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

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.

Clinical implications of APEX1 and Jagged1 as chemoresistance factors in biliary tract cancer

“…Recently, colon cancer progression was reported to be driven by APEX1-mediated upregulation of Jagged1/Notch activity, but there have been no reports on the association between APEX1 and Jagged1 in biliary cancer [11]. Given that biliary cells may belong to the gastrointestinal tract, we performed western blotting to analyze Jagged1 activity in biliary cancer cell lines, and surprisingly, we found that the chemoresistant group (SNU-245, SNU-1079, and SNU-1196) showed strong APEX1 and Jagged1 expression simultaneously, but the chemosensitive group (SNU-308 and SNU-478) showed only APEX1 expression (Fig.…”

“…This therapeutic option was developed by understanding the genetic profile and pathogenesis of specific cancers such as non-small cell lung cancer, colon cancer, and breast cancer. However, targeted therapy for biliary cancer has seen little progress, and no well-known markers for biliary cancer have been identified to date [101112]. Therefore, our study aimed at investigating molecular factors (APEX1) for chemoresistance (especially cisplatin) in biliary cancer cells at first.…”

Selective regulation of Notch ligands during angiogenesis is mediated by vimentin

“…The view that vimentin potentiates Jagged function is corroborated by the data showing that Jagged expression correlates with vimentin expression in several tissues and in cancer, in particular. Elevated expression of both vimentin and Jagged has been implicated in tumor progression (6,8,10,16,(73)(74)(75)(76). Furthermore, observations in vimentin knockout mice links vimentin to defects in wound healing, fibrosis, inflammation, epidermal aging, and epithelial mesenchymal transition in cancer (4,7,8).…”

miR-146a Exerts Differential Effects on Melanoma Growth and Metastatization

“…LFNG is a O-fucose-b1,3-N-acetylglucosaminyltransferase able to glycosylate epidermal growth factor (EGF)-like repeats on the extracellular domain of NOTCH, thereby enhancing DELTA-mediated and inhibiting JAGGED-mediated NOTCH activation (33,34). JAGGED1-dependent NOTCH activation is crucial for colon and prostate cancer cells proliferation and migration (35,36). Zhang and colleagues demonstrated that loss of LFNG alters NOTCH signaling in the prostate, leading to intraepithelial neoplasia (37) and Xu and colleagues described that the mammary-specific deletion of Lfng induces basal-like breast cancer facilitating JAG-GED/NOTCH signaling (38).…”