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Analysis of secretome changes uncovers an autocrine/paracrine component in the ability of c -Myc to modulate cell proliferation and motility


Pocsfalvi, G; Votta, G; De Vincenzo, A; Fiume, I; Raj, D A A; Marra, G; Stoppelli, M P; Iaccarino, I (2011). Analysis of secretome changes uncovers an autocrine/paracrine component in the ability of c -Myc to modulate cell proliferation and motility. Journal of Proteome Research, 10(12):5326-5337.

Abstract

Proteins secreted by cancer cells are a major component of tumor microenvironment. However, little is known on the impact of single oncogenic lesions on the expression of secreted proteins at early stages of tumor development. Because c-Myc over-expression is among the most frequent alterations in cancer, here we investigated the effect of sustained c-Myc expression on the secretome of a non-transformed human epithelial cell line (hT-RPE). By using a quantitative proteomic approach we have identified 125 proteins in conditioned media of hT-RPE/MycER cells upon c-Myc induction. Analysis of the 49 proteins significantly down-regulated by c-Myc, revealed a marked enrichment of factors associated with growth inhibition and cellular senescence. Accordingly, media conditioned by hT-RPE cells expressing c-Myc show an increased ability to sustain hT-RPE cellular proliferation/viability. We also find a marked down-regulation of several structural and regulatory components of the extracellular matrix (ECM), which correlates with an increased chemotactic potency of the conditioned media towards fibroblasts, a major cellular component of tumor stroma. In accordance with these data, the expression of the majority of the genes encoding proteins down-regulated in hT-RPE was significantly reduced also in colorectal adenomatous polyps, early tumors in which c-Myc is invariably over-expressed. These findings help to elucidate the significance of c-Myc over-expression at early stages of tumor development and uncover a remarkable autocrine/paracrine component in the ability of c-Myc to stimulate proliferation, sustain tumor maintenance and modulate cell migration.

Proteins secreted by cancer cells are a major component of tumor microenvironment. However, little is known on the impact of single oncogenic lesions on the expression of secreted proteins at early stages of tumor development. Because c-Myc over-expression is among the most frequent alterations in cancer, here we investigated the effect of sustained c-Myc expression on the secretome of a non-transformed human epithelial cell line (hT-RPE). By using a quantitative proteomic approach we have identified 125 proteins in conditioned media of hT-RPE/MycER cells upon c-Myc induction. Analysis of the 49 proteins significantly down-regulated by c-Myc, revealed a marked enrichment of factors associated with growth inhibition and cellular senescence. Accordingly, media conditioned by hT-RPE cells expressing c-Myc show an increased ability to sustain hT-RPE cellular proliferation/viability. We also find a marked down-regulation of several structural and regulatory components of the extracellular matrix (ECM), which correlates with an increased chemotactic potency of the conditioned media towards fibroblasts, a major cellular component of tumor stroma. In accordance with these data, the expression of the majority of the genes encoding proteins down-regulated in hT-RPE was significantly reduced also in colorectal adenomatous polyps, early tumors in which c-Myc is invariably over-expressed. These findings help to elucidate the significance of c-Myc over-expression at early stages of tumor development and uncover a remarkable autocrine/paracrine component in the ability of c-Myc to stimulate proliferation, sustain tumor maintenance and modulate cell migration.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2011
Deposited On:31 Oct 2011 13:45
Last Modified:05 Apr 2016 15:03
Publisher:American Chemical Society
ISSN:1535-3893
Additional Information:This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Proteome Research, copyright © American Chemical Society after peer review and technical editing by the publisher.
Publisher DOI:https://doi.org/10.1021/pr200584y
PubMed ID:22011035
Permanent URL: https://doi.org/10.5167/uzh-50436

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