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. 2010 Jun 21;16(23):2881-8.
doi: 10.3748/wjg.v16.i23.2881.

Expression and significance of TLR4 and HIF-1alpha in pancreatic ductal adenocarcinoma

Jian-Jun Zhang  1 , He-Shui Wu, Lin Wang, Yuan Tian, Jing-Hui Zhang, Hai-Long Wu
Affiliations

Expression and significance of TLR4 and HIF-1alpha in pancreatic ductal adenocarcinoma

Jian-Jun Zhang et al. World J Gastroenterol. .

Abstract

Aim: 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.

Conclusion: 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.

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Figures

Figure 1
Figure 1
Toll-like receptor (TLR) 4 and hypoxia-inducible transcription factor-1α (HIF-1α) mRNA in pancreatic carcinoma and adjacent tissues. aP < 0.05 vs adjacent tissues. A: TLR4 mRNA in 30 cases of pancreatic carcinoma and adjacent tissues was determined by real-time polymerase chain reaction (PCR); B: HIF-1α mRNA in 30 cases of pancreatic carcinoma and adjacent tissues was determined by real-time PCR.
Figure 2
Figure 2
Expression of TLR4 and HIF-1α protein in pancreatic carcinoma tissue. Brown color displays the positive expression. A: Expression of TLR4 protein in carcinoma tissue (SP, × 100); B: Expression of TLR4 protein in carcinoma tissue (SP, × 400); C: Expression of HIF-1α protein in carcinoma tissue (SP, × 100); D: Expression of HIF-1α protein in carcinoma tissue (SP, × 400); E: Expression of NF-κB p65 protein in carcinoma tissue (SP, × 100); F: Expression of NF-κB p65 protein in carcinoma tissue (SP, × 400).
Figure 3
Figure 3
Correlation between TLR4 mRNA and HIF-1α mRNA.
Figure 4
Figure 4
Kaplan-Meier analysis overall survival depending on TLR4 and HIF-1α expression in pancreatic ductal adenocarcinoma. A: The mean survival of patients with negative TLR4 expression in tumor tissues was significantly longer than those with TLR4 positive expression (P = 0.011); B: The mean survival of patients with negative HIF-1α expression in tumor tissues was significantly longer than those with HIF-1α positive expression (P = 0.005); C: Survival of patients with both negative TLR4 and HIF-1α expression was significantly longer than those with both positive TLR4 and HIF-1α expression (P = 0.014).
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