Objective:The role of non-alcoholic steatohepatitis(NASH)in hepatitis B virus(HBV)reactivation following liver transplantation for hepatocellular carcinoma(HCC)remains unclear,and the metabolic differences between pat...Objective:The role of non-alcoholic steatohepatitis(NASH)in hepatitis B virus(HBV)reactivation following liver transplantation for hepatocellular carcinoma(HCC)remains unclear,and the metabolic differences between patients with NASH and those with HBV reactivation are also yet to be elucidated.This study is to investigate the impact of NASH on HBV reactivation risk and prognosis following liver transplantation for HCC,and to develop a predictive model and identify therapeutic targets.Methods:This study included 274 patients who underwent liver transplantation for HCC.The HBV reactivation status of patients with NASH was analyzed,and the metabolic characteristics of peripheral blood were examined to compare NASH and non-NASH patients with or without HBV reactivation.Results:The HBV reactivation free survival was better in non-NASH patients(P<0.0001).Furthermore,NASH patients with HBV reactivation had worse recurrence-free survival(RFS)than non-NASH patients with HBV reactivation(P=0.016).In contrast,the RFS of NASH patients without HBV reactivation was comparable to that of non-NASH patients without HBV reactivation(P=0.810).Subsequently,we constructed a model to predict HBV reactivation by incorporating 7 clinical indicators using the Least Absolute Shrinkage and Selection Operator-Cox(LASSO-Cox)approach.The area under the receiver operating characteristic curve(AUROC)values for predictions at 500,1,000,and 1,500 d were 0.759,0.809,and 0.814,respectively.Finally,metabolic pathway analysis identified key pathways involved in HBV reactivation,and glutamine was found to be an independent protective factor against HBV reactivation following liver transplantation for HCC.Conclusions:NASH patients are more prone to HBV reactivation following liver transplantation for HCC and exhibit worse recurrence-free survival.Glutamine may serve as a potential therapeutic target or predictive biomarker for HBV reactivation.展开更多
Objective:Lung metastasis is a common and fatal complication of liver transplantation for hepatocellular carcinoma(HCC).The precise prediction of post-transplant lung metastasis in the early phase is of great value.Me...Objective:Lung metastasis is a common and fatal complication of liver transplantation for hepatocellular carcinoma(HCC).The precise prediction of post-transplant lung metastasis in the early phase is of great value.Methods:The mRNA profiles of primary and paired lung metastatic lesions were analyzed to determine key signaling pathways.We enrolled 241 HCC patients who underwent liver transplantation from three centers.Tissue microarrays were used to evaluate the prognostic capacity of tumor necrosis factor(TNF),tumor necrosis factor receptor 1(TNFR1),and TNFR2,particularly for post-transplant lung metastasis.Results:Comparison of primary and lung metastatic lesions revealed that the TNF-dependent signaling pathway was related to lung metastasis of HCC.The expression of TNF was degraded in comparison to that in para-tumor tissues(P<0.001).The expression of key receptors in the TNF-dependent signaling pathway,TNFR1 and TNFR2,was higher in HCC tissues than in para-tumor tissues(P<0.001).TNF and TNFR1 showed no relationship with patients’outcomes,whereas elevated TNFR2 in tumor tissue was significantly associated with worse overall survival(OS)and increased recurrence risk(5-year OS rate:31.9%vs.62.5%,P<0.001).Notably,elevated TNFR2 levels were also associated with an increased risk of post-transplant lung metastasis(hazard ratio:1.146;P<0.001).Cox regression analysis revealed that TNFR2,Hangzhou criteria,age,and hepatitis B surface antigen were independent risk factors for post-transplant lung metastasis,and a novel nomogram was established accordingly.The nomogram achieved excellent prognostic efficiency(area under time-dependent receiver operating characteristic=0.755,concordance-index=0.779)and was superior to conventional models,such as the Milan criteria.Conclusions:TNFR2 is a potent prognostic biomarker for predicting post-transplant lung metastasis in patients with HCC.A nomogram incorporating TNFR2 deserves to be a helpful prognostic tool in liver transplantation for HCC.展开更多
