Introduction Primary liver cancer, the second most common cause of cancer related death worldwide, presents ethnic, etiological, sex, and geographical diversity2 （Figure 1A）. At the histological level, liver cancer ...Introduction Primary liver cancer, the second most common cause of cancer related death worldwide, presents ethnic, etiological, sex, and geographical diversity2 （Figure 1A）. At the histological level, liver cancer includes two major types： hepatocellular carcinoma （HCC, about 80%） and cholangiocarcinoma （CCA, about 15%）. Many etiological factors contribute to HCC development, such as hepatitis B virus （HBV）, hepatitis C virus （HCV）, aflatoxin B1 （AFB1）, alcohol, and metabolic diseases3. By contrast, the major risk factors for CCA are liver flukes （Opisthorchis viverrini and Clonorchis sinensis） and primary sclerosing cholangitis4,展开更多
Background:Hepatocellular carcinoma(HCC)remains a significant global health challenge.While firstline treatments with immune checkpoint inhibitors(ICIs)have improved patient outcomes,the selection of effective second-...Background:Hepatocellular carcinoma(HCC)remains a significant global health challenge.While firstline treatments with immune checkpoint inhibitors(ICIs)have improved patient outcomes,the selection of effective second-line therapies remains unclear.This study evaluated the efficacy and safety of regorafenib as a second-line option in advanced HCC patients post-progression on ICI-based therapies.Methods:Advanced HCC patients from eight hospitals in China who received regorafenib after progression on first-line ICI therapies,alone or combined with ICIs were enrolled.Clinical data were collected,and propensity score matching(PSM)was used to ensure comparability between treatment groups.The primary endpoint was overall survival(OS).The secondary endpoints were progression-free survival(PFS),objective response rate(ORR),disease control rate(DCR),and treatment-related adverse events.The study was registered at www.chictr.org.cn(ChiCTR2400091318).Results:A total of 149 patients were included:113 in the combination therapy group(Rego-ICI group)and 36 in the regorafenib monotherapy group(Rego group).After PSM,the Rego-ICI group showed significantly improved OS[19.0 vs.11.0 months,hazard ratio(HR)=0.426,95%confidence interval(CI):0.235–0.772,P=0.005]and PFS(4.0 vs.3.0 months,HR=0.539,95%CI:0.337–0.863,P=0.010)compared to the Rego group.Differences in ORR and DCR were not statistically significant(ORR:19.4%vs.9.7%,P=0.226;DCR:64.2%vs.48.4%,P=0.139),but the Rego-ICI group showed better disease control.Regorafenib plus ICI improved both OS and PFS with no new safety signals.Conclusions:The combination of ICIs and regorafenib significantly enhances OS in advanced HCC patients post-progression on first-line ICI treatments.These findings support the potential of regorafenib plus ICIs as an effective second-line therapy.展开更多
BACKGROUND Massive hepatocyte death is the core event in acute liver failure(ALF).Gasdermin D(GSDMD)-mediated pyroptosis is a type of highly inflammatory cell death.However,the role of hepatocyte pyroptosis and its me...BACKGROUND Massive hepatocyte death is the core event in acute liver failure(ALF).Gasdermin D(GSDMD)-mediated pyroptosis is a type of highly inflammatory cell death.However,the role of hepatocyte pyroptosis and its mechanisms of expanding inflammatory responses in ALF are unclear.AIM To investigate the role and mechanisms of GSDMD-mediated hepatocyte pyroptosis through in vitro and in vivo experiments.METHODS The expression of pyroptosis pathway-associated proteins in liver tissues from ALF patients and a hepatocyte injury model was examined by Western blot.GSDMD short hairpin RNA(shRNA)was used to investigate the effects of downregulation of GSDMD on monocyte chemotactic protein 1(MCP1)and its receptor CC chemokine receptor-2(CCR2)in vitro.For in vivo experiments,we used GSDMD knockout mice to investigate the role and mechanism of GSDMD in a D-galactose/lipopolysaccharide(D-Galn/LPS)-induced ALF mouse model.RESULTS The levels of pyroptosis pathway-associated proteins in liver tissue from ALF patients and a hepatocyte injury model increased