The IGF axis and hepatocarcinogenesis

Jg, Scharf; Dombrowski, Frank; Ramadori, Giuliano

doi:10.1136/mp.54.3.138

Cited by 161 publications

(164 citation statements)

References 83 publications

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“…Interestingly, recent studies have revealed that the antiapoptotic activity of MK reduces the sensitivity of cells to cytotoxic drugs used clinically and may thus participate in the development of resistance to chemotherapy (Mirkin et al, 2005). This type of autocrine stimulation was extensively studied for EGF and IGF-1 receptor-mediated biological functions (Maheshwari et al, 2001;Scharf and Braulke, 2003;Singh and Harris, 2005) and is now also extended to the ALK receptor.…”

Section: Discussionmentioning

confidence: 99%

Recruitment of insulin receptor substrate-1 and activation of NF-κB essential for midkine growth signaling through anaplastic lymphoma kinase

et al. 2006

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Anaplastic lymphoma kinase (ALK) is a transmembrane receptor tyrosine kinase in the insulin receptor superfamily. We recently demonstrated that the growth factors pleiotrophin (PTN) and midkine (MK) are ligands for ALK and that upon ALK activation, insulin receptor substrate-1 (IRS-1) and other substrates are phosphorylated. Here, the role of IRS-1 in ligand-mediated ALK signaling is investigated in interleukin-3 (IL-3)-dependent 32D murine myeloid cells. These cells do not express ALK and IRS family members, and do not respond to exogenously added PTN or MK. We show that expression of ALK plus IRS-1 renders these cells independent of IL-3 owing to the activation of ALK by endogenous MK. Mutational analysis reveals that this transformed phenotype of 32D cells requires kinase-active ALK as well as the interaction of ALK with IRS-1. Furthermore, 32D/ IRS-1/ALK cells display an enhanced activation of mitogen-activated protein kinase and PI3-kinase pathways, and a selective transcriptional activation of nuclear factor (NF)-jB. Small interfering RNA-mediated knockdown of the endogenous MK or p65/NF-jB revealed that both these are rate limiting for the transformed phenotype induced by ALK plus IRS-1. We conclude that the recruitment of IRS-1 to activated ALK and the activation of NF-jB are essential for the autocrine growth and survival signaling of MK.

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Section: Discussionmentioning

confidence: 99%

Recruitment of insulin receptor substrate-1 and activation of NF-κB essential for midkine growth signaling through anaplastic lymphoma kinase

et al. 2006

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“…The liver is the major source of circulating IGF peptides. In contrast to foetal liver, IGF-2 is downregulated, and IGF-1 is upregulated in the adult organ (Scharf et al, 2001). IGF-2 gene expression is controlled by mechanisms such as parental imprinting resulting in downregulation of one allele.…”

Section: Discussionmentioning

confidence: 99%

Focal overexpression of insulin-like growth factor 2 by hepatocytes and cholangiocytes in viral liver cirrhosis

et al. 2003

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Insulin-like growth factor (IGF)-2 is overexpressed in hepatocellular carcinoma and accompanying dysplastic lesions. IGF-2 signalling is mediated through IGF-1 receptor (IGF-1R), while mannose 6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF-2R) controls pericellular levels of free IGF-2. We studied, by in situ hybridisation and immunohistology, 18 liver specimens with cirrhosis of different aetiology without neoplastic or dysplastic lesions. Immunohistology was also performed for insulin receptor IGF-1R and IGF-binding proteins 3 and 4. High focal levels of IGF-2 RNA were found in some hepatocytes of all livers with HBV-or HCV-induced cirrhosis (n ¼ 10), but in only one of the cirrhoses with nonviral aetiology (n ¼ 8). IGF-2 was overexpressed in biliary duct epithelial cells in one case. Compared with noncirrhotic liver, all cirrhotic specimens showed reduced hepatocellular expression of M6P/IGF-2R protein, which contrasted with enhanced expression in perisinusoidal cells. Immunostaining for the other antigens did not reveal significant differences. Upregulation of IGF-2 in some hepatocytes may lead to high focal IGF-2 levels sufficient to saturate local IGF-2 binding capacities, and may result in an increased susceptibility to cellular dedifferentiation and, ultimately, liver cancer. Downregulation of hepatocellular M6P/IGF-2R and upregulation of IGF-2 seem to be early events in hepatocarcinogenesis prior to the appearance of morphologically distinct dysplastic lesions. Elevated focal IGF-2 transcript levels may therefore indicate an increased risk for hepatocellular and cholangiocellular carcinomas.

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“…51 While the findings from the partial hepatectomy model attribute a growth-promoting role to IGFBP-1, data from experimental and clinical HCC are more consistent with a growthinhbitory effect of IGFBP-1 on liver tumor progression 81,82 which is most likely caused by reducing the bioavailability of IGF-II. The role of IGFBP-1 in those patients in whom IGFBP-1 expression is increased is unknown.…”

Section: Pathways Important For the Regulation Of The G 1 /S Restrictmentioning

confidence: 96%

“…IGFBP proteins are also able to exert IGF independent effects through modulation of integrin signaling pathways and in some instances by transcriptional activation of target genes. 81,83 The potential for IGFBP-1 to directly regulate growth associated genes has not yet been demonstrated.…”

Section: Pathways Important For the Regulation Of The G 1 /S Restrictmentioning

confidence: 99%

Cell cycle regulation and hepatocarcinogenesis

Greenbaum¹

2004

Cancer Biology & Therapy

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The IGF axis and hepatocarcinogenesis

Cited by 161 publications

References 83 publications

Recruitment of insulin receptor substrate-1 and activation of NF-κB essential for midkine growth signaling through anaplastic lymphoma kinase

Recruitment of insulin receptor substrate-1 and activation of NF-κB essential for midkine growth signaling through anaplastic lymphoma kinase

Focal overexpression of insulin-like growth factor 2 by hepatocytes and cholangiocytes in viral liver cirrhosis

Cell cycle regulation and hepatocarcinogenesis

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