The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets

Abstract

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. Different signalling pathways have been identified to be implicated in the pathogenesis of HCC; among these, GH, IGF and somatostatin (SST) pathways have emerged as some of the major pathways implicated in the development of HCC. Physiologically, GH-IGF-SST system plays a crucial role in liver growth and development since GH induces IGF1 and IGF2 secretion and the expression of their receptors, involved in hepatocytes cell proliferation, differentiation and metabolism. On the other hand, somatostatin receptors (SSTRs) are exclusively present on the biliary tract. Importantly, the GH-IGF-SST system components have been indicated as regulators of hepatocarcinogenesis. Reduction of GH binding affinity to GH receptor, decreased serum IGF1 and increased serum IGF2 production, overexpression of IGF1 receptor, loss of function of IGF2 receptor and appearance of SSTRs are frequently observed in human HCC. In particular, recently, many studies have evaluated the correlation between increased levels of IGF1 receptors and liver diseases and the oncogenic role of IGF2 and its involvement in angiogenesis, migration and, consequently, in tumour progression. SST directly or indirectly influences tumour growth and development through the inhibition of cell proliferation and secretion and induction of apoptosis, even though SST role in hepatocarcinogenesis is still opened to argument.This review addresses the present evidences suggesting a role of the GH-IGF-SST system in the development and progression of HCC, and describes the therapeutic perspectives, based on the targeting of GH-IGF-SST system, which have been hypothesised and experimented in HCC.

Potassium diformate influences gene expression of GH/IGF-I axis and glucose homeostasis in weaning piglets

“…primarily in the liver, liver IGF-I knockout mice had 70% reduced plasma IGF-I (Sjögren et al, 2001) (Britt-Marie Iresjö1 2013. It is reported that, hepatic IGF-I acted directly on the hepatocytes in a GH-independent manner, regulated hepatocytes cell proliferation, differentiation and metabolism (Takahashi., 2012;Pivonello et al, 2014). Present observation agree with this, KDF treatment did not change the level of HDL, LDL, TC, TG and BG, but it dramatically increased the mRNA expressions of PCK, G6PC, and FBPase in liver, which are the key regulatory enzymes for hepatic gluconeogenesis (Ghafoory et al, 2013).…”

β-ionone modulates the expression of miRNAs and genes involved in the metastatic phenotype of microdissected persistent preneoplastic lesions in rats submitted to hepatocarcinogenesis

“…Thus, treatment with βI promoted an increase in the expression of miR‐34a relative to the CO group, which shows that βI is also capable of modulating this tumor suppressor miRNA in the promotion phase of hepatocarcinogenesis. Igf2 , the target of miR‐34a, frequently shows increased expression in HCC cells and plays an important role in the process of metastasis . In this study, we observed lower expression levels of this gene in pPNLs from animals treated with βI relative to the CO group.…”

“…The target gene Igf2 , which shows increased expression in HCC cells and plays an important role in the dissemination of neoplastic cells, was also analyzed . In this study, no differences were found in the expression of this gene in the surrounding tissues between the βI and CO groups ( P > 0.05; Figure A).…”

Type 1 IGF Receptor Localization in Paediatric Gliomas: Significant Association with WHO Grading and Clinical Outcome

“…En este caso, el hígado sintetiza la mayoría del IGF-1 circulante en respuesta al estímulo de la hormona de crecimiento (GH), principal mediador del crecimiento postnatal. La GH es producida por la hipófisis anterior y su secreción de manera pulsátil está en parte controlada por dos neuropéptidos hipotalámicos, la hormona liberadora de la hormona de crecimiento (GHRH) y la somatostatina (SS) (5). La GHRH actúa estimulando la síntesis y secreción de GH, mientras que la SS la inhibe.…”