WISP-3 drives LUAD metastasis by suppressing miR-5004-5p to upregulate MMP-12.

Lung adenocarcinoma (LUAD) is characterized by a high propensity for metastasis and poor clinical outcomes. Although members of the cellular communication network (CCN) family exhibit context-dependent roles in tumor progression, the function of WNT1-inducible signaling pathway protein 3 (WISP-3), also known as CCN6, in LUAD remains incompletely understood. In this study, we demonstrate that WISP-3 is significantly upregulated in LUAD tissues and is associated with unfavorable patient survival. Functional assays revealed that WISP-3 enhances cell migration and wound healing capacity in LUAD cells. Mechanistically, WISP-3 activates proto-oncogene tyrosine-protein kinase Src (Src) and focal adhesion kinase (FAK) signaling, leading to suppression of microRNA-5004-5p (miR-5004-5p). We further show that miR-5004-5p negatively regulated matrix metalloproteinase-12 (MMP-12) expression through interaction with the 3' untranslated region (3'UTR) of MMP-12 mRNA. Suppression of miR-5004-5p by WISP-3 was accompanied by increased MMP-12 expression. Notably, MMP-12 was elevated in LUAD tissues and correlates with poor patient prognosis, supporting its role as a clinically relevant downstream effector. Restoration of miR-5004-5p or inhibition of Src/FAK signaling significantly attenuated WISP-3-induced migratory and MMP-12 expression. Collectively, our findings identify a WISP-3-driven signaling cascade that promotes LUAD metastasis through miR-5004-5p suppression and subsequent MMP-12 upregulation. This study provides new insights into the context-specific function of WISP-3 and highlights the WISP-3/Src/FAK/miR-5004-5p/MMP-12 axis as a potential therapeutic target in LUAD.