Objective:Patient-derived xenograft(PDX)models provide a promising preclinical platform for hepatocellular carcinoma(HCC).However,the molecular features associated with successful engraftment of PDX models have not be...Objective:Patient-derived xenograft(PDX)models provide a promising preclinical platform for hepatocellular carcinoma(HCC).However,the molecular features associated with successful engraftment of PDX models have not been revealed.Methods:HCC tumor samples from 76 patients were implanted in immunodeficient mice.The molecular expression was evaluated by immunohistochemistry.Patient and tumor characteristics as well as tumor molecular expressions were compared for PDX engraftment using the Chi-square test.The independent prediction parameters were identified by logistic regression analyses.Results:The engraftment rate for PDX models from patients with HCC was 39.47%(30/76).Tumors from younger patients and patients with elevated preoperative alpha-fetoprotein level had higher engraftment rates.Tumors with poor differentiation and vascular invasion were related to engraftment success.The positive expression of CK19,CD133,glypican-3(GPC3),and Ki67 in tumor samples was associated with engraftment success.Logistic regression analyses indicated that GPC3 and Ki67 were two of the strongest predictors of PDX engraftment.Tumors with GPC3/Ki67 phenotypes showed heterogeneous engraftment rates,with 71.9%in GPC3^(+)/Ki67^(+)tumors,30.8%in GPC3^(-)/Ki67^(+)tumors,15.0%in GPC3^(+)/Ki67^(-)tumors,and 0 in GPC3^(-)/Ki67^(-)tumors.Conclusions:Successful engraftment of HCC PDXs was significantly related to molecular features.Tumors with the GPC3+/Ki67+phenotype were the most likely to successfully establish HCC PDXs.展开更多
Pulmonary metastasis is a life-threatening complication for patients with hepatocellular carcinoma(HCC)undergoing liver transplantation(LT).In addition to the common mechanisms underlying tumor metastasis,another inev...Pulmonary metastasis is a life-threatening complication for patients with hepatocellular carcinoma(HCC)undergoing liver transplantation(LT).In addition to the common mechanisms underlying tumor metastasis,another inevitable factor is that the application of immunosuppressive agents,including calcineurin inhibitors(CNIs)and rapamycin inhibitors(mTORis),after transplantation could influence tumor recurrence and metastasis.In recent years,several studies have reported that mTORis,unlike CNIs,have the capacity to modulate the tumorigenic landscape post-liver transplantation by targeting metastasis-initiating cells and reshaping the pulmonary microenvironment.Therefore,we focused on the effects of immunosuppressive agents on the lung metastatic microenvironment and how mTORis impact tumor growth in distant organs.This revelation has provided profound insights into transplant oncology,leading to a renewed understanding of the use of immunosuppressants after LT for HCC.展开更多
This study evaluated the accuracy,completeness,and comprehensibility of responses from mainstream large language models(LLMs)to hepatitis C virus(HCV)-related questions,aiming to assess their performance in addressing...This study evaluated the accuracy,completeness,and comprehensibility of responses from mainstream large language models(LLMs)to hepatitis C virus(HCV)-related questions,aiming to assess their performance in addressing patient queries about disease and lifestyle behaviors.The models selected were ChatGPT-4o,Gemini 2.0 Pro,Claude 3.5 Sonnet,and DeepSeek V3,with 12 questions chosen by two HCV experts from the domains of prevention,diagnosis,and treatment.展开更多
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
