Hepatocellular carcinoma(HCC) is the third leading cause of cancer-related deaths worldwide. Only 30%-40% of the patients with HCC are eligible for curative treatments, which include surgical resection as the first op...Hepatocellular carcinoma(HCC) is the third leading cause of cancer-related deaths worldwide. Only 30%-40% of the patients with HCC are eligible for curative treatments, which include surgical resection as the first option, liver transplantation and percutaneous ablation. Unfortunately, there is a high frequency of tumor recurrence after surgical resection and most HCC seem resistant to conventional chemotherapy and radiotherapy. Sorafenib, a multi-tyrosine kinase inhibitor, is the only chemotherapeutic option for patients with advanced hepatocellular carcinoma. Patients treated with Sorafenib have a significant increase in overall survival of about three months. Therefore, there is an urgent need to develop alternative treatments. Due to its role in cell growth and development, the insulin-like growth factor system is commonly deregulated in many cancers. Indeed, the insulin-like growth factor(IGF) axis has recently emerged as a potential target for hepatocellular carcinoma treatment. To this aim, several inhibitors of the pathway have been developed suchas monoclonal antibodies, small molecules, antisense oligonucleotides or small interfering RNAs. However recent studies suggest that, unlike most tumors, HCC development requires increased signaling through insulin growth factor Ⅱ rather than insulin growth factor Ⅰ. This may have great implications in the future treatment of HCC. This review summarizes the role of the IGF axis in liver carcinogenesis and the current status of the strategies designed to target the IGF-Ⅰ signaling pathway for hepatocellular carcinoma treatment.展开更多
IM To determine whether antisense insulinlike growth factorI(IGFI) gene can modulate CEA and AFP expression in human hepatoma cells (HepG2).METHODS Transfection of HepG2 cells was accomplished using Lipofectin reage...IM To determine whether antisense insulinlike growth factorI(IGFI) gene can modulate CEA and AFP expression in human hepatoma cells (HepG2).METHODS Transfection of HepG2 cells was accomplished using Lipofectin reagent. Northern blot analysis confirmed the antisense IGFI RNA of the transfected cells. CEA and AFP levels were measured using radioimmunoassay.RESULTS Human hepatoma cell lines (HepG2) were transfected with antisense IGFI gene. Northern blot analysis confirmed that antisense IGFI RNA was expressed in the transfected cells. The effect of antisense IGFI gene on CEA and AFP expression was demonstrated by the fact that the CEA and AFP levels in the supernatant of transfected cell culture were significantly lower as compared with the parent cells, 〔CEA 70μg/L±076μg/L and 329μg/L±180μg/L (P<005) and AFP 5363μg/L±602μg/L and 90μg/L±526μg/L (P<001), respectively〕.CONCLUSION The malignant potentiality of the transfected cells was partially suppressed. Antisense IGFI gene can modulate the expression of CEA and AFP in human hepatoma cell lines (HepG2).展开更多
AIM： To examine the underlying mechanisms of erlotinib-induced growth inhibition in hepatocellular carcinoma （HCC）. METHODS： Erlotinib-induced alterations in gene expression were evaluated using cDNA array technol...AIM： To examine the underlying mechanisms of erlotinib-induced growth inhibition in hepatocellular carcinoma （HCC）. METHODS： Erlotinib-induced alterations in gene expression were evaluated using cDNA array technology; changes in protein expression and/or protein activation due to erlotinib treatment as well as IGF-1-induced EGFR transactivation were investigated using Western blotting. RESULTS： Erlotinib treatment inhibited the mitogen activated protein （MAP）-kinase pathway and signal transducer of activation and transcription （STAT）- mediated signaling which led to an altered expression of apoptosis and cell cycle regulating genes as demonstrated by cDNA array technology. Overexpression of proapoptotic factors like caspases and gadds associated with a down-regulation of antiapoptotic factors like Bcl-2, Bcl-XL or jun D accounted for erlotinib＇s potency to induce apoptosis. Downregulation of cell cycle regulators promoting the G1/S-transition