Enhanced Expression of TRIM46 in Ovarian Cancer Cells Induced by Tumor-Associated Macrophages Promotes Invasion via the Wnt/β-Catenin Pathway.

Metastasis presents significant challenges in ovarian cancer treatment. Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) facilitate metastasis through epithelial-mesenchymal transition, yet the molecular underlying mechanisms are not fully understood. Here, we identified that tripartite motif-containing 46 (TRIM46) is significantly upregulated in ovarian cancer cells treated with a conditioned medium derived from macrophages stimulated by ovarian cancer cells (OC-MQs). Furthermore, TRIM46 was highly expressed in late-stage ovarian cancer patients and was associated with poor prognosis. Silencing of TRIM46 suppressed cancer cell invasion stimulated by OC-MQ and mesenchymal marker expression without affecting cell viability. Gene set enrichment analysis showed that the Wnt/β-catenin pathway is enriched in the high-TRIM46 expression group. Importantly, the inhibition of TRIM46-mediated β-catenin nuclear translocation and ovarian cancer cell invasion was reversed by CHIR99021, a Wnt/β-catenin activator. Additionally, C-X-C motif chemokine ligand 8 (CXCL8) was identified as being highly expressed in peritoneal MQs from the ascites of ovarian cancer patients and was positively correlated with C-X-C chemokine receptor 1/2 (CXCR1/2) expression in tumor cells. Notably, pre-treatment with reparixin, a CXCR1/2 inhibitor, blocked OC-MQ-induced TRIM46 expression and cell invasion. These results suggest that CXCL8 derived from TAMs promotes human ovarian cancer cell invasion via the Wnt/β-catenin pathway by upregulating TRIM46.