High expression of the Notch ligand Jagged‐1 is associated with poor prognosis after surgery for colorectal cancer

Abstract

The importance of Notch signaling in colorectal cancer (CRC) carcinogenesis and progression has previously been presented. Increased expression of Jagged‐1 (JAG1), a Notch ligand, in CRC has been revealed, but the detailed prognostic significance of JAG1 in CRC has not been determined. Protein expression of JAG1 was examined using immunohistochemistry in 158 CRC specimens. Expression of JAG1 and E‐cadherin and their associations with clinicopathologic characteristics, overall survival (OS) and relapse‐free survival (RFS) were evaluated. In vitro studies using compounds to regulate intracellular signaling and small interfering RNA to silence JAG1 were performed in a colon cancer cell line. JAG1 expression in cancerous tissues was weak, moderate or strong in 32%, 36% and 32% of specimens, respectively, and correlated with histologic type and T stage. In multivariate analysis, JAG1 expression, histologic type and lymphatic invasion independently correlated with OS and RFS. The combination of high JAG1 expression and low E‐cadherin expression had an additive effect toward poorer OS and RFS compared with the low JAG1/high E‐cadherin expression subtype. A significant correlation between JAG1 expression and KRAS status was detected in groups stratified as high E‐cadherin expression. In vitro studies suggested that RAS‐MEK‐MAP kinase and the Wnt pathways positively regulated JAG1 expression. Gene silencing with siJAG1 indicated that JAG1 promotes the transition from epithelial to mesenchymal characteristics and cell growth. High expression of JAG1 is regulated by various pathways and is associated with poor prognosis through promoting the epithelial to mesenchymal transition and cell proliferation or maintaining cell survival in CRC.

Solasodine inhibits human colorectal cancer cells through suppression of the AKT/glycogen synthase kinase‐3β/β‐catenin pathway

“…(44) E-cadherin is a transmembrane molecule that mediates adhesion between adjacent cells, whose degree of expression has an inverse association with invasive capability in CRC. (45) Our results of wound-healing and Transwell assays showed that solasodine significantly reduces CRC cell migration and invasion.…”

“…Matrix metalloproteases are a family of enzymes that can destroy the activity of the ECM; among them, MMP‐2, MMP‐9, and MMP‐14 are crucial elements that give rise to CRC progression . E‐cadherin is a transmembrane molecule that mediates adhesion between adjacent cells, whose degree of expression has an inverse association with invasive capability in CRC . Our results of wound‐healing and Transwell assays showed that solasodine significantly reduces CRC cell migration and invasion.…”

Apelin13/APJ promotes proliferation of colon carcinoma by activating Notch3 signaling pathway

“…To date, four Notch receptors (Notch 1–4) and five Notch ligands (Delta-like 1 [DLL1], DLL3, DLL4, Jagged-1 (JAG1) and JAG2) have been reported [ 8 ]. JAG1, like the other ligands, interacts with Notch receptors to activate the cleavage of Notch receptors by c-secretase leading to the release of Notch intracellular domain (NICD) [ 8 , 9 ]. Subsequently, NICD forms a complex with a transcriptional regulator in the nucleus to induce transcription of target genes, such as HES gene family.…”

Association of Notch and Hedgehog Pathway Activation With Prognosis in Early-stage Colorectal Cancer

“…The role of Jagged-1 in CRC still remains elusive. Overexpression has been correlated with bad prognosis, especially when combined with high levels of Notch2, and with increased probability for relapse and lymph node metastasis (44). Furthermore, Jagged-1 expression intensity has been correlated with higher grade, higher TNM stage, depth of infiltration and lymph node metastasis (45), something that was not replicated in our analysis, where more patients were included and Jagged-1 expression was statistically significantly associated with a lower grade at diagnosis.…”