significantly.The level of GSDMD-N protein increased most obviously(P<0.001).In vitro,downregulation of GSDMD by shRNA decreased the cell inhibition rate and the levels of MCP1/CCR2 proteins(P<0.01).In vivo,GSDMD knockout dramatically eliminated inflammatory damage in the liver and improved the survival of DGaln/LPS-induced ALF mice(P<0.001).Unlike the mechanism of immune cell pyroptosis that involves releasing interleukin(IL)-1βand IL-18,GSDMDmediated hepatocyte pyroptosis recruited macrophages via MCP1/CCR2 to aggravate hepatocyte death.However,this pathological process was inhibited after knocking down GSDMD.CONCLUSION GSDMD-mediated hepatocyte pyroptosis plays an important role in the pathogenesis of ALF,recruiting macrophages to release inflammatory mediators by upregulating MCP1/CCR2 and leading to expansion of the inflammatory responses.GSDMD knockout can reduce hepatocyte death and inflammatory responses,thus alleviating ALF.展开更多
BACKGROUND Liver fibrosis is a refractory disease whose persistence can eventually induce cirrhosis or even liver cancer.Early liver fibrosis is reversible by intervention.As a member of the transforming growth factor...BACKGROUND Liver fibrosis is a refractory disease whose persistence can eventually induce cirrhosis or even liver cancer.Early liver fibrosis is reversible by intervention.As a member of the transforming growth factor-beta(TGF-β)superfamily,bone morphogenetic protein 7(BMP7)has anti-liver fibrosis functions.However,little is known about BMP7 expression changes and its potential regulatory mechanism as well as the relationship between BMP7 and TGF-βduring liver fibrosis.In addition,the mechanism underlying the anti-liver fibrosis function of BMP7 needs to be further explored.AIM To investigate changes in the dynamic expression of BMP7 during liver fibrosis,interactions between BMP7 and TGF-β1,and possible mechanisms underlying the anti-liver fibrosis function of BMP7.METHODS Changes in BMP7 expression during liver fibrosis and the interaction between BMP7 and TGF-β1 in mice were observed.Exogenous BMP7 was used to treat mouse primary hepatic stellate cells(HSCs)to observe its effect on activation,migration,and proliferation of HSCs and explore the possible mechanism underlying the anti-liver fibrosis function of BMP7.Mice with liver fibrosis received exogenous BMP7 intervention to observe improvement of liver fibrosis by using Masson’s trichrome staining and detecting the expression of the HSC activation indicator alpha-smooth muscle actin(α-SMA)and the collagen formation associated protein type I collagen(Col I).Changes in the dynamic expression of BMP7 during liver fibrosis in the human body were further observed.RESULTS In the process of liver fibrosis induced by carbon tetrachloride(CCl4)in mice,BMP7 protein expression first increased,followed by a decrease;there was a similar trend in the human body.This process was accompanied by a sustained increase in TGF-β1 protein expression.In vitro experiment results showed that TGF-β1 inhibited BMP7 expression in a time-and dose-dependent manner.In contrast,high doses of exogenous BMP7 inhibited TGF-β1-induced activation,migration,and proliferation of HSCs;this inhibitory effect was associated with upregulation of pSmad1/5/8 and downregulation of phosphorylation of Smad3 and p38 by BMP7.In vivo experiment results showed that exogenous BMP7 improved liver fibrosis in mice.CONCLUSION During liver fibrosis,BMP7 protein expression first increases and then decreases.This changing trend is associated with inhibition of BMP7 expression by sustained upregulation of TGF-β1 in a time-and dose-dependent manner.Exogenous BMP7 could selectively regulate TGF-β/Smad pathway-associated factors to inhibit activation,migration,and proliferation of HSCs and exert antiliver fibrosis functions.Exogenous BMP7 has the potential to be used as an antiliver fibrosis drug.展开更多
