Xu Xuefeng, Xu Zihong, Cai Yaowu, Chen Xintong, Huang Chaoqing
The School of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian, 350122, China.
Department of Gastrointestinal Surgery, The First Hospital of Putian City, Putian, Fujian, 351100, China.
Cell Biochem Biophys. 2025 Mar;83(1):1289-1298. doi: 10.1007/s12013-024-01562-9. Epub 2024 Oct 29.
Gastric cancer (GC) is a frequently occurring malignancy with poor prognosis. Casein kinase 2 interacting protein-1 (CKIP-1) is a PH domain-containing protein implicated in regulating tumorigenesis and macrophage homeostasis. This study aimed to elucidate the role and potential mechanism of CKIP-1 in the progression of GC. CKIP-1 expression in GC tumor and para-carcinoma tissues was detected using RT-qPCR. Then, human monocyte cell line THP-1 was treated with PMA, interleukin (IL)-4 and IL-13 to induce M2-polarized macrophages. CD206, arginase-1 (Arg-1) and transforming growth factorβ1 (TGFβ1) expression in M2-polarized macrophages with or without CKIP-1 overexpression was evaluated. Moreover, GC cell lines (MKN45 and HGC27 cells) were co-cultured with CKIP-1-overexpressed M2-polarized macrophages, and the viability, migration and invasion of GC cells were measured. Additionally, immunoblotting assessed the expression of JAK/STAT3 signaling-related proteins and STAT3 agonist Colivelin was used to treat GC cells to perform the rescue experiments to analyze the changes of malignant phenotypes of GC cells. Results showed that CKIP-1 was downregulated in GC tissues and M2-polarized macrophages. CKIP-1 overexpression inhibited M2 macrophage polarization and decreased TGFβ1 secretion. Besides, elevated CKIP-1 expression in M2-polarized macrophages inhibited the viability, migration and invasion of GC cells. Furthermore, CKIP-1 overexpression inactivated JAK2/STAT3 signaling in GC cells by inhibiting TGFβ1 level. Specifically, Colivelin treatment abrogated the influences of CKIP-1 upregulation on the malignant phenotypes of GC cells. Collectively, CKIP-1 inhibits M2 macrophage polarization to suppress the progression of GC by inactivating JAK/STAT3 signaling pathway.
胃癌（GC）是一种常见的恶性肿瘤，预后较差。酪蛋白激酶2相互作用蛋白-1（CKIP-1）是一种含PH结构域的蛋白，与肿瘤发生和巨噬细胞稳态调节有关。本研究旨在阐明CKIP-1在GC进展中的作用及潜在机制。采用RT-qPCR检测GC肿瘤组织和癌旁组织中CKIP-1的表达。然后，用人单核细胞系THP-1与佛波酯（PMA）、白细胞介素（IL）-4和IL-13处理，诱导M2极化巨噬细胞。评估有无CKIP-1过表达的M2极化巨噬细胞中CD206、精氨酸酶-1（Arg-1）和转化生长因子β1（TGFβ1）的表达。此外，将GC细胞系（MKN45和HGC27细胞）与过表达CKIP-1的M2极化巨噬细胞共培养，检测GC细胞的活力、迁移和侵袭能力。另外，通过免疫印迹法评估JAK/STAT3信号相关蛋白的表达，并使用STAT3激动剂可利韦林（Colivelin）处理GC细胞进行挽救实验，以分析GC细胞恶性表型的变化。结果显示，CKIP-1在GC组织和M2极化巨噬细胞中表达下调。CKIP-1过表达抑制M2巨噬细胞极化并减少TGFβ1分泌。此外，M2极化巨噬细胞中CKIP-1表达升高抑制了GC细胞的活力、迁移和侵袭。此外，CKIP-1过表达通过抑制TGFβ1水平使GC细胞中的JAK2/STAT3信号失活。具体而言，可利韦林处理消除了CKIP-1上调对GC细胞恶性表型的影响。总体而言，CKIP-1通过使JAK/STAT3信号通路失活来抑制M2巨噬细胞极化，从而抑制GC的进展。
