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Colon cancer progression is driven by APEX1- mediated upregulation of Jagged

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摘要 : Aberrant expression of apurinic-apyrimidinic endonuclease–1 (APEX1) has been reported in numeroushuman solid tumors and is positively correlated with cancer progression; however, the role of APEX1 in tumorprogression is poorly defined.
Abstract: Aberrant expression of apurinic-apyrimidinic endonuclease–1 (APEX1) has been reported in numeroushuman solid tumors and is positively correlated with cancer progression; however, the role of APEX1 in tumorprogression is poorly defined. Here, we show that APEX1 contributes to aggressive colon cancer behaviorand functions as an upstream activator in the Jagged1/Notch signaling pathway. APEX1 overexpression orknockdown in human colon cancer cell lines induced profound changes in malignant properties such as cellproliferation, anchorage-independent growth, migration, invasion, and angiogenesis in vitro and in tumorformation and metastasis in mouse xenograft models. These oncogenic effects of APEX1 were mediated by theupregulation of Jagged1, a major Notch ligand. Furthermore, APEX1 expression was associated with Jagged1in various colon cancer cell lines and in tissues from colon cancer patients. This finding identifies APEX1 asa positive regulator of Jagged1/Notch activity and suggests that it is a potential therapeutic target in coloncancers that exhibit high levels of Jagged1/Notch signaling. Colon cancer progression is driven by APEX1- mediated upregulation of Jagged
Colon cancer progression is driven by APEX1- mediated upregulation of Jagged
Figure 10APEX1 upregulates Jagged1 expression by increasing EGR1 activity.(A) Control and APEX1-overexpressing GM00637 Cells were transfectedwith the indicated plasmids and harvested for a Jagged1 reporterassay. (B) Top: Jagged1 promoter constructs used for reporter assay.Middle: Reporter assay in GM00637 cells transfected with the indicatedJagged1 promoter fragments fused to pGL3 basic vector. Bottom: westernblot analysis of V5-APEX1 expression in GM00637 cells transfectedwith the indicated vectors. (C) Reporter assay in GM00637 cells withJagged1 promoter constructs (pC) with mutations in different EGR1regions (mE1, mE2, mE3). (D) EMSA analysis of 3 putative EGR1 consensussites (E1, E2, E3) of the Jagged1 promoter in the indicatedGM00637 cells. Unlabeled oligonucleotides were used as competitors.For supershift assays, anti-EGR1 antibody was added to the reactionmixtures prior to separating the DNA-protein complex. (E) ChIPassay for Jagged1 promoter (E2 site) in control and GM00637-APEX1cells. 原文链接:http://www.ncbi.nlm.nih.gov/pubmed/23863623 作者:广州赛诚生物 点击:
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