1 MAIN TEXT Patient-derived xenograft(PDX)models have garnered increasing attention since the last decade.These models are typically characterized by the implantation of fresh patient-derived tumor tissues into immuno...1 MAIN TEXT Patient-derived xenograft(PDX)models have garnered increasing attention since the last decade.These models are typically characterized by the implantation of fresh patient-derived tumor tissues into immunodeficient mice.PDX models are well recognized in academic laboratories,pharmaceutical institutions,and specialized commercial organizations as having the ability to recapitulate genomics,transcriptomics,proteomics,and metabolomics of the parental tumor tissue[1,2].Recently,these models have been successfully used in preclinical studies to identify potential biomarkers for drug response and resistance,and to measure tumor evolution in response to treatment[3,4].Favorable outcomes demonstrated using PDX models could be used as ideal models for preclinical research and clinical translation studies.展开更多
Liver diseases are worldwide problems closely associated with various stresses,such as endoplasmic reticulum stress.The exact interplay between stress and liver diseases remains unclear.Autophagy plays an essential ro...Liver diseases are worldwide problems closely associated with various stresses,such as endoplasmic reticulum stress.The exact interplay between stress and liver diseases remains unclear.Autophagy plays an essential role in maintaining homeostasis,and recent studies indicate tight crosstalk between stress and autophagy in liver diseases.Once the bal-ance between damage and autophagy is broken,autophagy can no longer resist injury or main-tain homeostasis.In recent years,FGF21(fibroblast growth factor 21)-induced autophagy has attracted much attention.FGF21 is regarded as a stress hormone and can be up-regulated by an abundance of signaling pathways in response to stress.Also,increased FGF21 activates autophagy by a complicated signaling network in which mTOR plays a pivotal role.This review summarizes the mechanism of FGF21-mediated autophagy and its derived application in the defense of stress in liver diseases and offers a glimpse into its promising prospect in future clinical practice.展开更多
Background and aims:Inflammatory factors play significant roles in the development and occurrence of hepatocellular carcinoma(HCC).However,the tumor-protective functions of growth differentiation factors(GDFs)in HCC a...Background and aims:Inflammatory factors play significant roles in the development and occurrence of hepatocellular carcinoma(HCC).However,the tumor-protective functions of growth differentiation factors(GDFs)in HCC are yet to be clarified.In this study,we aimed to evaluate the expression levels of 10 GDFs in tumor and paratumor tissues from patients with HCC and perform in vitro and in vivo experiments to elucidate the role of GDF7 in regulating the proliferation and metastasis of HCC.Methods:The gene expression of 10 GDFs was compared between HCC and paratumors using The Cancer Genome Atlas dataset and patient-derived tissues.A tumor microarray containing 108 HCC tissue samples was used to explore the prognostic value of GDF7 expression.Loss-of-function experiments were also performed in vitro and in vivo to investigate the role of GDF7 in HCC.Results:The mRNA and protein levels of GDF7 were significantly lower in HCC tumors than in paratumors(P<0.001).KaplaneMeier analysis showed that decreased GDF7 expression in HCC was associated with worse overall survival(5-year rate:61.8%vs.27.5%,P<0.001)and increased recurrence risk(P<0.001).Multivariate Cox regression analysis demonstrated that low GDF7 expression,the presence of microvascular invasion,and elevated alpha-fetoprotein(AFP)levels were independent risk factors for tumor recurrence and poor survival.Downregulation of GDF7 also increased the tumor growth in HCC cells and in an HCC xenograft model.GDF7 knockdown promoted migration and invasion via epithelial emesenchymal transition.Meanwhile,a negative correlation between JunB proto-oncogene(JUNB)and GDF7 was observed in HCC tissues.Modulating JUNB levels altered GDF7 protein expression.Conclusions:GDF7 is a potential biomarker for predicting superior outcomes in patients with HCC.GDF7 amplification is a potential therapeutic option for HCC.展开更多