This is first report about the simultaneous over-expression of both Insulin-like growth factor (IGF- I ) and its receptor (IGF- I R) at mRNA level in human primary hepatic Cancer (PHC). In 10 PHC samples from China, I...This is first report about the simultaneous over-expression of both Insulin-like growth factor (IGF- I ) and its receptor (IGF- I R) at mRNA level in human primary hepatic Cancer (PHC). In 10 PHC samples from China, IGF-I and IGF- I R were both over-expressed, whereas only a background signal was detected in normal liver. In 5 pairs of PHC and its non- tumorous adjacent liver tissues from South Africa, IGF- I and IGF- I R were also over-expressed in PHC. mRNA expression of IGF- I in all 5 cases and IGF- I R in 4 of 5 cases were higher in cancer than non- tumorous adjacent liver tissues. These results strongly implicate that an autocrine and/ or paracrine mechanism might be Involved in formation and progression of PHC.展开更多
Objective:To investigate the impact of metabolic dysfunction-associated steatotic liver disease(MASLD)on the efficacy of immune checkpoint inhibitor(ICI)-based therapy in patients with chronic hepatitis B(CHB)-related...Objective:To investigate the impact of metabolic dysfunction-associated steatotic liver disease(MASLD)on the efficacy of immune checkpoint inhibitor(ICI)-based therapy in patients with chronic hepatitis B(CHB)-related hepatocellular carcinoma(HCC).Methods:A total of 155 patients with CHB-related HCC who received ICI–based therapy(in the Department of Hepatology,Tianjin Second People’s Hospital and Department of Hepatobiliary Oncology,Tianjin Medical University Cancer Institute&Hospital)between April 2021 and December 2023 were evaluated.Patients were divided into two groups:MASLD concurrent with CHB[MASLD-CHB](n=38),and CHB(n=117).Results:The median progression-free survival(PFS,6.9 months vs.9.3 months;P=0.001),progressive disease(57.89%vs.37.61%;P=0.028),and disease control rate(42.11%vs.62.39%;P=0.028)in the MASLD-CHB group were significantly worse than the CHB group.The median overall survival was not attained.The percentage of CD4+PD1+(17.56%vs.8.89%;P<0.001)and CD8+PD1+T cells(10.50%vs.7.42%;P=0.005)in patient samples from the MASLD-CHB group were significantly higher than the CHB group.Concurrent MASLD[hazard ratio(HR)=1.921;95%CI,1.138–3.245;P=0.015]and alpha-fetoprotein levels after 3 months of treatment(HR=2.412;95%CI,1.360–4.279;P=0.003)were independent risk factors for PFS in all patients.Conclusions:ICI-based therapy in patients with CHB-related HCC and concurrent MASLD resulted in poorer efficacy and shorter PFS compared to patients with CHB-related HCC alone.展开更多
Objective:Effective adjuvant therapeutic strategies are urgently needed to overcome MAPK inhibitor(MAPKi)resistance,which is one of the most common forms of resistance that has emerged in many types of cancers.Here,we...Objective:Effective adjuvant therapeutic strategies are urgently needed to overcome MAPK inhibitor(MAPKi)resistance,which is one of the most common forms of resistance that has emerged in many types of cancers.Here,we aimed to systematically identify the genetic interactions underlying MAPKi resistance,and to further investigate the mechanisms that produce the genetic interactions that generate synergistic MAPKi resistance.Methods:We conducted a comprehensive pair-wise sgRNA-based high-throughput screening assay to identify synergistic interactions that sensitized cancer cells to MAPKi,and validated 3 genetic combinations through competitive growth,cell viability,and spheroid formation assays.We next conducted Kaplan-Meier survival analysis based on The Cancer Genome Atlas database and conducted immunohistochemistry to determine the clinical relevance of these synergistic combinations.We also investigated the MAPKi resistance mechanisms of these validated synergistic combinations by using co-immunoprecipitation,Western blot,qRTPCR,and immunofluorescence assays.Results:We constructed a systematic interaction network of MAPKi resistance and identified 3 novel synergistic combinations that effectively targeted MAPKi resistance(ITGB3+IGF1R,ITGB3+JNK,and HDGF+LGR5).We next analyzed their clinical relevance and the mechanisms by which they sensitized cancer cells to MAPKi exposure.Specifically,we discovered a novel protein complex,HDGF-LGR5,that adaptively responded to MAPKi to enhance cancer cell stemness,which was up-or downregulated by the inhibitors of ITGB3+JNK or ITGB3+IGF1R.Conclusions:Pair-wise sgRNA library screening provided systematic insights into elucidating MAPKi resistance in cancer cells.ITGB3-+IGF1R-targeting drugs(cilengitide+linsitinib)could be used as an effective therapy for suppressing the adaptive formation of the HDGF-LGR5 protein complex,which enhanced cancer stemness during MAPKi stress.展开更多