and overexpression of cyclin-dependent kinase inhibitors and gadds contributed to the induction of a G1/G0-arrest in response to erlotinib. Furthermore, we displayed the transactivation of EGFR-mediated signaling by the IGF-1-receptor and showed erlotinib＇s inhibitory effects on the receptor-receptor cross talk. CONCLUSION： Our study sheds light on the understanding of the mechanisms of action of EGFR-TK- inhibition in HCC-cells and thus might facilitate the design of combination therapies that act additively or synergistically. Moreover, our data on the pathways responding to erlotinib treatment could be helpful in predicting the responsiveness of tumors to EGFR-TKIs in the future.展开更多
Cerebral ageing is a complex biological process associated with progressing cerebrovascular disease and neuronal death. It does not always, however, associate with a functional decline, as the ageing mammalian brain r...Cerebral ageing is a complex biological process associated with progressing cerebrovascular disease and neuronal death. It does not always, however, associate with a functional decline, as the ageing mammalian brain retains considerable functional plasticity which supports successful cerebral ageing where age-related cognitive decline is modest. On the contrary, pathological cerebral ageing results in memory impairment and cognitive deterioration, with Alzheimer's disease(AD) being a florid example. Trophic/growth factors promote brain plasticity; among them are peptides which belong tothe insulin family. Preclinical research suggests that the evolutionarily conserved brain insulin/insulin-like growth factor-1(IGF-1) signalling system controls lifespan and protects against some features of AD such as neurodegeneration-related accumulation of toxic proteins and cognitive deficiencies, as observed in animal models. Insulin and IGF-1 activate cell signalling mechanisms which play protective and regenerative roles; abnormalities in the insulin/IGF-1 system may trigger a cascade of neurodegeneration in AD. AD patients show cerebral resistance to insulin which associates with IGF-I resistance and dysregulation of insulin/IGF-1 receptors as well as cognitive deterioration. This review is focused on the roles of the insulin/IGF-1 signalling system in cerebral ageing and its potential involvement in neurodegeneration in the human brain as seen against the background of preclinical evidence.展开更多
基金Supported by Ministerio de Ciencia e Innovacion BIO2009/09295 and SAF2012-40003FEDER funding,funds from the"UTE project CIMA"+1 种基金the project RNAREG(CSD2009-00080)from The Ministry of Science and Innovation under the programme CONSOLIDER INGENIO 2010
文摘Hepatocellular carcinoma(HCC) is the third leading cause of cancer-related deaths worldwide. Only 30%-40% of the patients with HCC are eligible for curative treatments, which include surgical resection as the first option, liver transplantation and percutaneous ablation. Unfortunately, there is a high frequency of tumor recurrence after surgical resection and most HCC seem resistant to conventional chemotherapy and radiotherapy. Sorafenib, a multi-tyrosine kinase inhibitor, is the only chemotherapeutic option for patients with advanced hepatocellular carcinoma. Patients treated with Sorafenib have a significant increase in overall survival of about three months. Therefore, there is an urgent need to develop alternative treatments. Due to its role in cell growth and development, the insulin-like growth factor system is commonly deregulated in many cancers. Indeed, the insulin-like growth factor(IGF) axis has recently emerged as a potential target for hepatocellular carcinoma treatment. To this aim, several inhibitors of the pathway have been developed suchas monoclonal antibodies, small molecules, antisense oligonucleotides or small interfering RNAs. However recent studies suggest that, unlike most tumors, HCC development requires increased signaling through insulin growth factor Ⅱ rather than insulin growth factor Ⅰ. This may have great implications in the future treatment of HCC. This review summarizes the role of the IGF axis in liver carcinogenesis and the current status of the strategies designed to target the IGF-Ⅰ signaling pathway for hepatocellular carcinoma treatment.
