Background:Antiangiogenic tyrosine kinase inhibitors(TKIs)provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma(HCC).However,patients with HCC often develop resistance toward a...
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Background:Antiangiogenic tyrosine kinase inhibitors(TKIs)provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma(HCC).However,patients with HCC often develop resistance toward antiangiogenic TKIs,and the underlying mechanisms are not *** aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in ***:We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC *** evaluated the prognosis,therapeutic response,and serum insulin-like growth factor-binding protein-1(IGFBP-1)levels of 31 lenvatinib-treated HCC *** on the array of results,a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were ***,in vivo genetic and pharmacological gain-and loss-of-function experiments were ***:In the patient cohort,IGFBP-1 was identified as the signaling molecule with the highest expression that was inversely associated with overall ***,antiangiogenic TKI treatment markedly elevated tumor IGFBP-1 levels via the hypoxia-hypoxia inducible factor ***-1 stimulated angiogenesis through activation of the integrinα5β1-focal adhesion kinase ***,loss of IGFBP-1 and integrinα5β1 by genetic and pharmacological approaches re-sensitized HCC to lenvatinib ***:Together,our data shed light onmechanisms underlying acquired resistance of HCC to antiangiogenic *** TKIs induced an increase of tumor IGFBP-1,which promoted angiogenesis through activating the IGFBP-1-integrinα5β1 *** data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP-1 inhibitors.
AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide(TAA)-induced liver injury, compensatory hepatocyte pr...
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AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide(TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma(HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAAinduced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9(SOX9) and Yes-associated protein(YAP), which regulate the transdifferentiation of hepatocytes to *** Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fibrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-deficient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-deficient *** STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.
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