Metastasis is responsible for the majority of deaths related to cancer and results from several interconnected processes including cell proliferation,angiogenesis,chemotaxis,cell adhesion,migration,and invasion into t...Metastasis is responsible for the majority of deaths related to cancer and results from several interconnected processes including cell proliferation,angiogenesis,chemotaxis,cell adhesion,migration,and invasion into the surrounding tissue.SDF-1αinduced chemotaxis plays an important role in cancer chemotaxis and metastasis.Binding of SDF-1α(CXCL12)to CXCR4 triggers activation of heterotrimeric G proteins that regulate actin polymerization and migration of cancer cells.展开更多
Background: Hepatocellular carcinoma (HCC) has a poor prognosis. Selective internal radiation therapy (SIRT) with microspheres is a treatment option for HCC. This study aimed to assess safety and survival (OS) in pati...Background: Hepatocellular carcinoma (HCC) has a poor prognosis. Selective internal radiation therapy (SIRT) with microspheres is a treatment option for HCC. This study aimed to assess safety and survival (OS) in patients with HCC treated with SIRT, to stratify patients with tumor vascularization and analyze the impact of sequential sorafenib treatment. Methods: Thirty-nine patients who received SIRT for HCC between 2010 and 2013 at our center were included in this retrospective analysis. Tumor vascularization was assessed using a combination of MRI, MAA-scintigraphy and angiography. Tumor vascularization was correlated with survival. Subgroups are treated with two commercially available 90Y-labeled products SIR-Spheres (n = 16) and TheraSpheres (n = 23) and sequential therapy with sorafenib compared to SIRT only was analyzed. Results: Adverse events occurred in 49% of patients with only four grade 3 and no grade 4 event. Median survival for all patients was 12.5 months (95% CI: 8.7 - 16.3). No significant differences were detectable between Thera Spheres or SIR Spheres. Survival was shorter in patients with low tumor vascularization score (OS: 3.8 months (95% CI 0 - 15.0), p = 0.043). Survival was longer with sorafenib upon progression after SIRT (n=16) with an OS of 17.4 months (95% CI: 12.1 – 22.7) compared to no sorafenib (n = 13;9.1 months;95% CI: 3.0 - 15.1) or progression upon sorafenib before SIRT (n = 10;8.6 months;95% CI: 5.5 - 11.7). Conclusions: SIRT is safe in HCC patients. Tumor vascularization by radiography and scintigraphy may predict survival benefit. Sorafenib is active after SIRT and significantly prolongs survival.展开更多
Laparoscopic liver resection(LLR)for liver tumors has increased dramatically in the past two decades with less complications,blood loss,packed red blood cell(pRBC)transfusions,and shorter length of stay(LOS)compared t...Laparoscopic liver resection(LLR)for liver tumors has increased dramatically in the past two decades with less complications,blood loss,packed red blood cell(pRBC)transfusions,and shorter length of stay(LOS)compared to open liver resection(OLR)(1-5).Specifically for colorectal cancer liver metastases(CRLM),multiple studies consisting of case-match series,propensity score analyses,and meta-analyses have shown clinical benefits with improved short-term outcomes and comparable long-term survival comparing LLR to OLR(6-15).Another benefit is that LLR for CRLM allows for quicker recovery with earlier initiation of adjuvant systemic chemotherapy compared to OLR(16-18).展开更多