Background and aims:Cytokeratin 19-positive(CK19t)hepatocellular carcinoma(HCC)is an aggressive subtype with poor outcomes.The initiation and development of CK19t HCC in the background of liver cirrhosis remains uncle...Background and aims:Cytokeratin 19-positive(CK19t)hepatocellular carcinoma(HCC)is an aggressive subtype with poor outcomes.The initiation and development of CK19t HCC in the background of liver cirrhosis remains unclear.This study investigated the role of the cirrhosis-related gene C-C motif chemokine ligand 16(CCL16)in the development of CK19t HCC.Methods:Datasets from Gene Expression Omnibus(GEO),The Cancer Genome Atlas(TCGA)and International Cancer Genome Consortium(ICGC)were analyzed to screen and validate the genes associated with CK19t HCC.A total of 102 HCC patients were included for tissue microarray analysis.Gain-of-function experiments were conducted to investigate the biological functions of CCL16.CIBERSORT was used to investigate the correlation of CCL16 and immune infiltration.Results:GEO dataset analysis showed that CK19t HCC had lower expression of CCL16.In both TCGA dataset and our HCC cohort,CCL16 expression was negatively correlated with CK19 expression(P<0.05)and its expression was higher in para-tumor than tumor tissues(P<0.001).Moreover,low CCL16 expression was related to advanced stage and poor overall survival(P<0.05).CCL16 overexpression downregulated CK19 expression and impacted the sphere formation ability of HCC cells.Overexpression of CCL16 inhibited the cell proliferation,migration,and invasion of HCC cell lines.Immune analysis showed HCC with high CCL16 expression had more infiltration of mast cells.HCC patients with both low CCL16 expression and low mast cells had the worst prognosis(P<0.001).Conclusion:Our data indicated that CCL16 downregulated the expression of CK19 and inhibited the malignant phenotype of HCC.展开更多
Aim:Pneumonia is the most frequent early postoperative complication in liver transplantation(LT)recipients.Inflammation may provide a favorable environment for tumor implantation,so we aimed to evaluate the impact of ...Aim:Pneumonia is the most frequent early postoperative complication in liver transplantation(LT)recipients.Inflammation may provide a favorable environment for tumor implantation,so we aimed to evaluate the impact of pneumonia on pulmonary metastasis of hepatocellular carcinoma(HCC)and reveal its underlying mechanism.Methods:A training cohort with 234 LT recipients were recorded and analyzed.Using the propensity-score method,we matched covariates between patients with and without pneumonia.A model for predicting pulmonary metastasis was built and validated in an independent validating cohort containing 179 subjects.A mouse model was built to mimic HCC pulmonary metastasis.The potential pathway was revealed by cytokine array analysis and validated in vitro.Results:Pneumonia was an independent risk factor for pulmonary metastasis in liver transplant recipients.It promoted pulmonary metastasis in both the clinical setting and the mouse model.In vitro,LPS-stimulated VEGF secretion from macrophages in the lung significantly reduced cell apoptosis and activated PI3K/AKT/cas-9 signaling.Administration of VEGF receptor2 inhibitor Vatalanib could reduce metastasis and improve prognosis in pneumonia mice.Conclusion:Pneumonia promotes HCC pulmonary metastasis by activating PI3K/AKT/Cas-9 signaling in HCC cells via macrophage-originated VEGF.Vatalanib might be efficient in reducing HCC pulmonary metastasis in liver transplant recipients with pneumonia.展开更多
基金supported by the Major Research Plan of the National Natural Science Foundation of China(No.92159202)the National Key Research and Development Program of China(No.2021YFA1100500)+2 种基金the Key Research&Development Plan of Zhejiang Province(No.2019C03050)National S&T Major Project(No.2017ZX10203205)the Health Science&Technology Plan of Zhejiang Province(No.2022RC060)。
