miR-28-3p suppresses gastric cancer growth and EMT-driven metastasis by targeting the ARF6/Hedgehog axis

Hua Ji; Sicheng Liu; Libo Yang; Yunhua Wu; Huanqing Zhang; Xueqing Liu; Linhai Li; Lihua Li

doi:10.1016/j.mcp.2025.102010

miR-28-3p suppresses gastric cancer growth and EMT-driven metastasis by targeting the ARF6/Hedgehog axis

Mol Cell Probes. 2025 Jan 7:102010. doi: 10.1016/j.mcp.2025.102010. Online ahead of print.

Authors

Hua Ji¹, Sicheng Liu¹, Libo Yang¹, Yunhua Wu¹, Huanqing Zhang¹, Xueqing Liu¹, Linhai Li², Lihua Li³

Affiliations

¹ Department of Medical Oncology, The First People's Hospital of Yunnan Province/The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, 650000, China; Faculty of Medicine, Kunming University of Science and Technology, Kunming, 650000, China.
² Faculty of Medicine, Kunming University of Science and Technology, Kunming, 650000, China; Department of General Surgery, The First People's Hospital of Yunnan Province/The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, 650000, China. Electronic address: linhai@kust.edu.cn.
³ Department of Medical Oncology, The First People's Hospital of Yunnan Province/The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, 650000, China; Faculty of Medicine, Kunming University of Science and Technology, Kunming, 650000, China. Electronic address: huaqi90@163.com.

PMID: 39788390
DOI: 10.1016/j.mcp.2025.102010

Abstract

Gastric cancer (GC), among the most prevalent malignant tumors globally, demonstrates a rapid metastasis rate leading to high mortality. While microRNAs (miRNAs) have been recognized as critical regulators of tumor progression, the specific role of miR-28-3p in GC remains unclear. In this study, we demonstrate that miR-28-3p acts as a tumor suppressor by inhibiting GC cell proliferation and EMT-driven migration in vitro, as well as tumor growth and metastasis in vivo. Mechanistically, miR-28-3p directly targets ADP ribosylation factor 6 (ARF6), a small GTPase identified as an oncogene in GC. We reveal that ARF6 is significantly upregulated in GC and activates the GLI1/2-dependent Hedgehog signaling pathway, promoting tumor growth and EMT. Notably, ARF6 knockdown mitigates the pro-tumor effects caused by miR-28-3p deficiency, while combined ARF6 inhibition and Hedgehog pathway suppression exhibit synergistic anti-tumor effects. This study establishes the miR-28-3p-ARF6-Hedgehog signaling axis as a critical regulatory pathway in GC progression. Our findings provide novel insights into GC pathogenesis and highlight the therapeutic potential of targeting this axis for innovative treatment strategies.

Keywords: ADP ribosylation factor 6; Hedgehog signaling pathway; epithelial-mesenchymal transition; gastric cancer; miR-28-3p.