Wang Yi-Yue, Choi Min-Jun, Kim Jin-Hyung, Choi Jung-Hye
Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China.
Department of Biomedical and Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
Cells. 2025 Feb 2;14(3):214. doi: 10.3390/cells14030214.
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.
转移是卵巢癌治疗中的重大挑战。肿瘤微环境（TME）中的肿瘤相关巨噬细胞（TAM）通过上皮-间质转化促进转移，但其分子机制尚未完全阐明。在此，我们发现，在用源自卵巢癌细胞刺激的巨噬细胞（OC-MQ）的条件培养基处理的卵巢癌细胞中，含三联基序的蛋白46（TRIM46）显著上调。此外，TRIM46在晚期卵巢癌患者中高表达，且与预后不良相关。沉默TRIM46可抑制OC-MQ刺激的癌细胞侵袭和间充质标志物表达，而不影响细胞活力。基因集富集分析表明，Wnt/β-连环蛋白通路在高TRIM46表达组中富集。重要的是，Wnt/β-连环蛋白激活剂CHIR99021可逆转TRIM46介导的β-连环蛋白核转位抑制和卵巢癌细胞侵袭。此外，C-X-C基序趋化因子配体8（CXCL8）在卵巢癌患者腹水中的腹膜MQ中高表达，且与肿瘤细胞中的C-X-C趋化因子受体1/2（CXCR1/2）表达呈正相关。值得注意的是，用CXCR1/2抑制剂瑞帕霉素预处理可阻断OC-MQ诱导的TRIM46表达和细胞侵袭。这些结果表明，源自TAM的CXCL8通过上调TRIM46，经由Wnt/β-连环蛋白通路促进人卵巢癌细胞侵袭。
