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Colon cancer progression is driven by APEX1-mediated upregulation of Jagged
Mi-Hwa Kim, … , In-Youb Chang, Ho Jin You
Mi-Hwa Kim, … , In-Youb Chang, Ho Jin You
Published July 1, 2013
Citation Information: J Clin Invest. 2013;123(8):3211-3230. https://doi.org/10.1172/JCI65521.
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Research Article Oncology Article has an altmetric score of 7

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

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Abstract

Aberrant expression of apurinic-apyrimidinic endonuclease–1 (APEX1) has been reported in numerous human solid tumors and is positively correlated with cancer progression; however, the role of APEX1 in tumor progression is poorly defined. Here, we show that APEX1 contributes to aggressive colon cancer behavior and functions as an upstream activator in the Jagged1/Notch signaling pathway. APEX1 overexpression or knockdown in human colon cancer cell lines induced profound changes in malignant properties such as cell proliferation, anchorage-independent growth, migration, invasion, and angiogenesis in vitro and in tumor formation and metastasis in mouse xenograft models. These oncogenic effects of APEX1 were mediated by the upregulation of Jagged1, a major Notch ligand. Furthermore, APEX1 expression was associated with Jagged1 in various colon cancer cell lines and in tissues from colon cancer patients. This finding identifies APEX1 as a positive regulator of Jagged1/Notch activity and suggests that it is a potential therapeutic target in colon cancers that exhibit high levels of Jagged1/Notch signaling.

Authors

Mi-Hwa Kim, Hong-Beum Kim, Sang Pil Yoon, Sung-Chul Lim, Man Jin Cha, Young Jin Jeon, Sang Gon Park, In-Youb Chang, Ho Jin You

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Figure 10

APEX1 upregulates Jagged1 expression by increasing EGR1 activity.

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APEX1 upregulates Jagged1 expression by increasing EGR1 activity.
(A) Co...
(A) Control and APEX1-overexpressing GM00637 cells were transfected with the indicated plasmids and harvested for a Jagged1 reporter assay. (B) Top: Jagged1 promoter constructs used for reporter assay. Middle: Reporter assay in GM00637 cells transfected with the indicated Jagged1 promoter fragments fused to pGL3 basic vector. Bottom: Western blot analysis of V5-APEX1 expression in GM00637 cells transfected with the indicated vectors. (C) Reporter assay in GM00637 cells with Jagged1 promoter constructs (pC) with mutations in different EGR1 regions (mE1, mE2, mE3). (D) EMSA analysis of 3 putative EGR1 consensus sites (E1, E2, E3) of the Jagged1 promoter in the indicated GM00637 cells. Unlabeled oligonucleotides were used as competitors. For supershift assays, anti-EGR1 antibody was added to the reaction mixtures prior to separating the DNA-protein complex. (E) ChIP assay for Jagged1 promoter (E2 site) in control and GM00637-APEX1 cells. (F–I) JAG1 mRNA (F and H) and Jagged1 protein (G and I) levels in GM00637-APEX1 and SW480-APEX1 cells (F and G) or in DLD1 cells (H and I) transfected with control or EGR1 siRNA. Results in A–C, F, and H are mean ± SD (n = 3). **P < 0.01.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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