Different patterns of NF-κB and Notch1 signaling contribute to tumor-induced lymphangiogenesis of esophageal squamous cell carcinoma

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.

Expression of ALDH1 in breast invasive ductal carcinoma: an independent predictor of early tumor relapse

“…Both immunohistochemistry and real-time PCR experiments demonstrated a strong association of ALDH1 with the reversed NOTCH1 expression in breast cancer. Although several studies showed that NOTCH family member levels were elevated in various breast tumor samples and cell lines and upregulation of specific NOTCH proteins would lead to increased tumor cell proliferation and invasion [33-35], our findings demonstrated that moderate or high expression of NOTCH1 was parallel to the absence or little expression of ALDH1 expression and this inconsistency seemed NOTCH signaling pathway may played a negative role on ALDH1-positive breast cancer cells, which was similarly with the finding that NOTCH signaling might serve as a tumor suppressor in some solid tumors [21,22]. Thus, clinical benefits by regulation of NOTCH potentially in targeting ALDH1-positive breast cancer cells may be a complex question worth researching.…”

“…Previously, up regulation of NOTCH ligands led to elevation of the mammosphere number, and conversely, down regulation abrogated mammosphere formation, providing evidence that the NOTCH signal pathway contributes to mammary gland development [18]. On the other hand, although overexpression of NOTCH ligands in a transgenic mouse model triggered breast cancer, supporting the theory that NOTCH contributes to cancer development [19,20], the finding that NOTCH signaling is diminished in some solid tumors would seem to suggest that NOTCH might serve as a tumor suppressor [21,22]. However, no evidence of an association of the NOTCH signaling pathway with proliferation or suppression of the ALDH1-expressing cellular subcomponent displaying early tumor relapse characteristics has been obtained to date.…”

Expression of Notch-1 and its clinical significance in different histological subtypes of human lung adenocarcinoma

“…Recently, Notch-1 was widely studied and reported to aberrantly express in malignant tumors [15-19]. It was considered as a highly controversial gene because of its complex biological functions.…”

Baicalein induces apoptosis in esophageal squamous cell carcinoma cells through modulation of the PI3K/Akt pathway

“…One particular function of NF-κB is to promote cell survival through the induction of target genes, whose products inhibit components of the apoptotic machinery in normal and cancerous cells (33). It has been demonstrated that NF-κB plays a key role in progression, apoptosis and lymph node metastasis in ESCC (34–36). As a downstream component of the PI3K/Akt pathway (37), NF-κB primarily resides in the cytosol in an inactive form; a heterodimer composed of p50 and p65 through an interaction with the inhibitory protein IκB (38).…”