Authors' Affiliations: Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Auf der Morgenstelle; Department of Pediatrics I; Institute for Medical Microbiology and Hygiene, University Hospital Tübingen, Tübingen, Germany; Division of Molecular Genetic Epidemiology; Junior Research Group Toll-Like Receptors and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein; Department of General Internal Medicine; POPGEN Biobank Project, Christian-Albrechts University, Kiel, Germany; and Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden.
Cancer Res. 2013 Dec 15;73(24):7232-42. doi: 10.1158/0008-5472.CAN-13-1746. Epub 2013 Oct 23.
Toll-like receptors (TLR) are overexpressed on many types of cancer cells, including colorectal cancer cells, but little is known about the functional relevance of these immune regulatory molecules in malignant settings. Here, we report frequent single-nucleotide polymorphisms (SNP) in the flagellin receptor TLR5 and the TLR downstream effector molecules MyD88 and TIRAP that are associated with altered survival in a large cohort of Caucasian patients with colorectal cancer (n = 613). MYD88 rs4988453, a SNP that maps to a promoter region shared with the acetyl coenzyme-A acyl-transferase-1 (ACAA1), was associated with decreased survival of patients with colorectal cancer and altered transcriptional activity of the proximal genes. In the TLR5 gene, rs5744174/F616L was associated with increased survival, whereas rs2072493/N592S was associated with decreased survival. Both rs2072493/N592S and rs5744174/F616L modulated TLR5 signaling in response to flagellin or to different commensal and pathogenic intestinal bacteria. Notably, we observed a reduction in flagellin-induced p38 phosphorylation, CD62L shedding, and elevated expression of interleukin (IL)-6 and IL-1β mRNA in human primary immune cells from TLR5 616LL homozygote carriers, as compared with 616FF carriers. This finding suggested that the well-documented effect of cytokines like IL-6 on colorectal cancer progression might be mediated by TLR5 genotype-dependent flagellin sensing. Our results establish an important link between TLR signaling and human colorectal cancer with relevance for biomarker and therapy development.
Toll 样受体 (TLR) 在包括结直肠癌细胞在内的许多类型的癌细胞上过度表达，但在恶性环境中这些免疫调节分子的功能相关性知之甚少。在这里，我们报告了 flagellin 受体 TLR5 及其 TLR 下游效应分子 MyD88 和 TIRAP 中的频繁单核苷酸多态性 (SNP)，这些 SNP 与在一个大型高加索人群的结直肠癌患者队列中（n = 613）与生存改变相关。位于与乙酰辅酶 A 酰基转移酶-1 (ACAA1) 共享启动子区域的 MYD88 rs4988453 SNP 与结直肠癌患者的生存降低以及近端基因的转录活性改变相关。在 TLR5 基因中，rs5744174/F616L 与生存增加相关，而 rs2072493/N592S 与生存减少相关。rs2072493/N592S 和 rs5744174/F616L 均调节 TLR5 信号对鞭毛蛋白或不同共生和致病肠道细菌的反应。值得注意的是，与 TLR5 616FF 携带者相比，我们在 TLR5 616LL 纯合子携带者的人类原代免疫细胞中观察到鞭毛蛋白诱导的 p38 磷酸化、CD62L 脱落以及白细胞介素 (IL)-6 和 IL-1β mRNA 表达的降低。这一发现表明，像 IL-6 这样的细胞因子对结直肠癌进展的众所周知的影响可能是由 TLR5 基因型依赖性鞭毛蛋白感知介导的。我们的研究结果在结直肠癌患者中建立了 TLR 信号与人类结直肠癌之间的重要联系，这对生物标志物和治疗方法的发展具有重要意义。