文摘Objective:The role of non-alcoholic steatohepatitis(NASH)in hepatitis B virus(HBV)reactivation following liver transplantation for hepatocellular carcinoma(HCC)remains unclear,and the metabolic differences between patients with NASH and those with HBV reactivation are also yet to be elucidated.This study is to investigate the impact of NASH on HBV reactivation risk and prognosis following liver transplantation for HCC,and to develop a predictive model and identify therapeutic targets.Methods:This study included 274 patients who underwent liver transplantation for HCC.The HBV reactivation status of patients with NASH was analyzed,and the metabolic characteristics of peripheral blood were examined to compare NASH and non-NASH patients with or without HBV reactivation.Results:The HBV reactivation free survival was better in non-NASH patients(P<0.0001).Furthermore,NASH patients with HBV reactivation had worse recurrence-free survival(RFS)than non-NASH patients with HBV reactivation(P=0.016).In contrast,the RFS of NASH patients without HBV reactivation was comparable to that of non-NASH patients without HBV reactivation(P=0.810).Subsequently,we constructed a model to predict HBV reactivation by incorporating 7 clinical indicators using the Least Absolute Shrinkage and Selection Operator-Cox(LASSO-Cox)approach.The area under the receiver operating characteristic curve(AUROC)values for predictions at 500,1,000,and 1,500 d were 0.759,0.809,and 0.814,respectively.Finally,metabolic pathway analysis identified key pathways involved in HBV reactivation,and glutamine was found to be an independent protective factor against HBV reactivation following liver transplantation for HCC.Conclusions:NASH patients are more prone to HBV reactivation following liver transplantation for HCC and exhibit worse recurrence-free survival.Glutamine may serve as a potential therapeutic target or predictive biomarker for HBV reactivation.
基金the National Key Research and Development Program of China(No.2021YFA1100500)the Major Research Plan of the National Natural Science Foundation of China(No.92159202)+2 种基金the Key Research&Development Plan of Zhejiang Province(No.2019C03050),the Key Research&Development Plan of Zhejiang Province(No.2021C03118)National S&T Major Project(No.2017ZX10203205)the Health Science&Technology Plan of Zhejiang Province(No.2022RC060)。
文摘Objective:Lung metastasis is a common and fatal complication of liver transplantation for hepatocellular carcinoma(HCC).The precise prediction of post-transplant lung metastasis in the early phase is of great value.Methods:The mRNA profiles of primary and paired lung metastatic lesions were analyzed to determine key signaling pathways.We enrolled 241 HCC patients who underwent liver transplantation from three centers.Tissue microarrays were used to evaluate the prognostic capacity of tumor necrosis factor(TNF),tumor necrosis factor receptor 1(TNFR1),and TNFR2,particularly for post-transplant lung metastasis.Results:Comparison of primary and lung metastatic lesions revealed that the TNF-dependent signaling pathway was related to lung metastasis of HCC.The expression of TNF was degraded in comparison to that in para-tumor tissues(P<0.001).The expression of key receptors in the TNF-dependent signaling pathway,TNFR1 and TNFR2,was higher in HCC tissues than in para-tumor tissues(P<0.001).TNF and TNFR1 showed no relationship with patients’outcomes,whereas elevated TNFR2 in tumor tissue was significantly associated with worse overall survival(OS)and increased recurrence risk(5-year OS rate:31.9%vs.62.5%,P<0.001).Notably,elevated TNFR2 levels were also associated with an increased risk of post-transplant lung metastasis(hazard ratio:1.146;P<0.001).Cox regression analysis revealed that TNFR2,Hangzhou criteria,age,and hepatitis B surface antigen were independent risk factors for post-transplant lung metastasis,and a novel nomogram was established accordingly.The nomogram achieved excellent prognostic efficiency(area under time-dependent receiver operating characteristic=0.755,concordance-index=0.779)and was superior to conventional models,such as the Milan criteria.Conclusions:TNFR2 is a potent prognostic biomarker for predicting post-transplant lung metastasis in patients with HCC.A nomogram incorporating TNFR2 deserves to be a helpful prognostic tool in liver transplantation for HCC.