Protein arginine methyltransferase 5(PRMT5)acts as an oncogene in liver cancer,yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined.Here,we demonstrat...Protein arginine methyltransferase 5(PRMT5)acts as an oncogene in liver cancer,yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined.Here,we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8^(+)T-cell-mediated antitumor immunity both in vivo and in vitro.Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule,fibrinogen-like protein 1(FGL1).Mechanistically,PRMT5 catalyzed symmetric dimethylation of transcription factor 12(TCF12)at arginine 554(R554),prompting the binding of TCF12 to FGL1 promoter region,which transcriptionally activated FGL1 in tumor cells.Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression,which promoted CD8^(+)T-cell-mediated antitumor immunity.Notably,combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice.Collectively,our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.展开更多
Intrahepatic cholangiocarcinoma(ICC)poses a significant threat to human health owing to its high malignancy rate and poor prognosis.Sur-gery is the most effective treatment option for ICC.However,the prognosis remains...Intrahepatic cholangiocarcinoma(ICC)poses a significant threat to human health owing to its high malignancy rate and poor prognosis.Sur-gery is the most effective treatment option for ICC.However,the prognosis remains unfavorable even after surgical resection.Therefore,neo-adjuvant therapy has emerged as a potential treatment option for patients with ICC.Neoadjuvant therapy can improve patient prognosis by reducing the tumor size and eliminating tiny lesions that are not visible to the naked eye.Nevertheless,specific treatment options for neoad-juvant therapy are unavailable.This review summarizes the studies on neoadjuvant therapy for ICC in the last decade,including chemotherapy,radiotherapy,interventional therapy,targeted therapy,and immunotherapy,with the aim of providing suggestions for the selection of clinical treatment options for patients with ICC.Current reports suggest that chemotherapy is the most effective neoadjuvant treatment option.How-ever,radiotherapy and interventional therapies require further investigation to obtain conclusive recommendations.Although targeted thera-pies and immunotherapies have been studied less extensively,several ongoing clinical trials are investigating these promising approaches.展开更多
Background Antitumor drugs(such as chemotherapy,targeted therapy,immunotherapy,etc.)and local treatments like surgery and radiotherapy are widely used in cancer treatment,but they often carry the risk of liver injury,...Background Antitumor drugs(such as chemotherapy,targeted therapy,immunotherapy,etc.)and local treatments like surgery and radiotherapy are widely used in cancer treatment,but they often carry the risk of liver injury,which seriously affects the prognosis and quality of life of patients.Therefore,liver protection is of crucial importance in cancer treatment.Methods Relevant experts organized by the Oncology Hepatology Committee of China Anti-Cancer Association Association formulated this guideline based on the latest research achievements and clinical practice experience at home and abroad,aiming to provide comprehensive and systematic guidance for clinicians on liver protection.Results This guideline elaborates on the importance of liver protection during cancer treatment,comprehensively introduces the pathophysiological mechanisms,diagnosis,treatment,and preventive measures of antitumor treatment-related liver injury.Conclusion This guideline is helpful for clinicians to formulate individualized treatment plans,improve the treatment outcome and quality of life of cancer patients,and provides an important reference for the clinical practice of liver protection in cancer treatment.展开更多
Liver metastases pose a serious challenge in the field of systemic cancer treatment,as this organ has a particular microenvironment that favours malignant cells disseminating to settle there.We outline major steps of ...Liver metastases pose a serious challenge in the field of systemic cancer treatment,as this organ has a particular microenvironment that favours malignant cells disseminating to settle there.We outline major steps of liver immune tolerance in metastasis including pre-metastatic niche formation,immune evasion during circulation,establishment of an intrahepatic immune desert and metabolism,myeloid cell networks and gut