Exosomal miR-382-5p prevents pre-metastatic niche formation by inhibiting GPR176/GNAS-CXCR1/CXCR2 axis in colorectal cancer liver metastasis

Lingling Yang; Hui Zhu; Lifang Chen; Jingyu Zhang; Jun Huang; Liangtao Zeng; Zhen Zong

doi:10.1016/j.cellsig.2025.111963

Exosomal miR-382-5p prevents pre-metastatic niche formation by inhibiting GPR176/GNAS-CXCR1/CXCR2 axis in colorectal cancer liver metastasis

Cell Signal. 2025 Jun 25:111963. doi: 10.1016/j.cellsig.2025.111963. Online ahead of print.

Authors

Lingling Yang¹, Hui Zhu², Lifang Chen², Jingyu Zhang³, Jun Huang³, Liangtao Zeng⁴, Zhen Zong⁵

Affiliations

¹ Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China. Electronic address: ndefy20358@ncu.edu.cn.
² Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
³ Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
⁴ Department of Pathology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
⁵ Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China. Electronic address: zongzhenmd@126.com.

PMID: 40578589
DOI: 10.1016/j.cellsig.2025.111963

Abstract

Background: Mounting evidence suggests that tumor-derived exosomal miRNAs play a pivotal role in cancer metastasis and progression. This study aims to elucidate the mechanism by which exosomal miR-382-5p regulates colorectal cancer liver metastasis (CRCLM).

Methods: Exosomes were isolated using high-speed centrifuge and characterized by transmission electron microscopy. Both in vivo and in vitro assays were utilized to investigate the effects of exosomal miR-382-5p on angiogenesis and vascular permeability. The underlying molecular mechanisms were further explored through RNA pull-down, RNA immunoprecipitation (RIP), and co-immunoprecipitation (Co-IP) assays. Single-cell analysis was performed to validate clinical relevance.

Results: This study revealed that miR-382-5p expression was significantly downregulated in colorectal cancer (CRC), particularly in CRCLM, and was inversely correlated with metastatic progression. The overexpression of miR-382-5p suppressed the proliferation, migration, and invasion of CRC cells. Furthermore, in vivo and in vitro experiments demonstrated that CRC cell-derived exosomal miR-382-5p inhibited angiogenesis, vascular permeability and liver metastasis. Mechanistically, exosomal miR-382-5p was observed to downregulate GPR176 expression and disrupt its interaction with GNAS in the liver tissue of CRCLM models. Moreover, exosomal miR-382-5p reduced CXCR1/CXCR2 levels by inhibiting the GPR176-GNAS binding, thereby suppressing angiogenesis and vascular permeability. Single-cell analysis confirmed the upregulation and prognostic value of GPR176 and CXCR1/CXCR2 in CRC.

Conclusion: In summary, CRC cell-derived exosomal miR-382-5p inhibited the formation of the CRCLM pre-metastatic niche by targeting the GPR176/GNAS-CXCR1/CXCR2 axis, ultimately impeding liver metastasis development. These findings provide both mechanistic insights and clinical relevance for CRCLM diagnosis and therapy.

Keywords: Colorectal cancer liver metastasis; Exosomal miR-382-5p; GPR176; Pre-metastatic niche.