基金supported by grants from the National Science and Technology Major Project of China(No.2017ZX10203205)the National Natural Science Funds for Distinguished Young Scholar of China(No.81625003)+1 种基金Key Program National Natural Science Foundation of China(No.81930016)Key Research&Development Plan of Zhejiang Province(No.2019C03050)。
文摘Objective:Patient-derived xenograft(PDX)models provide a promising preclinical platform for hepatocellular carcinoma(HCC).However,the molecular features associated with successful engraftment of PDX models have not been revealed.Methods:HCC tumor samples from 76 patients were implanted in immunodeficient mice.The molecular expression was evaluated by immunohistochemistry.Patient and tumor characteristics as well as tumor molecular expressions were compared for PDX engraftment using the Chi-square test.The independent prediction parameters were identified by logistic regression analyses.Results:The engraftment rate for PDX models from patients with HCC was 39.47%(30/76).Tumors from younger patients and patients with elevated preoperative alpha-fetoprotein level had higher engraftment rates.Tumors with poor differentiation and vascular invasion were related to engraftment success.The positive expression of CK19,CD133,glypican-3(GPC3),and Ki67 in tumor samples was associated with engraftment success.Logistic regression analyses indicated that GPC3 and Ki67 were two of the strongest predictors of PDX engraftment.Tumors with GPC3/Ki67 phenotypes showed heterogeneous engraftment rates,with 71.9%in GPC3^(+)/Ki67^(+)tumors,30.8%in GPC3^(-)/Ki67^(+)tumors,15.0%in GPC3^(+)/Ki67^(-)tumors,and 0 in GPC3^(-)/Ki67^(-)tumors.Conclusions:Successful engraftment of HCC PDXs was significantly related to molecular features.Tumors with the GPC3+/Ki67+phenotype were the most likely to successfully establish HCC PDXs.
基金supported by the Major Research Plan of the National Natural Science Foundation of China(Grant No.92159202)the Key Research&Development Plan of Zhejiang Province(Grant No.2024C03051)+2 种基金the National Key Research and Development Program of China(Grant No.2021YFA1100500)the National Natural Science Foundation of China(Grant No.82303387)Natural Science Foundation of Zhejiang Province(Grant No.LQ23H160048)。
文摘Pulmonary metastasis is a life-threatening complication for patients with hepatocellular carcinoma(HCC)undergoing liver transplantation(LT).In addition to the common mechanisms underlying tumor metastasis,another inevitable factor is that the application of immunosuppressive agents,including calcineurin inhibitors(CNIs)and rapamycin inhibitors(mTORis),after transplantation could influence tumor recurrence and metastasis.In recent years,several studies have reported that mTORis,unlike CNIs,have the capacity to modulate the tumorigenic landscape post-liver transplantation by targeting metastasis-initiating cells and reshaping the pulmonary microenvironment.Therefore,we focused on the effects of immunosuppressive agents on the lung metastatic microenvironment and how mTORis impact tumor growth in distant organs.This revelation has provided profound insights into transplant oncology,leading to a renewed understanding of the use of immunosuppressants after LT for HCC.
基金funded by the National Key Research and Development Program of China(No.2021YFA1100500)the National Natural Science Foundation of China(No.82370662)the Key Research&Development Plan of Zhejiang Province(No.2024C03051).
文摘This study evaluated the accuracy,completeness,and comprehensibility of responses from mainstream large language models(LLMs)to hepatitis C virus(HCV)-related questions,aiming to assess their performance in addressing patient queries about disease and lifestyle behaviors.The models selected were ChatGPT-4o,Gemini 2.0 Pro,Claude 3.5 Sonnet,and DeepSeek V3,with 12 questions chosen by two HCV experts from the domains of prevention,diagnosis,and treatment.
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This work was funded by grants from the National Science and Technology Major Project of China(2017ZX10203205)the National Natural Science Funds for Distinguished Young Scholar of China(81625003)+1 种基金the Key Research&Development Plan of Zhejiang Province(2019C03050)the National Natural Science Foundation of China(81702858).
