Oncotarget

Research Papers:

Dual tumor suppressing and promoting function of Notch1 signaling in human prostate cancer

Karine Lefort, Paola Ostano, Maurizia Mello-Grand, Valérie Calpini, Maria Scatolini, Antonella Farsetti, Gian Paolo Dotto and Giovanna Chiorino _

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Oncotarget. 2016; 7:48011-48026. https://doi.org/10.18632/oncotarget.10333

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Abstract

Karine Lefort1, Paola Ostano2, Maurizia Mello-Grand2, Valérie Calpini1, Maria Scatolini3, Antonella Farsetti4,5, Gian Paolo Dotto1,6, Giovanna Chiorino2

1Department of Biochemistry, University of Lausanne, Lausanne, Switzerland

2Laboratory of Cancer Genomics, Fondazione “Edo ed Elvo Tempia Valenta”, Biella, Italy

3Laboratory of Molecular Oncology, Fondazione “Edo ed Elvo Tempia Valenta”, Biella, Italy

4Institute of Cell Biology and Neurobiology, National Research Council, Rome, Italy

5Internal Medicine Clinic III, Goethe University, Frankfurt am Main, Germany

6Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, USA

Correspondence to:

Giovanna Chiorino, email: giovanna.chiorino@fondazionetempia.org

Karine Lefort, email: karine.lefort@unil.ch

Keywords: Notch, prostate cancer

Received: January 15, 2016     Accepted: June 12, 2016     Published: June 30, 2016

ABSTRACT

Adenocarcinomas of the prostate arise as multifocal heterogeneous lesions as the likely result of genetic and epigenetic alterations and deranged cell-cell communication. Notch signaling is an important form of intercellular communication with a role in growth/differentiation control and tumorigenesis. Contrasting reports exist in the literature on the role of this pathway in prostate cancer (PCa) development. We show here that i) compared to normal prostate tissue, Notch1 expression is significantly reduced in a substantial fraction of human PCas while it is unaffected or even increased in others; ii) acute Notch activation both inhibits and induces process networks associated with prostatic neoplasms; iii) down-modulation of Notch1 expression and activity in immortalized normal prostate epithelial cells increases their proliferation potential, while increased Notch1 activity in PCa cells suppresses growth and tumorigenicity through a Smad3-dependent mechanism involving p21WAF1/CIP1; iv) prostate cancer cells resistant to Notch growth inhibitory effects retain Notch1-induced upregulation of pro-oncogenic genes, like EPAS1 and CXCL6, also overexpressed in human PCas with high Notch1 levels. Taken together, these results reconcile conflicting data on the role of Notch1 in prostate cancer.


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