microbiome-mediated coordinated tolerance.We then combine new combination and integrative therapies that are intended to break this tolerance;these include immunochemotherapy regimens,synergistic antiangiogenics and immunotherapies,dual immune checkpoint blockade and myeloid-cell reprogramming,combined locoregional and systemic therapies and new microenvironmental targeting.Each strategy is assessed with regard to its potential disruption of hepatic immune quiescence,improved clinical translation and durable antitumour activity.We suggest a proposed solution termed Liver-metastasis-oriented shared-mechanism therapeutic strategy,which may target multiple metastatic bottlenecks due to similarities.This framework provides a basis for personalizing combination therapies and designing future clinical trials for treating liver metastases,with organ-specific considerations and will be the subject of a commentary.展开更多
基金supported,in part,by the Precision Medical Research Program from Ministry of Science and Technology of China(Grant No.YL 2017YFC0908400)National Science and Technology Major Project for Infectious Disease and Funding(Grant No.YL 17-163-12-ZT-005-095-01)+2 种基金Science and Technology Commission in Ministry of National Defense of China(Grant No.YL 17-163-12-ZT-005-095-01)Xinwei Wang was supported by the intramural research program of the Center for Cancer Research,National Cancer Institute of the United StatesJunfang Ji was supported by the Thousand Young Talents Plan of China,National Natural Science Foundation of China(Grant No.81672905)
文摘Introduction Primary liver cancer, the second most common cause of cancer related death worldwide, presents ethnic, etiological, sex, and geographical diversity2 （Figure 1A）. At the histological level, liver cancer includes two major types： hepatocellular carcinoma （HCC, about 80%） and cholangiocarcinoma （CCA, about 15%）. Many etiological factors contribute to HCC development, such as hepatitis B virus （HBV）, hepatitis C virus （HCV）, aflatoxin B1 （AFB1）, alcohol, and metabolic diseases3. By contrast, the major risk factors for CCA are liver flukes （Opisthorchis viverrini and Clonorchis sinensis） and primary sclerosing cholangitis4,
基金supported by a grant from the Zhongda Hospital Affiliated to Southeast University,Jiangsu Province High-Level Hospital Construction Funds(No.YKK24270)。
文摘Background:Hepatocellular carcinoma(HCC)remains a significant global health challenge.While firstline treatments with immune checkpoint inhibitors(ICIs)have improved patient outcomes,the selection of effective second-line therapies remains unclear.This study evaluated the efficacy and safety of regorafenib as a second-line option in advanced HCC patients post-progression on ICI-based therapies.Methods:Advanced HCC patients from eight hospitals in China who received regorafenib after progression on first-line ICI therapies,alone or combined with ICIs were enrolled.Clinical data were collected,and propensity score matching(PSM)was used to ensure comparability between treatment groups.The primary endpoint was overall survival(OS).The secondary endpoints were progression-free survival(PFS),objective response rate(ORR),disease control rate(DCR),and treatment-related adverse events.The study was registered at www.chictr.org.cn(ChiCTR2400091318).Results:A total of 149 patients were included:113 in the combination therapy group(Rego-ICI group)and 36 in the regorafenib monotherapy group(Rego group).After PSM,the Rego-ICI group showed significantly improved OS[19.0 vs.11.0 months,hazard ratio(HR)=0.426,95%confidence interval(CI):0.235–0.772,P=0.005]and PFS(4.0 vs.3.0 months,HR=0.539,95%CI:0.337–0.863,P=0.010)compared to the Rego group.Differences in ORR and DCR were not statistically significant(ORR:19.4%vs.9.7%,P=0.226;DCR:64.2%vs.48.4%,P=0.139),but the Rego-ICI group showed better disease control.Regorafenib plus ICI improved both OS and PFS with no new safety signals.Conclusions:The combination of ICIs and regorafenib significantly enhances OS in advanced HCC patients post-progression on first-line ICI treatments.These findings support the potential of regorafenib plus ICIs as an effective second-line therapy.