文摘1 MAIN TEXT Patient-derived xenograft(PDX)models have garnered increasing attention since the last decade.These models are typically characterized by the implantation of fresh patient-derived tumor tissues into immunodeficient mice.PDX models are well recognized in academic laboratories,pharmaceutical institutions,and specialized commercial organizations as having the ability to recapitulate genomics,transcriptomics,proteomics,and metabolomics of the parental tumor tissue[1,2].Recently,these models have been successfully used in preclinical studies to identify potential biomarkers for drug response and resistance,and to measure tumor evolution in response to treatment[3,4].Favorable outcomes demonstrated using PDX models could be used as ideal models for preclinical research and clinical translation studies.
基金supported by the National Key Research and Development Program of China(No.2021YFA1100500)the Major Research Plan of the National Natural Science Foundation of China(No.92159202)+2 种基金the Key Program,National Natural Science Foundation of China(No.81930016)the Young Program of National Natural Science Funds(China)(No.82000617)A Project Supported by Scientific Research Fund of Zhejiang Provincial Education Department(China)(No.Y202250784).
文摘Liver diseases are worldwide problems closely associated with various stresses,such as endoplasmic reticulum stress.The exact interplay between stress and liver diseases remains unclear.Autophagy plays an essential role in maintaining homeostasis,and recent studies indicate tight crosstalk between stress and autophagy in liver diseases.Once the bal-ance between damage and autophagy is broken,autophagy can no longer resist injury or main-tain homeostasis.In recent years,FGF21(fibroblast growth factor 21)-induced autophagy has attracted much attention.FGF21 is regarded as a stress hormone and can be up-regulated by an abundance of signaling pathways in response to stress.Also,increased FGF21 activates autophagy by a complicated signaling network in which mTOR plays a pivotal role.This review summarizes the mechanism of FGF21-mediated autophagy and its derived application in the defense of stress in liver diseases and offers a glimpse into its promising prospect in future clinical practice.
基金the National Key Research and Development Programof China(No.2021YFA1100500)the Major Research Plan of the National Natural Science Foundation of China(No.92159202)+4 种基金the Key Research&Development Plan of Zhejiang Province(No.2021C03118)the National Natural Science Foundation of China(No.82303387 and No.82300742)the Natural Science Foundation of Zhejiang Province(No.LQ23H160048 and No.LQ22H160052)the Health Science&Technology Plan of Zhejiang Province(No.2022RC060)supported by the Construction Fund of Medical Key Disciplines of Hangzhou(No.OO20200093).
文摘Background and aims:Inflammatory factors play significant roles in the development and occurrence of hepatocellular carcinoma(HCC).However,the tumor-protective functions of growth differentiation factors(GDFs)in HCC are yet to be clarified.In this study,we aimed to evaluate the expression levels of 10 GDFs in tumor and paratumor tissues from patients with HCC and perform in vitro and in vivo experiments to elucidate the role of GDF7 in regulating the proliferation and metastasis of HCC.Methods:The gene expression of 10 GDFs was compared between HCC and paratumors using The Cancer Genome Atlas dataset and patient-derived tissues.A tumor microarray containing 108 HCC tissue samples was used to explore the prognostic value of GDF7 expression.Loss-of-function experiments were also performed in vitro and in vivo to investigate the role of GDF7 in HCC.Results:The mRNA and protein levels of GDF7 were significantly lower in HCC tumors than in paratumors(P<0.001).KaplaneMeier analysis showed that decreased GDF7 expression in HCC was associated with worse overall survival(5-year rate:61.8%vs.27.5%,P<0.001)and increased recurrence risk(P<0.001).Multivariate Cox regression analysis demonstrated that low GDF7 expression,the presence of microvascular invasion,and elevated alpha-fetoprotein(AFP)levels were independent risk factors for tumor recurrence and poor survival.Downregulation of GDF7 also increased the tumor growth in HCC cells and in an HCC xenograft model.GDF7 knockdown promoted migration and invasion via epithelial emesenchymal transition.Meanwhile,a negative correlation between JunB proto-oncogene(JUNB)and GDF7 was observed in HCC tissues.Modulating JUNB levels altered GDF7 protein expression.Conclusions:GDF7 is a potential biomarker for predicting superior outcomes in patients with HCC.GDF7 amplification is a potential therapeutic option for HCC.
