Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

Breuhahn, Kai

doi:10.3748/wjg.14.1690

Cited by 63 publications

(52 citation statements)

References 109 publications

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“…Receptor dimers engaging IR-A can also bind the mitogen IGF-II with a high affinity. IGF-II is overexpressed in HCC notably as a result of loss of promoter-specific imprinting and reactivation of fetal promoters (14). Consistently, IGF-II Figure 4.…”

Section: Discussionmentioning

confidence: 62%

“…The structural feature of IR-A isoform confers specific functional properties in terms of ligand affinity. Indeed, IR-A is a high-affinity receptor not only for insulin but also for IGF-II, a fetal growth peptide produced by the liver, which is overexpressed in HCC tumors and cell lines (14). IR-A also displays a faster internalization and recycling kinetics and a higher propensity to signal proliferation and survival compared with IR-B (15).…”

Section: Introductionmentioning

confidence: 99%

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Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors

et al. 2013

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Insulin receptor (IR) exists as two isoforms resulting from the alternative splicing of IR pre-mRNA. IR-B promotes the metabolic effects of insulin, whereas IR-A rather signals proliferative effects. IR-B is predominantly expressed in the adult liver. Here, we show that the alternative splicing of IR pre-mRNA is dysregulated in a panel of 85 human hepatocellular carcinoma (HCC) while being normal in adjacent nontumor liver tissue. An IR-B to IR-A switch is frequently observed in HCC tumors regardless of tumor etiology. Using pharmacologic and siRNA approaches, we show that the autocrine or paracrine activation of the EGF receptor (EGFR)/mitogen-activated protein/extracellular signal-regulated kinase pathway increases the IR-A:IR-B ratio in HCC cell lines, but not in normal hepatocytes, by upregulating the expression of the splicing factors CUGBP1, hnRNPH, hnRNPA1, hnRNPA2B1, and SF2/ASF. In HCC tumors, there is a significant correlation between the expression of IR-A and that of splicing factors. Dysregulation of IR pre-mRNA splicing was confirmed in a chemically induced model of HCC in rat but not in regenerating livers after partial hepatectomy. This study identifies a mechanism responsible for the generation of mitogenic IR-A and provides a novel interplay between IR and EGFR pathways in HCC. Increased expression of IR-A during neoplastic transformation of hepatocytes could mediate some of the adverse effects of hyperinsulinemia on HCC. Cancer Res; 73(13); 3974-86. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors

et al. 2013

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“…In contrast, activation of insulin receptors by insulin results primarily in metabolic effects (6,9,10). Increased expression of IGF-II or IR-A occurs during fetal development and in certain types of cancers including breast, colorectal, thyroid, bladder, hepatocellular carcinoma, and osteosarcoma (5,(11)(12)(13)(14)(15)(16)(17)(18). The overexpression of IR-A and IGF-II may be a potential mechanism leading to resistance to IGF-1R-directed therapies (19,20).…”

Section: Introductionmentioning

confidence: 99%

Dual IGF-I/II–Neutralizing Antibody MEDI-573 Potently Inhibits IGF Signaling and Tumor Growth

et al. 2011

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“…According to studies, overexpression of IGF-II and IGF-IR has been implicated in cell proliferation and inhibition of apoptosis [18]. In support of this, low expression of IGF I and progressive increase in the level of expression of IGF-IR, IGF-II, and IGF substrates during the hepatocarcinogenesis process was detected at mRNA and protein level, which was associated with cell increased proliferation and reduced apoptosis has been observed in HCC cell lines and rat models as well as in human HCC samples [18]. Other studies also indicated that the major tumorpromoting effects of IGF ligands on HCC exerted through IGF-1R [19][20][21][22].…”

Section: Igf Pathwaymentioning

confidence: 99%

Potential Molecular Targets and Drugs for Treatment of Hepatocellular Carcinoma

Mekuria¹,

Abdi²

2017

J Cancer Sci Ther

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Hepatocellular Carcinoma (HCC) is a common type of primary liver cancer. According to the recent world cancer report, the disease ranked as the sixth most common cancer worldwide and the third largest cause of cancer-related death. Deregulation of numerous signaling pathways have been implicate in pathogenesis of HCC, including IGF, EGF/TGF, HGF/cMet, WNT, Hedgehog, notch, hippo, VEGF, PDGF, and FGF. Besides, intracellular mediators such as MAPK and PI3K/AKT/mTOR play a role in HCC development and progression. Currently sorafenib is the only molecularly targeted drug available to treat advanced HCC. It only extends survival by a matter of months. Moreover, there is no alternative agent for patients progressing under treatment with sorafenib. Thus, there remains a critical need for both continued molecular characterization and aggressive drug development. This review provided and updated appraisal of the deregulated signaling and epigenetic pathways, targeted therapeutics that is being investigated and possible challenges in drug development for HCC. Nevertheless, c-Met over-expression was reported to be related to increased metastatic potential and poor prognosis in patients with HCC, providing a rationale for its therapeutic inhibition [26]. Pathways related to neo-angiogenesisHigh vascularization is a hallmark of human HCC [8]. This angiogenesis process relies on autocrine and paracrine interactions between tumor cells, vascular endothelial cells, and pericytes. Tumor cells release pro-angiogenic factors in response to hypoxic conditions and nutrient deprivation and thus activate endothelial cells [27]. Activated endothelial cells break down extracellular matrix and basement membrane which result in a release of angiogenic factors which includes VEGF, FGF, PDGF, and TGF β [16]. These angiogenic factors in turn activate endothelial cells through TKR and their intracellular mediator's MAPK and PI3K/Akt/mTOR pathways, which lead to proliferation and migration of endothelial cells to form a new tubular structure and lumen for new vessels and finally, pericytes are activated and recruited to stabilize the new blood vessels [27,28]. has become a potential investigating area of research to identify target(s) to inhibit proliferation of HCC and metastasis. IGF pathwayThe pathway consists of circulating ligands IGF-I, IGF-II, and the receptor IGF-IR. It has been known for its involvement in the regulation of cell growth and energy metabolism [17]. According to studies, overexpression of IGF-II and IGF-IR has been implicated in cell proliferation and inhibition of apoptosis [18]. In support of this, low expression of IGF I and progressive increase in the level of expression of IGF-IR, IGF-II, and IGF substrates during the hepatocarcinogenesis process was detected at mRNA and protein level, which was associated with cell increased proliferation and reduced apoptosis has been observed in HCC cell lines and rat models as well as in human HCC samples [18]. Other studies also indicated that the major tumorpromoting e...

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Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

Cited by 63 publications

References 109 publications

Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors

Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors

Dual IGF-I/II–Neutralizing Antibody MEDI-573 Potently Inhibits IGF Signaling and Tumor Growth

Potential Molecular Targets and Drugs for Treatment of Hepatocellular Carcinoma

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