Jagged1 Expression Regulated by Notch3 and Wnt/β-catenin Signaling Pathways in Ovarian Cancer

Xu Chen,Michael M Wang,Ie-Ming Shih,Tian-Li Wang,Soo Jung Lee,Alexander Stoeck

doi:10.18632/oncotarget.127

Xu Chen, Michael M Wang + Show 4 more

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https://doi.org/10.18632/oncotarget.127

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Abstract

Ovarian serous carcinoma is a highly aggressive neoplastic disease in women. Our previous studies have demonstrated Notch3 gene amplification and upregulation in many ovarian serous carcinomas and Notch pathway activity contributed to drug resistance. Among different Notch3 ligands, Jagged1 is most dominant in ovarian cancer, and Notch3 pathway activity correlated with Jagged1 expression level in ovarian carcinoma tissues. In this study, we found that Jagged1 expression depended on Notch3 pathway activation. Knockdown of either Notch3 or RBPjk, a Notch-interacting transcription factor critical in Notch signaling, suppressed Jagged1 expression in ovarian cancer cells. Moreover, Jagged1 expression was upregulated in human ovarian surface epithelial cells after ectopic expression of Notch3 intracellular domain and was upregulated in mouse epithelial cells isolated from Notch3-inducible mice after induction. We also found that inhibition of Wnt/β-catenin signaling reduced Jagged1 expression, and co-administration of shRNAs targeting both Notch3 and β-catenin reduced Jagged1 expression much more than targeting either individual gene. Taken together, our data suggested a positive regulatory loop between Notch3 and its ligand, Jagged1, in ovarian cancer cells. In addition, Wnt/β-catenin pathway activation also up-regulated Jagged1. Both mechanisms may sustain Notch3 signaling in ovarian cancer cells and contribute to the pathogenesis of ovarian carcinoma.

Highlights

Signaling pathways that are fundamental to development and tissue differentiation are usually found to participate in the pathogenesis of human cancer [1]
To demonstrate whether Notch3 signaling is essential for Jagged1 expression, we compared Jagged1 mRNA and protein levels between ovarian cancer cells transfected with Notch3 specific shRNAs and control shRNA
Different ovarian cancer cell lines were tested, and OVCAR3 and OVMANA ovarian cancer cell lines were used because both cell lines expressed abundant endogenous Notch3 and Jagged1

Summary

Introduction

Signaling pathways that are fundamental to development and tissue differentiation are usually found to participate in the pathogenesis of human cancer [1]. Hedgehog, Wnt, Notch, and TGF-β pathways were found to play critical roles in both processes. These pathways involve ligandreceptor interactions which initiate signal transduction that results in modulation of a set of downstream genes that mediate the ultimate functions of a specific pathway. Aberrant activation of these signaling pathways may confer an advantage to tumor cells for growth in the host environment. The role of an aberrant Notch signaling pathway in human cancer is well illustrated in T-cell acute lymphocytic leukemia (T-ALL). Activating point mutations occur in more than 50% of T-ALL cases, and interstitial deletions of the extracellular portion of human Notch occur in another 10% due to chromosomal translocation [2, 3]

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