Wang Zheng, Jiang Lingjuan, Bai Xiaoyin, Guo Mingyue, Zhou Runing, Zhou Qingyang, Yang Hong, Qian Jiaming
Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China; Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
Biomarker Discovery and Validation Facility, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
J Genet Genomics. 2025 Jan 6. doi: 10.1016/j.jgg.2024.12.020.
Colitis-associated colorectal cancer (CAC), a serious complication of ulcerative colitis (UC), is associated with a poor prognosis. The vitamin D receptor (VDR) is recognized for its protective role in UC and CAC through the maintenance of intestinal barrier integrity and the regulation of inflammation. This study demonstrates a significant reduction in mA-related genes, particularly methyltransferase like 14 (METTL14), in UC and CAC patients and identifies an association between METTL14 and VDR. In the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced mouse model, vitamin D treatment increases METTL14 expression and reduces tumor burden, while Vdr-knockout mice exhibit lower METTL14 levels and increased tumorigenesis. In vitro, the VDR agonist calcipotriol upregulates METTL14 in NCM460 cells, with this effect attenuated by VDR knockdown. VDR knockdown in DLD-1 colon cancer cells decreases METTL14 expression and promotes proliferation, which is reversed by METTL14 overexpression. Mechanistic studies reveal that VDR regulates METTL14 expression via promoter binding, modulating key target genes such as SOX4, DROSH, and PHLPP2. This study highlights the role of the VDR-METTL14 axis as a protective mechanism in CAC and suggests its potential as a therapeutic target for preventing and treating CAC.
结肠炎相关结直肠癌（CAC）是溃疡性结肠炎（UC）的一种严重并发症，预后较差。维生素D受体（VDR）因其通过维持肠道屏障完整性和调节炎症在UC和CAC中发挥的保护作用而被认可。本研究表明，UC和CAC患者中与m⁶A相关的基因，特别是甲基转移酶样14（METTL14）显著减少，并确定了METTL14与VDR之间的关联。在氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导的小鼠模型中，维生素D治疗可增加METTL14表达并减轻肿瘤负担，而Vdr基因敲除小鼠的METTL14水平较低且肿瘤发生增加。在体外，VDR激动剂卡泊三醇上调NCM460细胞中的METTL14，这种作用在VDR敲低时减弱。DLD-1结肠癌细胞中的VDR敲低会降低METTL14表达并促进增殖，而METTL14过表达可逆转这种情况。机制研究表明，VDR通过与启动子结合来调节METTL14表达，从而调节关键靶基因如SOX4、DROSH和PHLPP2。本研究强调了VDR-METTL14轴在CAC中的保护机制作用，并表明其作为预防和治疗CAC的治疗靶点的潜力。
