High Expression of Toll-like Receptor 4/myeloid Differentiation Factor 88 Signals Correlates with Poor Prognosis in Colorectal Cancer

Overview

Journal Br J Cancer

Specialty Oncology

Date 2010 Feb 11

PMID 20145615

Citations 128

Authors

E L Wang

Z R Qian

M Nakasono

T Tanahashi

K Yoshimoto

Y Bando

E Kudo

M Shimada

T Sano

Affiliations

Soon will be listed here.

Abstract

Background: The Toll-like receptor (TLR) 4 signalling pathway has been shown to have oncogenic effects in vitro and in vivo. To demonstrate the role of TLR4 signalling in colon tumourigenesis, we examined the expression of TLR4 and myeloid differentiation factor 88 (MyD88) in colorectal cancer (CRC).

Methods: The expression of TLR4 and MyD88 in 108 CRC samples, 15 adenomas, and 15 normal mucosae was evaluated by immunohistochemistry, and the correlations between their immunoscores and clinicopathological variables, including disease-free survival (DFS) and overall survival (OS), were analysed.

Results: Compared with normal mucosae and adenomas, 20% cancers displayed high expression of TLR4, and 23% cancers showed high expression of MyD88. The high expression of TLR4 and MyD88 was significantly correlated with liver metastasis (P=0.0001, P=0.0054). In univariate analysis, the high expression of TLR4 was significantly associated with shorter OS (hazard ratio (HR): 2.17; 95% confidence interval (95% CI): 1.15-4.07; P=0.015). The high expression of MyD88 expression was significantly associated with poor DFS and OS (HR: 2.33; 95% CI: 1.31-4.13; P=0.0038 and HR: 3.03; 95% CI: 1.67-5.48; P=0.0002). The high combined expression of TLR4 and MyD88 was also significantly associated with poor DFS and OS (HR: 2.25; 95% CI: 1.27-3.99; P=0.0053 and HR: 2.97; 95% CI: 1.64-5.38; P=0.0003). Multivariate analysis showed that high expressions of TLR4 (OS: adjusted HR: 1.88; 95% CI: 0.99-3.55; P=0.0298) and MyD88 (DFS: adjusted HR: 1.93; 95% CI: 1.01-3.67; P=0.0441; OS: adjusted HR: 2.25; 95% CI: 1.17-4.33; P=0.0112) were independent prognostic factors of OS. Furthermore, high co-expression of TLR4/MyD88 was strongly associated with both poor DFS and OS.

Conclusion: Our findings suggest that high expression of TLR4 and MyD88 is associated with liver metastasis and is an independent predictor of poor prognosis in patients with CRC.

Citing Articles

New Insights into the Pleiotropic Actions of Dipeptidyl Peptidase-4 Inhibitors Beyond Glycaemic Control.

Mangoura S, Ahmed M, Zaka A touchREV Endocrinol. 2024; 20(2):19-29.

PMID: 39526061 PMC: 11548370. DOI: 10.17925/EE.2024.20.2.5.

MiR-5195-3p predicts clinical prognosis and represses colorectal cancer progression by targeting TLR4/MyD88 signaling.

Lv Y, Guo S, Jin L, Wang K, Li Y, Li H Cell Div. 2024; 19(1):29.

PMID: 39390599 PMC: 11468180. DOI: 10.1186/s13008-024-00133-x.

Genetic association and functional implications of TLR4 rs1927914 polymorphism on colon cancer risk.

Li A, Gao H, Wu H, Xie Y, Jia Z, Yang Z BMC Cancer. 2024; 24(1):858.

PMID: 39026223 PMC: 11256370. DOI: 10.1186/s12885-024-12604-z.

The genomic landscape of the immune system in lung cancer: present insights and continuing investigations.

Roshan-Zamir M, Khademolhosseini A, Rajalingam K, Ghaderi A, Rajalingam R Front Genet. 2024; 15:1414487.

PMID: 38983267 PMC: 11231382. DOI: 10.3389/fgene.2024.1414487.

The Role of Natural Products from Herbal Medicine in TLR4 Signaling for Colorectal Cancer Treatment.

Luo Y, Zhang G, Hu C, Huang L, Wang D, Chen Z Molecules. 2024; 29(12).

PMID: 38930793 PMC: 11206024. DOI: 10.3390/molecules29122727.

