High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer.
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.


CONCLUSIONS
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.
Department of Human Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Japan.
E L
EL
Wang
Z R
ZR
Qian
M
M
Nakasono
T
T
Tanahashi
K
K
Yoshimoto
Y
Y
Bando
E
E
Kudo
M
M
Shimada
T
T
Sano
D002288:Adenocarcinoma, Mucinous / Q000378:metabolism* / Q000556:secondary; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000378:metabolism* / Q000556:secondary; D008297:Male; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000378:metabolism* / Q000556:secondary; D011379:Prognosis; D012007:Rectum / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D014408:Biomarkers, Tumor; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4