Sandoval Alexander Q, James Anika, Neufeld Kristi L
Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA.
Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA.
Cell Signal. 2025 Oct;134:111957. doi: 10.1016/j.cellsig.2025.111957. Epub 2025 Jun 20.
Adenomatous polyposis coli (APC) mutations and chronic inflammation can each promote colon cancer. Though both mice and humans with germline APC mutations show reduced tumorigenesis if treated with anti-inflammatory agents, direct links between APC and inflammation remain incomplete. In the current study, we examine a novel role for APC in intestinal inflammation via inhibition of neutrophil-recruiting chemokines CXCL1, 2, and 3. Patients with colorectal adenocarcinoma, the majority of whom would be expected to harbor APC mutations, showed upregulated CXCL1, 2, and 3 expression at early stages of disease. APC induction in cultured human colon cells reduced levels of CXCL1 and CXCL2 proteins and CXCL1, CXCL2, and CXCL3 RNAs and increased expression of signal transducer and activator of transcription 1 (STAT1), a potential negative regulator of CXCL1 transcription. By mining published Chromatin-immunoprecipitation sequencing (ChIP-Seq) data, we found regions of the STAT1 promoter and upstream CpG island as APC-bound. Methylation-specific PCR and bisulfite sequencing each revealed decreased methylation of the STAT1 CpG island upon APC induction. Intestinal tissue explants from mice compromised for nuclear Apc (Apc) secreted more CXCL1 and CXCL2 than wild-type explants. Conditioned media from APC-expressing cells recruited fewer neutrophils in a trans-well migration assay. In vivo, colon and ileal tissues from Apc mice displayed more neutrophils than Apc mice. Experimental evidence from in vitro and in vivo systems validates that nuclear APC can inhibit inflammation by suppressing neutrophil-recruiting chemokines CXCL1, 2, and 3, potentially via epigenetic regulation of STAT1. These findings offer a new target for managing inflammation in inflammatory bowel disease and reveal a new mechanism by which APC loss enables cancer progression.
腺瘤性结肠息肉病蛋白（APC）突变和慢性炎症均可促进结肠癌的发生。尽管携带种系APC突变的小鼠和人类在使用抗炎药治疗后肿瘤发生均减少，但APC与炎症之间的直接联系仍不完整。在本研究中，我们通过抑制中性粒细胞趋化因子CXCL1、2和3来研究APC在肠道炎症中的新作用。大多数预计携带APC突变的结直肠癌患者在疾病早期显示CXCL1、2和3表达上调。在培养的人结肠细胞中诱导APC可降低CXCL1和CXCL2蛋白水平以及CXCL1、CXCL2和CXCL3 RNA水平，并增加信号转导和转录激活因子1（STAT1）的表达，STAT1是CXCL1转录的潜在负调节因子。通过挖掘已发表的染色质免疫沉淀测序（ChIP-Seq）数据，我们发现STAT1启动子区域和上游CpG岛为APC结合位点。甲基化特异性PCR和亚硫酸氢盐测序均显示，诱导APC后STAT1 CpG岛的甲基化减少。核Apc功能受损的小鼠（Apc）的肠道组织外植体比野生型外植体分泌更多的CXCL1和CXCL2。在Transwell迁移试验中，来自表达APC细胞的条件培养基招募的中性粒细胞较少。在体内，Apc小鼠的结肠和回肠组织中的中性粒细胞比Apc小鼠更多。体外和体内系统的实验证据证实，核APC可通过抑制中性粒细胞趋化因子CXCL1、2和3来抑制炎症，这可能是通过对STAT1的表观遗传调控实现的。这些发现为炎症性肠病的炎症管理提供了新靶点，并揭示了APC缺失促进癌症进展的新机制。
