Abstract
The insulin-like growth factors (IGF) have a key role in the development of gynecological cancers, including endometrial tumors. Uterine serous carcinoma (USC) constitutes a defined histological category among endometrial cancers. Laron syndrome (LS) is a genetic type of dwarfism that results from mutation of the growth hormone receptor (GHR) gene, and is the best characterized entity under the spectrum of the congenital IGF1 deficiencies. Epidemiological studies have shown that LS patients are protected from cancer development. Recent genome-wide association studies conducted on LS-derived lymphoblastoid cells led to the identification of a series of metabolic genes whose over-representation in this condition might be linked to cancer protection. Our analyses led to the identification of ZYG11A, a potential cell cycle regulator, as a new downstream target for IGF1 action. The aim of the present paper was to investigate the regulation of ZYG11A gene expression by IGF1 and insulin in endometrial cancer cell lines and to assess the impact of tumor suppressor p53 on ZYG11A expression and biological action. Using USC-derived cell lines expressing a wild type or a mutant p53 gene, we demonstrate that IGF1 inhibited ZYG11A mRNA and protein levels in cells containing a wild type p53. On the other hand, IGF1 potently stimulated ZYG11A expression in mutant p53-expressing cells. Data presented here links the IGF1 and p53 signaling pathways with ZYG11A action. The clinical implications of the present study in endometrial and other types of cancer must be further investigated.
Highlights
The insulin-like growth factors (IGF) constitute a complex network of ligands, cell-surface receptors and binding proteins that, in a highly orchestrated manner, regulate growth and metabolism of multiple organs and tissues throughout life [1, 2]
Whereas high circulating IGF1 has been typically correlated with an enhanced risk of developing cancer, independent epidemiological surveys conducted on two cohorts of Laron syndrome (LS) and other congenital IGF1 deficient patients generated evidence that low endocrine IGF1 concentrations may, be associated with a diminished cancer incidence [20, 21]
Conducted genome-wide association studies identified a series of genes and signaling pathways that are either underor over-represented in LS patients and that might be associated with cancer protection in this pathology [22]
Summary
The insulin-like growth factors (IGF) constitute a complex network of ligands, cell-surface receptors and binding proteins that, in a highly orchestrated manner, regulate growth and metabolism of multiple organs and tissues throughout life [1, 2]. Most experimental and clinical evidence is consistent with the notion that INSR activation (mainly by insulin) is primarily involved in metabolic types of action whereas IGF1R activation www.oncotarget.com (mainly by IGF1 or IGF2) mediates predominantly growth and differentiative activities [5,6,7]. Epidemiological studies conducted over the past two decades provide firm evidence that high circulating IGF1 levels correlate with an increased cancer risk [8, 9]. This paradigm is true in a number of adult epithelial tumors typically associated with the endocrine system, including breast and prostate cancers [10, 11]. A putative correlation between low IGF1 dosages and cancer risk has not yet been investigated in a systematic fashion
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