Analysis of secretome changes uncovers an autocrine/paracrine component in the modulation of cell proliferation and motility by c-Myc.
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 overexpression is among the most frequent alterations in cancer, here we investigated the effect of sustained c-Myc expression on the secretome of a nontransformed 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 toward 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 overexpressed. These findings help to elucidate the significance of c-Myc overexpression 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.
Institute of Protein Biochemistry-CNR, Via P. Castellino 111, 80131 Naples, Italy.
Gabriella
G
Pocsfalvi
Giuseppina
G
Votta
Anna
A
De Vincenzo
Immacolata
I
Fiume
Delfin Albert Amal
DA
Raj
Giancarlo
G
Marra
Maria Patrizia
MP
Stoppelli
Ingram
I
Iaccarino
D000818:Animals; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D016922:Cellular Senescence; D002633:Chemotaxis; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D019295:Computational Biology; D017077:Culture Media, Conditioned / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007553:Isotope Labeling; D051379:Mice; D019899:Paracrine Communication; D040901:Proteomics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D041701:Swiss 3T3 Cells; D015533:Transcriptional Activation
D017077:Culture Media, Conditioned; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc