Insulin-like growth factor I binding in hepatocytes from human liver, human hepatoma, and normal, regenerating, and fetal rat liver.

José, F.; Poulos, John E.; Ittoop, Olivia; Pories, Walter J.; Flickinger, E G; Sinha, Madhur K.

doi:10.1172/jci113451

Cited by 261 publications

(163 citation statements)

References 41 publications

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“…Its is known that normal hepatocytes express few IGF-I receptors, and that growth of normal liver is not affected by circulating IGF-I [11,48,49]. In agreement with this, we have not detected the expression of IGF-I receptors in total liver homogenates of CO, CI nor healthy control rats treated with IGF-I, when analysed by Western blotting (data not shown).…”

Section: Discussionsupporting

confidence: 88%

“…In agreement with this, we have not detected the expression of IGF-I receptors in total liver homogenates of CO, CI nor healthy control rats treated with IGF-I, when analysed by Western blotting (data not shown). However, regenerating rat hepatocytes have been described to possess such receptors [48], thus it is possible that IGF-I could act on the parenchymal cell fraction that proliferates in the injured liver. In addition, IGF-I has been shown to stimulate the production of hepatocyte growth factor, a potent mitogen and hepatoprotective agent, by cultured hepatic stellate cells [50].…”

Section: Discussionmentioning

confidence: 99%

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Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-I

Mirpuri

Garcı́a-Trevijano

Castilla‐Cortázar

et al. 2002

The International Journal of Biochemistry & Cell Biology

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We have previously shown that the administration of low doses of insulin-like growth factor-I (IGF-I) to CCl 4 -cirrhotic rats improves liver function and reduces fibrosis. To better understand the mechanisms behind the hepatoprotective effects of IGF-I, and to identify those genes whose expression is affected in cirrhosis and after IGF-1 treatment, we have performed differential display of mRNA analysis by means of polymerase chain reaction (PCR) in livers from control and CCl 4 -cirrhotic rats treated or not with IGF-I. We have identified 16 genes that were up-or down-regulated in the cirrhotic liver. IGF-I treatment partially normalized the expression of eight of these genes, including serine proteinase inhibitors such as serpin-2 and alpha-1-antichymotripsin, alpha-1-acid glycoprotein, and alpha-2u-globulin. Additionally, we show that IGF-I enhanced the regenerative activity in the cirrhotic liver, as determined by the increased expression of the proliferating cell nuclear antigen (PCNA). Finally, IGF-I treatment partially restored the expression of growth hormone receptor (GHR) and the levels of global genomic DNA methylation, which are reduced in human and experimental cirrhosis. Taken together, our observations confirm the hepatoprotective effects of IGF-I, and suggest that this action can be exerted in part through the normalization of liver gene expression, growth hormone (GH) responsiveness and global genomic DNA methylation.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-I

Mirpuri

Garcı́a-Trevijano

Castilla‐Cortázar

et al. 2002

The International Journal of Biochemistry & Cell Biology

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“…Very few high-affinity binding sites for IGF-I have been demonstrated on adult rat hepatocytes (Caro et al, 1988), consistent with the low IGF-IR expression in preneoplastic hepatic foci and in normal hepatocytes of adjacent liver tissue seen in the Scharf et al present study. Furthermore, short-term and long-term metabolic actions of IGF-I on primary cultures of rat hepatocytes have been attributed to low-affinity IGF-I binding to the IR (Hartmann et al, 1990).…”

Section: Scharf Et Alsupporting

confidence: 90%

Analysis of the IGF Axis in Preneoplastic Hepatic Foci and Hepatocellular Neoplasms Developing after Low-Number Pancreatic Islet Transplantation into the Livers of Streptozotocin Diabetic Rats

Scharf¹,

Ramadori²,

Dombrowski

2000

Laboratory Investigation

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SUMMARY:Preneoplastic hepatic foci have been demonstrated in liver acini, which drain the blood from intraportally transplanted pancreatic islets in streptozotocin-induced diabetic rats with mild persisting diabetes. In long-term studies of this animal model, hepatocellular adenomas and carcinomas (HCC) developed after a sequence of characteristic preneoplastic hepatic foci. In this experimental model, the local hyperinsulinism is thought to have a causative role. Because insulin and the insulin-like growth factor (IGF) axis are closely linked, an altered gene expression of the IGF axis components is likely. Therefore, preneoplastic hepatic foci and HCC were studied for the expression of IGF axis components. Glycogen-storing "early" preneoplastic hepatic foci were detectable several days after pancreatic islet transplantation. Northern blot analysis, in-situ hybridization, and immunohistochemical studies of these "early" lesions demonstrated increased expressions of IGF-I and IGF binding protein-4 (IGFBP-4) in altered parenchymal cells, and a decreased expression of IGFBP-1. IGF-II was not detected in these preneoplastic foci. HCC arising in this model had decreased expressions of IGF-I and IGFBP-4 but IGFBP-1 expression was not significantly altered. Some HCC showed a more than 100-fold overexpression of IGF-II, whereas other tumors were completely negative for IGF-II expression. Low IGF-I receptor expression was detected in preneoplastic foci and adjacent nonaltered liver tissue. However, HCC tissue consistently showed an increased IGF-I receptor expression, rendering these tissues susceptible to the mitogenic effects of IGF. The altered gene expression in glycogen-storing preneoplastic hepatic foci, especially the up-regulation of IGF-I and IGFBP-4 with the down-regulation of IGFBP-1, resemble the insulin-dependent regulation of these components in normal rat hepatocytes. These data agree with previous studies demonstrating a correspondence of the focal character, morphology, and enzyme pattern of preneoplastic hepatic foci with insulin effects on hepatocytes. The development from preneoplastic foci to HCC may be driven by insulin itself and/or an altered IGF axis component or yet unidentified factors. (Lab Invest 2000, 80:1399-1411.

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“…IGF-mediated growth responsiveness is found in most GI cancer cells (15,18,19,22). Aberrant activation of IGF-IR by paracrine and autocrine loops has been reported (22,42), and the expression of IGF-IR/IGF-II may be useful for the prediction of recurrence and poor prognosis in esophageal squamous cell carcinoma (18).…”

Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas

Piao

Wang

Adachi

et al. 2008

Molecular Cancer Therapeutics

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Insulin-like growth factor-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal (GI) cancers. In this study, we sought to evaluate the effect of a new tyrosine kinase inhibitor of IGF-IR, NVP-AEW541, on the signal transduction and the progression of GI carcinomas. We assessed the effect of NVP-AEW541 on signal transduction, proliferation, survival, and migration in four GI cancer cells: colorectal adenocarcinoma HT29, pancreatic adenocarcinoma BxPC3, esophageal squamous cell carcinoma TE1, and hepatoma PLC/PRF/5. The effects of NVP-AEW541 alone and with chemotherapy were studied in vitro and in nude mouse xenografts. We also analyzed the effects of NVP-AEW541 on insulin signals and hybrid receptor formation between IGF-IR and insulin receptor. NVP-AEW541 blocked autophosphorylation of IGF-IR and both Akt and extracellular signal-regulated kinase activation by IGF but not by insulin. NVP-AEW541 suppressed proliferation and tumorigenicity in vitro in a dose-dependent manner in all cell lines. The drug inhibited tumor as a single agent and, when combined with stressors, up-regulated apoptosis in a dose-dependent fashion and inhibited mobility. NVP-AEW541 augmented the effects of chemotherapy on in vitro growth and induction of apoptosis. Moreover, the combination of NVP-AEW541 and chemotherapy was highly effective against tumors in mice. This compound did not influence hybrid receptor formation. Thus, NVP-AEW541 may have significant therapeutic utility in human GI carcinomas both alone and in combination with chemotherapy. [Mol Cancer Ther 2008;7(6):1483 -93]

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Insulin-like growth factor I binding in hepatocytes from human liver, human hepatoma, and normal, regenerating, and fetal rat liver.

Cited by 261 publications

References 41 publications

Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-I

Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-I

Analysis of the IGF Axis in Preneoplastic Hepatic Foci and Hepatocellular Neoplasms Developing after Low-Number Pancreatic Islet Transplantation into the Livers of Streptozotocin Diabetic Rats

Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas

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