title: The decrease of mineralcorticoid receptor drives angiogenic pathways in colorectal cancer.
abstract: Angiogenesis plays a crucial role in tumor growth and progression. Low expression of mineralocorticoid receptor (MR) in several malignant tumors correlates with disease recurrence and overall survival. Previous studies have shown that MR expression is decreased in colorectal cancer (CRC). Here we hypothesize that decreased MR expression can contribute to angiogenesis and poor patient survival in colorectal malignancies. In a cohort of CRC patients, we analyzed tumor MR expression, its correlation with tumor microvascular density and its impact on survival. Subsequently, we interrogated the role of MR in angiogenesis in an in vitro model, based on the colon cancer cell line HCT116, ingenierized to re-express a physiologically controlled MR. In CRC, decreased MR expression was associated with increased microvascular density and poor patient survival. In pchMR transfected HCT116, aldosterone or natural serum steroids largely inhibited mRNA expression levels of both VEGFA and its receptor 2/KDR. In CRC, MR activation may significantly decrease angiogenesis by directly inhibiting dysregulated VEGFA and hypoxia-induced VEGFA mRNA expression. In addition, MR activation attenuates the expression of the VEGF receptor 2/KDR, possibly dampening the activation of a VEGFA/KDR dependent signaling pathway important for the survival of tumor cells under hypoxic conditions.
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy. tiberio@med.unibs.it
authors.forename: Laura
authors.initials: L
authors.lastname: Tiberio
authors.forename: Riccardo
authors.initials: R
authors.lastname: Nascimbeni
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Villanacci
authors.forename: Claudio
authors.initials: C
authors.lastname: Casella
authors.forename: Anna
authors.initials: A
authors.lastname: Fra
authors.forename: Valeria
authors.initials: V
authors.lastname: Vezzoli
authors.forename: Lucia
authors.initials: L
authors.lastname: Furlan
authors.forename: Giuliano
authors.initials: G
authors.lastname: Meyer
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parrinello
authors.forename: Maurizio D
authors.initials: MD
authors.lastname: Baroni
authors.forename: Bruno
authors.initials: B
authors.lastname: Salerni
authors.forename: Luisa
authors.initials: L
authors.lastname: Schiaffonati
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000450:Aldosterone / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D009389:Neovascularization, Pathologic; D011379:Prognosis; D018161:Receptors, Mineralocorticoid / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D018161:Receptors, Mineralocorticoid; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000450:Aldosterone; D040301:Vascular Endothelial Growth Factor Receptor-2
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