基金Supported by the National Natural Science Foundation of China,No.81570543 and No.81560104
文摘BACKGROUND Massive hepatocyte death is the core event in acute liver failure(ALF).Gasdermin D(GSDMD)-mediated pyroptosis is a type of highly inflammatory cell death.However,the role of hepatocyte pyroptosis and its mechanisms of expanding inflammatory responses in ALF are unclear.AIM To investigate the role and mechanisms of GSDMD-mediated hepatocyte pyroptosis through in vitro and in vivo experiments.METHODS The expression of pyroptosis pathway-associated proteins in liver tissues from ALF patients and a hepatocyte injury model was examined by Western blot.GSDMD short hairpin RNA(shRNA)was used to investigate the effects of downregulation of GSDMD on monocyte chemotactic protein 1(MCP1)and its receptor CC chemokine receptor-2(CCR2)in vitro.For in vivo experiments,we used GSDMD knockout mice to investigate the role and mechanism of GSDMD in a D-galactose/lipopolysaccharide(D-Galn/LPS)-induced ALF mouse model.RESULTS The levels of pyroptosis pathway-associated proteins in liver tissue from ALF patients and a hepatocyte injury model increased significantly.The level of GSDMD-N protein increased most obviously(P<0.001).In vitro,downregulation of GSDMD by shRNA decreased the cell inhibition rate and the levels of MCP1/CCR2 proteins(P<0.01).In vivo,GSDMD knockout dramatically eliminated inflammatory damage in the liver and improved the survival of DGaln/LPS-induced ALF mice(P<0.001).Unlike the mechanism of immune cell pyroptosis that involves releasing interleukin(IL)-1βand IL-18,GSDMDmediated hepatocyte pyroptosis recruited macrophages via MCP1/CCR2 to aggravate hepatocyte death.However,this pathological process was inhibited after knocking down GSDMD.CONCLUSION GSDMD-mediated hepatocyte pyroptosis plays an important role in the pathogenesis of ALF,recruiting macrophages to release inflammatory mediators by upregulating MCP1/CCR2 and leading to expansion of the inflammatory responses.GSDMD knockout can reduce hepatocyte death and inflammatory responses,thus alleviating ALF.
基金Supported by the National Natural Science Foundation of China,No.81560104 and No.81860115
文摘BACKGROUND Liver fibrosis is a refractory disease whose persistence can eventually induce cirrhosis or even liver cancer.Early liver fibrosis is reversible by intervention.As a member of the transforming growth factor-beta(TGF-β)superfamily,bone morphogenetic protein 7(BMP7)has anti-liver fibrosis functions.However,little is known about BMP7 expression changes and its potential regulatory mechanism as well as the relationship between BMP7 and TGF-βduring liver fibrosis.In addition,the mechanism underlying the anti-liver fibrosis function of BMP7 needs to be further explored.AIM To investigate changes in the dynamic expression of BMP7 during liver fibrosis,interactions between BMP7 and TGF-β1,and possible mechanisms underlying the anti-liver fibrosis function of BMP7.METHODS Changes in BMP7 expression during liver fibrosis and the interaction between BMP7 and TGF-β1 in mice were observed.Exogenous BMP7 was used to treat mouse primary hepatic stellate cells(HSCs)to observe its effect on activation,migration,and proliferation of HSCs and explore the possible mechanism underlying the anti-liver fibrosis function of BMP7.Mice with liver fibrosis received exogenous BMP7 intervention to observe improvement of liver fibrosis by using Masson’s trichrome staining and detecting the expression of the HSC activation indicator alpha-smooth muscle actin(α-SMA)and the collagen formation associated protein type I collagen(Col I).Changes in the dynamic expression of BMP7 during liver fibrosis in the human body were further observed.RESULTS In the process of liver fibrosis induced by carbon tetrachloride(CCl4)in mice,BMP7 protein expression first increased,followed by a decrease;there was a similar trend in the human body.This process was accompanied by a sustained increase in TGF-β1 protein expression.In vitro experiment results showed that TGF-β1 inhibited BMP7 expression in a time-and dose-dependent manner.In contrast,high doses of exogenous BMP7 inhibited TGF-β1-induced activation,migration,and proliferation of HSCs;this inhibitory effect was associated with upregulation of pSmad1/5/8 and downregulation of phosphorylation of Smad3 and p38 by BMP7.In vivo experiment results showed that exogenous BMP7 improved liver fibrosis in mice.CONCLUSION During liver fibrosis,BMP7 protein expression first increases and then decreases.This changing trend is associated with inhibition of BMP7 expression by sustained upregulation of TGF-β1 in a time-and dose-dependent manner.Exogenous BMP7 could selectively regulate TGF-β/Smad pathway-associated factors to inhibit activation,migration,and proliferation of HSCs and exert antiliver fibrosis functions.Exogenous BMP7 has the potential to be used as an antiliver fibrosis drug.
