Expression and significance of TLR4 and HIF-1alpha in pancreatic ductal adenocarcinoma.
OBJECTIVE
To investigate the expression of toll-like receptor (TLR) 4, nuclear factor-kappaB (NF-kappaB) p65 and hypoxia-inducible transcription factor 1alpha (HIF-1alpha) in pancreatic ductal adenocarcinoma and their clinical significance.


METHODS
The mRNA of TLR4 and HIF-1alpha were investigated by real-time polymerase chain reaction in 30 cases of pancreatic ductal adenocarcinoma and its adjacent tissues, and expression of TLR4, NF-kappaB p65 and HIF-1alpha protein were detected by immunohistochemistry in 65 cases of pancreatic ductal adenocarcinoma tissues and 38 cases of corresponding adjacent tissues. The relationship between TLR4 or HIF-1alpha and pathologic features, as well as the association between TLR4 and HIF-1alpha, were also analyzed. Kaplan-Meier method was used to assess the impact of expression of TLR4 and HIF-1alpha on survival of patients with pancreatic cancer.


RESULTS
The relative quantification of TLR4 and HIF-1alpha mRNA in tumor tissues was 0.81 +/- 0.10 and 0.87 +/- 0.11, respectively, significantly higher than that in adjacent tissues (0.81 +/- 0.10 vs 0.70 +/- 0.16, P = 0.002; 0.87 +/- 0.11 vs 0.68 +/- 0.13, P = 0.000). The protein expression of TLR4, NF-kappaB p65 and HIF-1alpha in tumor tissues was 69.20%, 66.15% and 70.80%, respectively, being significantly higher than that in adjacent normal tissues (69.20% vs 39.50%, P = 0.003; 66.15% vs 31.58%, P = 0.001; 70.80% vs 36.80%, P = 0.001). There was no significant correlation between TLR4 or HIF-1alpha expression and the age, gender, tumor location, the degree of tumor differentiation in the patients (P > 0.05). However, there was significant correlation between the expression of TLR4 or HIF-1alpha and tumor size, lymph node metastasis, venous invasion and clinical staging (P < 0.05). The expression of TLR4 and HIF-1alpha had a significant impact on survival of patients with pancreatic adenocarcinoma.


CONCLUSIONS
TLR4, NF-kappaB p65 and HIF-1alpha are overexpressed in pancreatic adenocarcinoma, TLR4 may be partly involved in up-regulating HIF-1alpha, and both synergestically promote development of pancreatic adenocarcinoma.
Zhang
Jian-Jun
JJ
Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.
Wu
He-Shui
HS
Wang
Lin
L
Tian
Yuan
Y
Zhang
Jing-Hui
JH
Wu
Hai-Long
HL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C498143:RELA protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA