Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma(HCC).A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed.In this study,we aimed to dissec...Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma(HCC).A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed.In this study,we aimed to dissect the underlying mechanism of lenvatinib resistance(LR)and provide effective treatment strategies.We established an HCC model of acquired LR.Cell counting,migration,self-renewal ability,chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells.Molecular and biochemical strategies such as RNA-sequencing,immunoprecipitation,mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms.Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance.We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α(HIF-1α)pathway activation is responsible for acquired LR in HCC.Phosphorylated non-muscle myosin heavy chain 9(MYH9)at Ser1943,p-MYH9(Ser1943),could recruit ubiquitin-specific protease 22(USP22)to deubiquitinate and stabilize HIF-1αin lenvatinib-resistant HCC.Clinically,p-MYH9(Ser1943)expression was upregulated in HCC samples,which predicted poor prognosis and LR.A casein kinase-2(CK2)inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro.Therefore,the p-MYH9(Ser1943)/USP22/HIF-1αaxis is critical for LR and cancer stemness.For the diagnosis and treatment of LR in HCC,p-MYH9(Ser1943),USP22,and HIF-1αmight be valuable as novel biomarkers and targets.展开更多
Dyslipidemia exhibits a high incidence after liver transplantation,in which tacrolimus,a widely used immunosuppressant,plays a fundamental role.MicroRNAs and related circRNAs represent a class of noncoding RNAs that h...Dyslipidemia exhibits a high incidence after liver transplantation,in which tacrolimus,a widely used immunosuppressant,plays a fundamental role.MicroRNAs and related circRNAs represent a class of noncoding RNAs that have been recognized as important regulators of genes associated with lipid metabolism.However,their transcriptional activities and functional mechanisms in tacrolimus-related dyslipidemia remain unclear.In this study,we observed that tacrolimus could induce triglyceride accumulation in hepatocytes by stimulating sterol response element-binding proteins(SREBPs)and miR-33a.Our in silico and experimental analyses identified miR-33a as a direct target of circFASN.Tacrolimus could downregulate circFASN and result in elevated miR-33a in vivo and in vitro.Overexpression of circFASN or silencing of miR-33a decreased the promoting effects of tacrolimus on triglyceride accumulation.Clinically,the incidence of dyslipidemia in liver transplant recipients with elevated serum miR-33a after liver transplantation was higher than that in patients without elevated serum miR-33a(46.3%vs.18.8%p=0.012,n=73).Our results showed that the circFASN/miR-33a regulatory system plays a distinct role in tacrolimus-induced disruption of lipid homeostasis.MiR-33a is likely a risk factor for tacrolimus-related dyslipidemia,providing a potential therapeutic target to combat tacrolimus-induced dyslipidemia after liver transplantation.展开更多
基金National Key Research and Development Program of China(2022YFA1106800),National Natural Science Foundation of China(82203070,82200726,82200727,92159202 and 82273270)Project of Medical and Health Technology Program in Zhejiang Province(2024KY853).
文摘Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma(HCC).A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed.In this study,we aimed to dissect the underlying mechanism of lenvatinib resistance(LR)and provide effective treatment strategies.We established an HCC model of acquired LR.Cell counting,migration,self-renewal ability,chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells.Molecular and biochemical strategies such as RNA-sequencing,immunoprecipitation,mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms.Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance.We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α(HIF-1α)pathway activation is responsible for acquired LR in HCC.Phosphorylated non-muscle myosin heavy chain 9(MYH9)at Ser1943,p-MYH9(Ser1943),could recruit ubiquitin-specific protease 22(USP22)to deubiquitinate and stabilize HIF-1αin lenvatinib-resistant HCC.Clinically,p-MYH9(Ser1943)expression was upregulated in HCC samples,which predicted poor prognosis and LR.A casein kinase-2(CK2)inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro.Therefore,the p-MYH9(Ser1943)/USP22/HIF-1αaxis is critical for LR and cancer stemness.For the diagnosis and treatment of LR in HCC,p-MYH9(Ser1943),USP22,and HIF-1αmight be valuable as novel biomarkers and targets.
基金supported by the National Natural Science Foundation of China(General Program)[Grant number:81570589]the National Natural Science Funds for Distinguished Young Scholars of China[Grant number:81625003]+1 种基金the National Natural Science Foundation of China(Key Program)[Grant number:81930016]the Cheung Kong Scholars Program of China and National Science and Technology Major Project[Grant number:2017ZX100203205].
文摘Dyslipidemia exhibits a high incidence after liver transplantation,in which tacrolimus,a widely used immunosuppressant,plays a fundamental role.MicroRNAs and related circRNAs represent a class of noncoding RNAs that have been recognized as important regulators of genes associated with lipid metabolism.However,their transcriptional activities and functional mechanisms in tacrolimus-related dyslipidemia remain unclear.In this study,we observed that tacrolimus could induce triglyceride accumulation in hepatocytes by stimulating sterol response element-binding proteins(SREBPs)and miR-33a.Our in silico and experimental analyses identified miR-33a as a direct target of circFASN.Tacrolimus could downregulate circFASN and result in elevated miR-33a in vivo and in vitro.Overexpression of circFASN or silencing of miR-33a decreased the promoting effects of tacrolimus on triglyceride accumulation.Clinically,the incidence of dyslipidemia in liver transplant recipients with elevated serum miR-33a after liver transplantation was higher than that in patients without elevated serum miR-33a(46.3%vs.18.8%p=0.012,n=73).Our results showed that the circFASN/miR-33a regulatory system plays a distinct role in tacrolimus-induced disruption of lipid homeostasis.MiR-33a is likely a risk factor for tacrolimus-related dyslipidemia,providing a potential therapeutic target to combat tacrolimus-induced dyslipidemia after liver transplantation.