基金supported by the Key Research&Development Plan of Zhejiang Province(No.2024C03051)the Major Research Plan of the National Natural Science Foundation of China(No.92159202)+3 种基金the National Key Research and Development Program of China(No.2021YFA1100500)the National Science&Technology Major Project of China(No.2017ZX10203205)the National Natural Science Foundation of China(No.82303387)the Health Science&Technology Plan of Zhejiang Province(No.2022RC060).
文摘Background and aims:Cytokeratin 19-positive(CK19t)hepatocellular carcinoma(HCC)is an aggressive subtype with poor outcomes.The initiation and development of CK19t HCC in the background of liver cirrhosis remains unclear.This study investigated the role of the cirrhosis-related gene C-C motif chemokine ligand 16(CCL16)in the development of CK19t HCC.Methods:Datasets from Gene Expression Omnibus(GEO),The Cancer Genome Atlas(TCGA)and International Cancer Genome Consortium(ICGC)were analyzed to screen and validate the genes associated with CK19t HCC.A total of 102 HCC patients were included for tissue microarray analysis.Gain-of-function experiments were conducted to investigate the biological functions of CCL16.CIBERSORT was used to investigate the correlation of CCL16 and immune infiltration.Results:GEO dataset analysis showed that CK19t HCC had lower expression of CCL16.In both TCGA dataset and our HCC cohort,CCL16 expression was negatively correlated with CK19 expression(P<0.05)and its expression was higher in para-tumor than tumor tissues(P<0.001).Moreover,low CCL16 expression was related to advanced stage and poor overall survival(P<0.05).CCL16 overexpression downregulated CK19 expression and impacted the sphere formation ability of HCC cells.Overexpression of CCL16 inhibited the cell proliferation,migration,and invasion of HCC cell lines.Immune analysis showed HCC with high CCL16 expression had more infiltration of mast cells.HCC patients with both low CCL16 expression and low mast cells had the worst prognosis(P<0.001).Conclusion:Our data indicated that CCL16 downregulated the expression of CK19 and inhibited the malignant phenotype of HCC.
基金supported by Grant Zhejiang Provincial Natural Science Foundation of China(LQ22H160052)National Natural Science Foundation of China(82300742)The Major Research Plan of the National Natural Science Foundation of China(92159202).
文摘Aim:Pneumonia is the most frequent early postoperative complication in liver transplantation(LT)recipients.Inflammation may provide a favorable environment for tumor implantation,so we aimed to evaluate the impact of pneumonia on pulmonary metastasis of hepatocellular carcinoma(HCC)and reveal its underlying mechanism.Methods:A training cohort with 234 LT recipients were recorded and analyzed.Using the propensity-score method,we matched covariates between patients with and without pneumonia.A model for predicting pulmonary metastasis was built and validated in an independent validating cohort containing 179 subjects.A mouse model was built to mimic HCC pulmonary metastasis.The potential pathway was revealed by cytokine array analysis and validated in vitro.Results:Pneumonia was an independent risk factor for pulmonary metastasis in liver transplant recipients.It promoted pulmonary metastasis in both the clinical setting and the mouse model.In vitro,LPS-stimulated VEGF secretion from macrophages in the lung significantly reduced cell apoptosis and activated PI3K/AKT/cas-9 signaling.Administration of VEGF receptor2 inhibitor Vatalanib could reduce metastasis and improve prognosis in pneumonia mice.Conclusion:Pneumonia promotes HCC pulmonary metastasis by activating PI3K/AKT/Cas-9 signaling in HCC cells via macrophage-originated VEGF.Vatalanib might be efficient in reducing HCC pulmonary metastasis in liver transplant recipients with pneumonia.
