Jia Jing, Huang Yisen, Chen Qiwei, Hou Jianbin, Liu Yan, Xie Lifeng, Li Xinyu, Yang Chunkang
Department of Gastrointestinal Surgery, Quanzhou First Hospital Affiliated to Fujian Medical University, 250 Dongjie, Licheng District, Quanzhou, 362002, Fujian, China.
Department of Gastroenterology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362002, Fujian, China.
Biochem Genet. 2025 Feb;63(1):606-622. doi: 10.1007/s10528-024-10673-0. Epub 2024 Mar 13.
This study aims to elucidate the role and mechanisms of Death Receptor 6 (DR6), a member of the tumor necrosis factor receptor superfamily, in the malignant progression of colorectal cancer (CRC). The association of DR6 expression levels and CRC patient survival was examined using the CRC cohort data from GEPIA database. The functional role of DR6 in CRC cells was investigated by performing loss-of-function and gain-of-function experiments based on CCK-8 proliferation assay, transwell migration and invasion assay, and sphere-forming assays. Xenograft model of CRC cells in nude mouse was established to evaluate the impact of DR6 knockdown on CRC tumorigenesis. Elevated expression of DR6 was correlated with an unfavorable prognosis in CRC patients. In vitro functional assays demonstrated that silencing DR6 considerably suppressed the proliferation, migration, invasion, and stemness of CRC cells, whereas its overexpression showed an opposite effect. DR6 knockdown also attenuated tumor formation of CRC cells in the nude mice. Mechanistically, silencing DR6 reduced the phosphorylation of AKT and NF-κB in CRC cells, and the treatment with an AKT activator (SC79) abrogated the inhibitory effects of DR6 knockdown on the malignant features of CRC cells. Our data suggest that DR6 contributes to the malignant progression of CRC by activating AKT/NF-κB pathway, indicating its clinical potential as a prognostic marker and therapeutic target for CRC.
本研究旨在阐明肿瘤坏死因子受体超家族成员死亡受体6（DR6）在结直肠癌（CRC）恶性进展中的作用及机制。利用GEPIA数据库中的CRC队列数据，检测DR6表达水平与CRC患者生存的相关性。通过基于CCK-8增殖试验、Transwell迁移和侵袭试验以及成球试验进行功能缺失和功能获得实验，研究DR6在CRC细胞中的功能作用。建立CRC细胞裸鼠异种移植模型，以评估DR6敲低对CRC肿瘤发生的影响。DR6表达升高与CRC患者预后不良相关。体外功能试验表明，沉默DR6可显著抑制CRC细胞的增殖、迁移、侵袭和干性，而其过表达则显示出相反的效果。DR6敲低还减弱了CRC细胞在裸鼠中的肿瘤形成。机制上，沉默DR6可降低CRC细胞中AKT和NF-κB的磷酸化，用AKT激活剂（SC79）处理可消除DR6敲低对CRC细胞恶性特征的抑制作用。我们的数据表明，DR6通过激活AKT/NF-κB途径促进CRC的恶性进展，表明其作为CRC预后标志物和治疗靶点的临床潜力。
