title: Notch pathway promotes ovarian cancer growth and migration via CXCR4/SDF1α chemokine system.
abstract: Ovarian cancer is the most deadly gynecological malignancy. Understanding the molecular pathogenesis of ovarian cancer is critical to provide new targeted therapeutic strategies. Recent evidence supports a role for Notch in ovarian cancer progression and associates its dysregulation to poor overall survival. Similarly, CXCR4/SDF1α signalling correlates with ovarian cancer progression and metastasis. Recent findings indicate that Notch promotes CXCR4/SDF1α signalling and its effect on cell growth and migration; nonetheless, up to now, the association between Notch and CXCR4/SDFα in ovarian cancer has not been reported. Thereby, the aim of this study was to investigate if Notch and CXCR4/SDF1α cooperate in determining ovarian cancer growth, survival and migration. To address this issue, Notch signalling was inhibited by using γ-secretase inhibitors, or upregulated by forcing of Notch1 expression in ovarian cancer cell lines. Our results indicated that Notch activity influenced tumour cell growth and survival and positively regulated CXCR4 and SDF1α expression. CXCR4/SDF1α signalling mediated the effect of Notch pathway on ovarian cancer cell growth and SDF1α-driven migration. Additionally, for the first time, we demonstrated that Notch signalling activation can be detected in ovarian cancer specimens by immunohistochemistry analysis of the Notch transcriptional target, HES6 and is positively correlated with high expression levels of CXCR4 and SDF1α. Our results demonstrate that Notch affects ovarian cancer cell biology through the modulation of CXCR4/SDF1α signalling and suggest that Notch inhibition may be a rationale therapeutic approach to hamper ovarian cancer progression mediated by the CXCR4/SDF1α axis.
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, via A. Di Rudinì 8, I-20142, Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Chiaramonte
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, via A. Di Rudinì 8, I-20142, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Colombo
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, via A. Di Rudinì 8, I-20142, Milan, Italy; Unit of Pathology, Department of Health Sciences, Università degli Studi di Milano, A.O. San Paolo, via A. Di Rudinì 8, I-20142, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Bulfamante
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, via A. Di Rudinì 8, I-20142, Milan, Italy; Unit of Pathology, Department of Health Sciences, Università degli Studi di Milano, A.O. San Paolo, via A. Di Rudinì 8, I-20142, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Falleni
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, via A. Di Rudinì 8, I-20142, Milan, Italy; Unit of Pathology, Department of Health Sciences, Università degli Studi di Milano, A.O. San Paolo, via A. Di Rudinì 8, I-20142, Milan, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Tosi
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, via A. Di Rudinì 8, I-20142, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Garavelli
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, via A. Di Rudinì 8, I-20142, Milan, Italy.
authors.forename: D
authors.initials: D
authors.lastname: De Simone
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, via A. Di Rudinì 8, I-20142, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Vigolo
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.
authors.forename: K
authors.initials: K
authors.lastname: Todoerti
authors.affiliation: Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Hematology, Fondazione Cà Granda IRCCS Policlinico, via F. Sforza,35, 20122, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Neri
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, via A. Di Rudinì 8, I-20142, Milan, Italy. Electronic address: natalia.platonova@unimi.it.
authors.forename: N
authors.initials: N
authors.lastname: Platonova
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D054377:Chemokine CXCL12; D004151:Dipeptides; D051881:Receptor, Notch1; D019718:Receptors, CXCR4; D012097:Repressor Proteins; C527276:CXCR4 protein, human; C411859:HES6 protein, human; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497761:NOTCH1 protein, human
keywords: CXCR4; Cell growth; Migration; Notch pathway; Ovarian cancer; SDF1α