Abstract
Insulin-like growth factor (IGF) signaling plays an important autocrine, paracrine and endocrine role in growth promotion involving various tissues and organs. Synthesis of both IGFs (IGF-1 and IGF-2) in normal conditions takes place mainly in the liver even if the proteins can be produced in every cell of the human body. The alterations in the IGF signaling axis in human hepatocarcinogenesis are described, but mechanisms of the interactions between expression of oncogenic hepatitisC virus (HCV) proteins and components of the IGF system in progression of chronic hepatitis C to primary hepatocellular carcinoma (HCC) have been poorly recognised. In advanced stages of liver diseases, lowered serum levels of IGF-1 and IGF-2 have been documented. This was supposed to reflect significant damage to liver parenchyma, a decreased number of growth hormone receptors and a decreased genomic expression of IGF binding proteins (IGF BPs). In HCC, a decreased tissue expression of IGF-1, and an increased expression of IGF-1 receptor (IGF-1R) were noted, compared to the control. Potential mechanisms of augmented IGF-2 expression in HCC were also described and dysregulation of IGF signaling in HCC was concluded to occur predominantly at the level of IGF-2 bioavailability. The review aimed at presentation of involvement of IGF-1, IGF-1R and IGF BPs (mostly IGF BP-3 and IGF BP-6) in HCV-related hepatocarcinogenesis. Manifestation of various mRNA transcripts and IGF-1 proteins and their potential involvement in carcinogenesis are also discussed.
Highlights
Insulin-like growth factor (IGF) signaling plays an important autocrine, paracrine and endocrine role in growth promotion involving various tissues and organs
hepatitis C virus (HCV) proteins were found to be involved in control of cell cycle, through their interaction with such cell cycle control proteins as p53, p21, cyclins, proliferating cell nuclear antigen (PCNA), transcription factors, proto-oncogenes (c-fos, c-jun), growth factors/cytokines, e.g. tumour necrosis factor (TNF)-α, transforming growth factor (TGF)-β and their receptors and proteins of apoptosis [8,9,10,11,12,13]
The results observed in tissue samples suggest that IGF-2 might be responsible for IGF-1 receptor (IGF-1R) activation [83]
Summary
In HCV-related hepatocarcinogenesis, participation of viral proteins: core (C), non-structural 3 (NS3) and NS5 proteins themselves used to be accentuated [1,2,3]. The six exons are alternatively spliced into multiple transcripts, encoding specific circulating and tissue-specific isoforms of the IGF-1 peptide [27,28]. A markedly higher expression of the protein is detected in embryonal life [71], in which it significantly modulates growth and differentiation of muscles [70] It exerts its effect on cells due to binding with, first of all, IGF-1R. IGF-1 exerts a mitogenic effect influencing stimulation of cyclin D1 and of some proto-oncogenes (c-FOS, c-JUN) expression It acts anti-apoptotically and modulates body immune response by control of cytokine production (e.g. IL-3 and IL-14) [68]. IGF-1 controls expression of over 50 genes linked to mitogenesis and cell differentiation It exerts mitogenic activity mainly through stimulation of DNA synthesis and of cyclin D1 expression [68]. In studies on mice IGF-2R was demonstrated to be paternally imprinted, and to be crucial for regulating normal fetal growth, circulating IGF-2, and heart development [82]
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