The MIR181A2HG/miR-5680/VCAN-CD44 Axis Regulates Gastric Cancer Lymph Node Metastasis by Promoting M2 Macrophage Polarization

Background: Lymphatic metastasis in gastric Cancer (GC) profoundly influences its prognosis, but the precise mechanism remains elusive. In this study, we identified the long noncoding RNA MIR181A2HG as being upregulated in GC and associated with LNs metastasis and prognosis.

Methods: The expression of MIR181A2HG in GC was identified through bioinformatics screening analysis and qRT-PCR validation. Both in vitro and in vivo functional studies revealed that MIR181A2HG facilitates lymphangiogenesis and lymphatic metastasis. Techniques such as immunofluorescence, immunohistochemistry, qRT-PCR, ELISA, CHIP, RNA-pulldown, luciferase reporter assay, and Co-IP were employed to investigate the mechanism of MIR181A2HG in LNs metastasis of GC.

Results: MIR181A2HG overexpressed in GC signifies an unfavorable prognosis and drives M2 polarization of TAMs enhancing lymphangiogenesis. Mechanistically, MIR181A2HG/miR-5680 axis as a novel ceRNA regulatory axis to upregulate versican (VCAN). On one hand, VCAN interacts with CD44 receptors on the surface of TAMs through paracrine secretion, promoting M2 macrophage polarization and subsequently enhancing the secretion of VEGF-C, ultimately facilitating lymphangiogenesis. On the Other hand, VCAN binds to CD44 receptors on the surface of GC cells through autocrine secretion, activating the Hippo pathway and upregulating SP1, thereby promoting the transcription of MIR181A2HG and establishing a feedback loop driving lymphatic metastasis.

Conclusion: This study highlights the pivotal role of MIR181A2HG in GC progression and LNs metastasis. MIR181A2HG-based targeted therapy would represent a novel strategy for GC.

CD44; MIR181A2HG; VCAN; gastric cancer; lymphatic metastasis; macrophage; miR‐5680.