The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510080, China.
Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
Acta Biochim Biophys Sin (Shanghai). 2023 Nov 25;55(11):1819-1832. doi: 10.3724/abbs.2023235.
Despite substantial advancements in screening, surgery, and chemotherapy, colorectal cancer remains the second most lethal form of the disease. Nuclear factor kappa B (NF-κB) signaling is a critical driver facilitating the malignant transformation of chronic inflammatory bowel diseases. In this study, deregulated miRNAs that could play a role in colon cancer are analyzed and investigated for specific functions using cancer cells and using a subcutaneous xenograft model. miRNA downstream targets are analyzed, and predicted binding and regulation are verified. miR-1262, an antitumor miRNA, is downregulated in colon cancer tissue samples and cell lines. miR-1262 overexpression suppresses colon cancer malignant behaviors and tumor development and metastasis in a subcutaneous xenograft model and a lung metastasis mouse model . miR-1262 directly targets fibroblast growth factor receptor 1 (FGFR1) and inhibits FGFR1 expression. FGFR1 overexpression shows oncogenic functions through the regulation of cancer cell proliferation, invasion, and migration; when cotransfected, lv-FGFR1 partially attenuates the antitumor effects of agomir-1262. NF-κB binds to the miR-1262 promoter region and inhibits transcription activity. The NF-κB inhibitor CAPE exerts antitumor effects; miR-1262 inhibition partially reverses CAPE effects on colon cancer cells. Conclusively, miR-1262 serves as an antitumor miRNA in colon cancer by targeting FGFR1. The NF-κB/miR-1262/FGFR1 axis modulates colon cancer cell phenotypes, including proliferation, invasion, and migration.
尽管在筛查、手术和化疗方面取得了重大进展，但结直肠癌仍然是第二致命的疾病形式。核因子 kappa B（NF-κB）信号是促进慢性炎症性肠病恶性转化的关键驱动因素。在这项研究中，分析了失调的 miRNA，这些 miRNA 可能在结肠癌中发挥作用，并使用癌细胞和皮下异种移植模型研究其特定功能。分析了 miRNA 下游靶标，并验证了预测的结合和调节。miR-1262 是一种抗肿瘤 miRNA，在结肠癌组织样本和细胞系中下调。miR-1262 的过表达抑制了结肠癌的恶性行为和皮下异种移植模型和肺转移小鼠模型中的肿瘤发展和转移。miR-1262 直接靶向成纤维细胞生长因子受体 1（FGFR1）并抑制 FGFR1 的表达。FGFR1 的过表达通过调节癌细胞的增殖、侵袭和迁移表现出致癌功能；当共转染时，lv-FGFR1 部分减弱 agomir-1262 的抗肿瘤作用。NF-κB 结合 miR-1262 启动子区域并抑制转录活性。NF-κB 抑制剂 CAPE 发挥抗肿瘤作用；miR-1262 的抑制部分逆转了 CAPE 对结肠癌细胞的作用。总之，miR-1262 通过靶向 FGFR1 作为结肠癌中的抗肿瘤 miRNA。NF-κB/miR-1262/FGFR1 轴调节结肠癌细胞表型，包括增殖、侵袭和迁移。
