2 research outputs found
Effects of polarization direction on removal characteristics of silver nanowire transparent conductive film by ultrashort pulsed laser
Tumorâderived insulinâlike growth factorâbinding proteinâ1 contributes to resistance of hepatocellular carcinoma to tyrosine kinase inhibitors
Abstract 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 understood. The aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in HCC. Methods We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC patients. We evaluated the prognosis, therapeutic response, and serum insulinâlike growth factorâbinding proteinâ1 (IGFBPâ1) levels of 31 lenvatinibâtreated HCC patients. Based on the array of results, a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were conducted. Additionally, in vivo genetic and pharmacological gainâ and lossâofâfunction experiments were performed. Results In the patient cohort, IGFBPâ1 was identified as the signaling molecule with the highest expression that was inversely associated with overall survival. Mechanistically, antiangiogenic TKI treatment markedly elevated tumor IGFBPâ1 levels via the hypoxiaâhypoxia inducible factor signaling. IGFBPâ1 stimulated angiogenesis through activation of the integrin α5ÎČ1âfocal adhesion kinase pathway. Consequently, loss of IGFBPâ1 and integrin α5ÎČ1 by genetic and pharmacological approaches reâsensitized HCC to lenvatinib treatment. Conclusions Together, our data shed light on mechanisms underlying acquired resistance of HCC to antiangiogenic TKIs. Antiangiogenic TKIs induced an increase of tumor IGFBPâ1, which promoted angiogenesis through activating the IGFBPâ1âintegrin α5ÎČ1 pathway. These data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBPâ1 inhibitors