title: Functional TLR5 genetic variants affect human colorectal cancer survival.
abstract: 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.
authors.affiliation: 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.
authors.forename: Sascha N
authors.initials: SN
authors.lastname: Klimosch
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
authors.forename: Jana
authors.initials: J
authors.lastname: Eckert
authors.forename: Jelena
authors.initials: J
authors.lastname: Knezevic
authors.forename: Melanie
authors.initials: M
authors.lastname: Bevier
authors.forename: Witigo
authors.initials: W
authors.lastname: von Schönfels
authors.forename: Nils
authors.initials: N
authors.lastname: Heits
authors.forename: Jessica
authors.initials: J
authors.lastname: Walter
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hinz
authors.forename: Jesus
authors.initials: J
authors.lastname: Lascorz
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.forename: Dominik
authors.initials: D
authors.lastname: Hartl
authors.forename: Julia-Stefanie
authors.initials: JS
authors.lastname: Frick
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Clemens
authors.initials: C
authors.lastname: Schafmayer
authors.forename: Alexander N R
authors.initials: AN
authors.lastname: Weber
mesh_terms: D000102:Acetyl-CoA C-Acyltransferase / Q000235:genetics; D000483:Alleles; D015179:Colorectal Neoplasms / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D005408:Flagellin / Q000235:genetics; D005838:Genotype; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D015996:Survival Rate; D051198:Toll-Like Receptor 5 / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D005408:Flagellin; C570764:ACAA1 protein, human; D000102:Acetyl-CoA C-Acyltransferase