Abstract
BackgroundLymph node involvement and tumor-induced lymphangiogenesis appear as the earliest features of esophageal squamous cell carcinoma (ESCC), although the molecular regulatory mechanisms involved have remained unclear. Our aim was to investigate the contribution of NF-κB and Notch1 signaling to lymph node involvement and tumor-induced lymphangiogenesis in ESCC.Material and methodsNF-κB and Notch1 expression in 60 tissue samples of ESCC were assessed by immunohistochemical staining. The correlations of NF-κB and Notch1 with lymph node involvement, lymphatic vessel density (LVD), podoplanin, and vascular endothelial growth factor-C (VEGF-C) were further evaluated to determine the association of NF-κB and Notch1 expression with tumor-induced lymphangiogenesis.ResultsChi-square tests revealed that NF-κB and Notch1 expression in ESCC tissues were significant associated with lymph node metastasis, LVD, podoplanin, and VEGF-C expression. Strong expression of NF-κB, but weak expression of Notch1, was observed in tumor tissues with lymph nodes involvement (P < 0.05 for both). The mean histoscores of LVD, podoplanin, and VEGF-C staining were higher in high-NF-κB-expressing tissue than in low-expressing tissue (P < 0.05 for each). In contrast, the mean histoscores of LVD and VEGF-C staining were lower in high-Notch1-expressing tissue than in low-expressing tissue (P < 0.05 for both). A multiple factors analysis of LVD and VEGF-C further demonstrated that LVD and VEGF-C status were significantly correlated with NF-κB and Notch1 expression in tumors. NF-κB and Notch1 expression were also significantly inversely correlated (P < 0.05).ConclusionThese results suggest that different patterns of NF-κB and Notch1 signaling contribute to lymph nodes metastasis and tumor-induced lymphangiogenesis of ESCC, and reveal that up-regulation of NF-κB is associated with down-regulation of Notch1 in tumor tissue.
Highlights
Lymph node involvement and tumor-induced lymphangiogenesis appear as the earliest features of esophageal squamous cell carcinoma (ESCC), the molecular regulatory mechanisms involved have remained unclear
Chi-square tests revealed that nuclear factor-B (NF-B) and Notch1 expression in ESCC tissues were significant associated with lymph node metastasis, lymphatic vessel density (LVD), podoplanin, and vascular endothelial growth factor-C (VEGF-C) expression
A multiple factors analysis of LVD and vascular endothelial growth factor (VEGF)-C further demonstrated that LVD and VEGF-C status were significantly correlated with NF-B and Notch1 expression in tumors
Summary
Lymph node involvement and tumor-induced lymphangiogenesis appear as the earliest features of esophageal squamous cell carcinoma (ESCC), the molecular regulatory mechanisms involved have remained unclear. Members of the Notch family of cell surface receptors and their ligands warrant attention based on their role in vasculogenesis and their potential to act as oncogenes in the pathogenesis of certain carcinomas These highly conserved proteins regulate “decisions” involved in cell-fate determination, including those involved in mammalian vascular development [15]. Notch signaling anomalies are found in melanoma, non-small cell lung cancer, cervical cancer and neuroblastoma, consistent with the presumed oncogenic role of Notch signaling during tumorigenesis, the finding that Notch signaling is diminished in epithelial squamous cell carcinoma of the skin would seem to suggest that Notch might serve as a tumor suppressor These apparently contradictory functions of Notch signaling strongly indicate that the outcome of Notch activation is dependent on malignant cellular context [17]
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