References

Earl T, Nicoud I, PIERCE J, Wright J, Majoras N, Rubin J . Silencing of TLR4 decreases liver tumor burden in a murine model of colorectal metastasis and hepatic steatosis. Ann Surg Oncol. 2009; 16(4):1043-50. DOI: 10.1245/s10434-009-0325-8. View

Scartozzi M, Bearzi I, Pierantoni C, Mandolesi A, Loupakis F, Zaniboni A . Nuclear factor-kB tumor expression predicts response and survival in irinotecan-refractory metastatic colorectal cancer treated with cetuximab-irinotecan therapy. J Clin Oncol. 2007; 25(25):3930-5. DOI: 10.1200/JCO.2007.11.5022. View

Kundu S, Lee C, Billips B, Habermacher G, Zhang Q, Liu V . The toll-like receptor pathway: a novel mechanism of infection-induced carcinogenesis of prostate epithelial cells. Prostate. 2007; 68(2):223-9. DOI: 10.1002/pros.20710. View

Wang J, Manning B, Wu Q, Blankson S, Bouchier-Hayes D, Redmond H . Endotoxin/lipopolysaccharide activates NF-kappa B and enhances tumor cell adhesion and invasion through a beta 1 integrin-dependent mechanism. J Immunol. 2003; 170(2):795-804. DOI: 10.4049/jimmunol.170.2.795. View

Schwartz A, Malgor R, Dickerson E, Weeraratna A, Slominski A, Wortsman J . Phenylmethimazole decreases Toll-like receptor 3 and noncanonical Wnt5a expression in pancreatic cancer and melanoma together with tumor cell growth and migration. Clin Cancer Res. 2009; 15(12):4114-22. PMC: 2765042. DOI: 10.1158/1078-0432.CCR-09-0005. View

Rakoff-Nahoum S, Medzhitov R . Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science. 2007; 317(5834):124-7. DOI: 10.1126/science.1140488. View

Wolpin B, Mayer R . Systemic treatment of colorectal cancer. Gastroenterology. 2008; 134(5):1296-310. PMC: 2528832. DOI: 10.1053/j.gastro.2008.02.098. View

Cario E, Podolsky D . Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun. 2000; 68(12):7010-7. PMC: 97811. DOI: 10.1128/IAI.68.12.7010-7017.2000. View

Fukata M, Abreu M . Role of Toll-like receptors in gastrointestinal malignancies. Oncogene. 2008; 27(2):234-43. PMC: 2821878. DOI: 10.1038/sj.onc.1210908. View

10.

Sun Q, Liu Q, Zheng Y, Cao X . Rapamycin suppresses TLR4-triggered IL-6 and PGE(2) production of colon cancer cells by inhibiting TLR4 expression and NF-kappaB activation. Mol Immunol. 2008; 45(10):2929-36. DOI: 10.1016/j.molimm.2008.01.025. View

11.

Wolpin B, Meyerhardt J, Mamon H, Mayer R . Adjuvant treatment of colorectal cancer. CA Cancer J Clin. 2007; 57(3):168-85. DOI: 10.3322/canjclin.57.3.168. View

12.

Ogino S, Kirkner G, Nosho K, Irahara N, Kure S, Shima K . Cyclooxygenase-2 expression is an independent predictor of poor prognosis in colon cancer. Clin Cancer Res. 2008; 14(24):8221-7. PMC: 2679582. DOI: 10.1158/1078-0432.CCR-08-1841. View

13.

Furrie E, Macfarlane S, Thomson G, Macfarlane G . Toll-like receptors-2, -3 and -4 expression patterns on human colon and their regulation by mucosal-associated bacteria. Immunology. 2005; 115(4):565-74. PMC: 1782176. DOI: 10.1111/j.1365-2567.2005.02200.x. View

14.

Huang B, Zhao J, Li H, He K, Chen Y, Chen S . Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res. 2005; 65(12):5009-14. DOI: 10.1158/0008-5472.CAN-05-0784. View

15.

Balkwill F, Coussens L . Cancer: an inflammatory link. Nature. 2004; 431(7007):405-6. DOI: 10.1038/431405a. View

16.

Kawamoto T, Ii M, Kitazaki T, Iizawa Y, Kimura H . TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain. Eur J Pharmacol. 2008; 584(1):40-8. DOI: 10.1016/j.ejphar.2008.01.026. View

17.

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun M . Cancer statistics, 2009. CA Cancer J Clin. 2009; 59(4):225-49. DOI: 10.3322/caac.20006. View

18.

Chang Y, Wu M, Lin J, Sheu B, Muta T, Inoue H . Induction of cyclooxygenase-2 overexpression in human gastric epithelial cells by Helicobacter pylori involves TLR2/TLR9 and c-Src-dependent nuclear factor-kappaB activation. Mol Pharmacol. 2004; 66(6):1465-77. DOI: 10.1124/mol.104.005199. View

19.

Tsukuma H, Ajiki W, Oshima A . [Cancer incidence in Japan]. Gan To Kagaku Ryoho. 2004; 31(6):840-6. View

20.

Lee S, Lim K . UDN glycoprotein regulates activities of manganese-superoxide dismutase, activator protein-1, and nuclear factor-kappaB stimulated by reactive oxygen radicals in lipopolysaccharide-stimulated HCT-116 cells. Cancer Lett. 2007; 254(2):274-87. DOI: 10.1016/j.canlet.2007.03.009. View