝转移中至关重要，但其在胃癌肝转移中的作用却不甚了解。本研究发现，Suprabasin（SBSN）是驱动胃癌肝转移的关键癌基因。SBSN在胃癌组织中上调，在肝转移中进一步升高，与不良预后相关。从机制上看，SBSN通过激活STAT3信号通路促进胃癌细胞的增殖、迁移和侵袭，这在体外和体内均有显示。利用胃癌细胞和肝星状细胞系 LX-2 的共培养模型，我们发现胃癌细胞中 SBSN 表达的增加会引发 EGF 分泌，通过 EGF/EGFR 轴激活 LX-2 细胞。活化的 LX-2 细胞随后分泌 CCL2，启动胃癌细胞的 CCL2/CCR2/JAK2 信号通路，促进胃癌细胞向肝脏迁移，促进定植和生长。我们的研究结果突显了 SBSN 在胃癌和肝转移中的预后意义，表明它是疾病进展的潜在生物标志物。SBSN 介导的 EGF/EGFR 和 CCL2/CCR2/JAK2 信号轴是 LX-2 激活和胃癌细胞迁移的关键，为靶向 SBSN 治疗胃癌肝转移提供了理论依据。

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

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.