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Recent Research Progress
JAG2 is one of the NOTCH ligands. It was found to be over-expressed in malignant plasma cells and myeloma cell lines derived from multiple myeloma patients. It has been shown that high JAG2 expression associates with aggressive anaplastic tumors and highly metastatic stages of medulloblastoma. The NOTCH pathway is an evolutionarily conserved signaling system involved in regulation of cell fate during embryonic development. In mammalian cells, NOTCH signaling consists of four receptors (NOTCH1-NOTCH4), three delta-like ligands (DLL1, DLL3, and DLL4), and two serrate-like ligands (JAG1 and JAG2). NOTCH is activated by a direct contact between cells expressing NOTCH ligands and receptors. Aberrant activation of NOTCH signaling is frequently observed in many human cancers including CRC (colorectal cancer cells). Besides, NOTCH signaling increases chemoresistance by protecting tumor cells from apoptosis.
JAG2 over-expression was first identified in malignant plasma cells from patients with multiple myeloma. Up-regulation of JAG2 expression was also observed in various cancers, including breast, pancreatic, bladder, and lung cancers, and was associated with the progression of these tumors. Some reports showed that JAG2 expression is increased in human colorectal carcinoma compared to that in the surrounding normal tissues, suggesting that dysregulation of JAG2 expression plays a role in CRC cell growth and progression to metastatic disease.
It has been shown that JAG2 expression is regulated by the aberrant Wnt/β-catenin signaling. In fact, JAG2 functions as a downstream mediator of Wnt/β-catenin signaling and targeting of JAG2 could generate growth arresting effects in CRC cells. It has been found that silencing of JAG2 suppresses the growth of CRC xenografts, while its over-expression increases tumor growth. Moreover, it has been shown that silencing of JAG2 interferes with DOX-induced cell cycle arrest through suppression of p21 expression, leading to increased apoptosis.
JAG2 expression was increased in human CRC cell lines
The average expression of JAG2 mRNA in tumor tissues was about 7 fold higher as compared to normal epithelium while the mRNA expression of other NOTCH ligands was not significantly different between tumor and normal epithelium. JAG2-induced increase in reporter activity was suppressed by DAPT, a γ-secretase inhibitor, suggesting that the expression of JAG2 may contribute to the activation of NOTCH signaling in intestinal tumors.
β-catenin signaling is involved in regulation of JAG2 expression
One report has shown that β-catenin signaling is involved in regulation of JAG2 expression. Knockdown of β-catenin significantly reduced JAG2 expression in specific CRC cell lines. In vivo, it has been analyzed JAG2 mRNA expression in the small intestine of adenomatous polyposis coli (Apc) CKO mice, which have floxed Apc alleles. JAG2 mRNA expression was significantly up-regulated upon deletion of Apc alleles.
Modulation of JAG2 affects tumorigenicity of CRC cells
Knockdown of JAG2 expression increased cytotoxic response to doxorubicin (DOX). However, knockdown of JAG1 did not affect the cytotoxic response to DOX. Knockdown of JAG2 decreased the rate of tumor growth. At harvest, the average volume of tumors from JAG2-knockdown cells was significantly reduced than those of tumors from control cells. Ectopic expression of JAG2 resulted in a significant increase in tumor size, suggesting that JAG2 enhances tumorigenicity of MC38 cells. All these evidences suggest that JAG2 plays an important role in tumorigenesis and development.