文摘IM To determine whether antisense insulinlike growth factorI(IGFI) gene can modulate CEA and AFP expression in human hepatoma cells (HepG2).METHODS Transfection of HepG2 cells was accomplished using Lipofectin reagent. Northern blot analysis confirmed the antisense IGFI RNA of the transfected cells. CEA and AFP levels were measured using radioimmunoassay.RESULTS Human hepatoma cell lines (HepG2) were transfected with antisense IGFI gene. Northern blot analysis confirmed that antisense IGFI RNA was expressed in the transfected cells. The effect of antisense IGFI gene on CEA and AFP expression was demonstrated by the fact that the CEA and AFP levels in the supernatant of transfected cell culture were significantly lower as compared with the parent cells, 〔CEA 70μg/L±076μg/L and 329μg/L±180μg/L (P<005) and AFP 5363μg/L±602μg/L and 90μg/L±526μg/L (P<001), respectively〕.CONCLUSION The malignant potentiality of the transfected cells was partially suppressed. Antisense IGFI gene can modulate the expression of CEA and AFP in human hepatoma cell lines (HepG2).
基金Supported by Deutsche Forschungsgemeinschaft (DFG),Deutsche Krebshilfe and Sonnenfeld-Stiftung Berlin
文摘AIM： To examine the underlying mechanisms of erlotinib-induced growth inhibition in hepatocellular carcinoma （HCC）. METHODS： Erlotinib-induced alterations in gene expression were evaluated using cDNA array technology; changes in protein expression and/or protein activation due to erlotinib treatment as well as IGF-1-induced EGFR transactivation were investigated using Western blotting. RESULTS： Erlotinib treatment inhibited the mitogen activated protein （MAP）-kinase pathway and signal transducer of activation and transcription （STAT）- mediated signaling which led to an altered expression of apoptosis and cell cycle regulating genes as demonstrated by cDNA array technology. Overexpression of proapoptotic factors like caspases and gadds associated with a down-regulation of antiapoptotic factors like Bcl-2, Bcl-XL or jun D accounted for erlotinib＇s potency to induce apoptosis. Downregulation of cell cycle regulators promoting the G1/S-transition and overexpression of cyclin-dependent kinase inhibitors and gadds contributed to the induction of a G1/G0-arrest in response to erlotinib. Furthermore, we displayed the transactivation of EGFR-mediated signaling by the IGF-1-receptor and showed erlotinib＇s inhibitory effects on the receptor-receptor cross talk. CONCLUSION： Our study sheds light on the understanding of the mechanisms of action of EGFR-TK- inhibition in HCC-cells and thus might facilitate the design of combination therapies that act additively or synergistically. Moreover, our data on the pathways responding to erlotinib treatment could be helpful in predicting the responsiveness of tumors to EGFR-TKIs in the future.
文摘Cerebral ageing is a complex biological process associated with progressing cerebrovascular disease and neuronal death. It does not always, however, associate with a functional decline, as the ageing mammalian brain retains considerable functional plasticity which supports successful cerebral ageing where age-related cognitive decline is modest. On the contrary, pathological cerebral ageing results in memory impairment and cognitive deterioration, with Alzheimer's disease(AD) being a florid example. Trophic/growth factors promote brain plasticity; among them are peptides which belong tothe insulin family. Preclinical research suggests that the evolutionarily conserved brain insulin/insulin-like growth factor-1(IGF-1) signalling system controls lifespan and protects against some features of AD such as neurodegeneration-related accumulation of toxic proteins and cognitive deficiencies, as observed in animal models. Insulin and IGF-1 activate cell signalling mechanisms which play protective and regenerative roles; abnormalities in the insulin/IGF-1 system may trigger a cascade of neurodegeneration in AD. AD patients show cerebral resistance to insulin which associates with IGF-I resistance and dysregulation of insulin/IGF-1 receptors as well as cognitive deterioration. This review is focused on the roles of the insulin/IGF-1 signalling system in cerebral ageing and its potential involvement in neurodegeneration in the human brain as seen against the background of preclinical evidence.
