癌症相关成纤维细胞（CAF）在肿瘤进展中至关重要。癌细胞中 TP53 的缺乏与基质的强烈活化有关。 apelin-apelin 受体 (APJ) 系统与抑制非肿瘤性器官纤维化中成纤维细胞向肌成纤维细胞的转变有关。本研究旨在阐明apelin-APJ系统在肿瘤成纤维细胞中的致癌作用。使用人类细胞系（TP53 野生结肠癌、HCT116 和 Caco-2；TP53 突变结肠癌、SW480 和 DLD-1；以及结肠成纤维细胞，CCD-18Co）、结直肠癌切除的人体组织样本以及免疫缺陷裸鼠异种移植模型。还分析了超速离心收集的外泌体作为癌细胞中 p53 表达和成纤维细胞中 APJ 表达介质的作用。与 p53 抑制的结肠癌细胞（HCT116sh p53 细胞）共培养的成纤维细胞中的 APJ 表达显着低于对照结肠癌细胞（HCT116sh 对照细胞）。用拮抗剂或小干扰 RNA 处理的 APJ 抑制成纤维细胞显示出肌成纤维细胞样特性，包括通过 Sma 和 Mad 相关蛋白 2/3 (Smad2/3) 的加速磷酸化增加增殖和迁移能力。此外，HCT116细胞与APJ抑制的成纤维细胞的异种移植显示肿瘤生长加速。相比之下，apelin 抑制成纤维细胞中磷酸化 Smad2/3 的上调。来自 HCT116sh p53 细胞的外泌体中富含的 MicroRNA 5703 可抑制 APJ 表达，而抑制 miR-5703 可减少癌细胞引起的成纤维细胞中的 APJ 抑制。癌细胞来源的外泌体中特定 microRNA 的 APJ 抑制在成纤维细胞中诱导 CAF 样特性。因此，肿瘤微环境中成纤维细胞中的APJ系统可能是一个有前途的治疗靶点。

Cancer‑associated fibroblasts (CAFs) are pivotal in tumor progression. TP53‑deficiency in cancer cells is associated with robust stromal activation. The apelin‑apelin receptor (APJ) system has been implicated in suppressing fibroblast‑to‑myofibroblast transition in non‑neoplastic organ fibrosis. The present study aimed to elucidate the oncogenic role of the apelin‑APJ system in tumor fibroblasts. APJ expression and the effect of APJ suppression in fibroblasts were investigated for p53 status in cancer cells using human cell lines (TP53‑wild colon cancer, HCT116, and Caco‑2; TP53‑mutant colon cancer, SW480, and DLD‑1; and colon fibroblasts, CCD‑18Co), resected human tissue samples of colorectal cancers, and immune‑deficient nude mouse xenograft models. The role of exosomes collected by ultracentrifugation were also analyzed as mediators of p53 expression in cancer cells and APJ expression in fibroblasts. APJ expression in fibroblasts co‑cultured with p53‑suppressed colon cancer cells (HCT116sh p53 cells) was significantly lower than in control colon cancer cells (HCT116sh control cells). APJ‑suppressed fibroblasts treated with an antagonist or small interfering RNA showed myofibroblast‑like properties, including increased proliferation and migratory abilities, via accelerated phosphorylation of Sma‑ and Mad‑related protein 2/3 (Smad2/3). In addition, xenografts of HCT116 cells with APJ‑suppressed fibroblasts showed accelerated tumor growth. By contrast, apelin suppressed the upregulation of phosphorylated Smad2/3 in fibroblasts. MicroRNA 5703 enriched in exosomes derived from HCT116sh p53 cells inhibited APJ expression, and inhibition of miR‑5703 diminished APJ suppression in fibroblasts caused by cancer cells. APJ suppression from a specific microRNA in cancer cell‑derived exosomes induced CAF‑like properties in fibroblasts. Thus, the APJ system in fibroblasts in the tumor microenvironment may be a promising therapeutic target.