文摘This is first report about the simultaneous over-expression of both Insulin-like growth factor (IGF- I ) and its receptor (IGF- I R) at mRNA level in human primary hepatic Cancer (PHC). In 10 PHC samples from China, IGF-I and IGF- I R were both over-expressed, whereas only a background signal was detected in normal liver. In 5 pairs of PHC and its non- tumorous adjacent liver tissues from South Africa, IGF- I and IGF- I R were also over-expressed in PHC. mRNA expression of IGF- I in all 5 cases and IGF- I R in 4 of 5 cases were higher in cancer than non- tumorous adjacent liver tissues. These results strongly implicate that an autocrine and/ or paracrine mechanism might be Involved in formation and progression of PHC.
基金supported by the National Natural Science Foundation of China (Grant No. 62375202)Natural Science Foundation of Tianjin (Grant No. 23JCYBJC00950)+2 种基金Tianjin Health Science and Technology Project Key Discipline Special (Grant No. TJWJ2022XK034)Tianjin Key Medical Discipline (Specialty) Construction Project (Grant No.TJYXZDXK-059B)Research Project in Key Areas of TCM in 2024 (Grant No. 2024022)
文摘Objective:To investigate the impact of metabolic dysfunction-associated steatotic liver disease(MASLD)on the efficacy of immune checkpoint inhibitor(ICI)-based therapy in patients with chronic hepatitis B(CHB)-related hepatocellular carcinoma(HCC).Methods:A total of 155 patients with CHB-related HCC who received ICI–based therapy(in the Department of Hepatology,Tianjin Second People’s Hospital and Department of Hepatobiliary Oncology,Tianjin Medical University Cancer Institute&Hospital)between April 2021 and December 2023 were evaluated.Patients were divided into two groups:MASLD concurrent with CHB[MASLD-CHB](n=38),and CHB(n=117).Results:The median progression-free survival(PFS,6.9 months vs.9.3 months;P=0.001),progressive disease(57.89%vs.37.61%;P=0.028),and disease control rate(42.11%vs.62.39%;P=0.028)in the MASLD-CHB group were significantly worse than the CHB group.The median overall survival was not attained.The percentage of CD4+PD1+(17.56%vs.8.89%;P<0.001)and CD8+PD1+T cells(10.50%vs.7.42%;P=0.005)in patient samples from the MASLD-CHB group were significantly higher than the CHB group.Concurrent MASLD[hazard ratio(HR)=1.921;95%CI,1.138–3.245;P=0.015]and alpha-fetoprotein levels after 3 months of treatment(HR=2.412;95%CI,1.360–4.279;P=0.003)were independent risk factors for PFS in all patients.Conclusions:ICI-based therapy in patients with CHB-related HCC and concurrent MASLD resulted in poorer efficacy and shorter PFS compared to patients with CHB-related HCC alone.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant Nos.31471255,31771483,81171515,31670991,and 61721003)the National Key Research and Development Program(Grant Nos.2017YFC0908400 and 2017YFC0908401).
文摘Objective:Effective adjuvant therapeutic strategies are urgently needed to overcome MAPK inhibitor(MAPKi)resistance,which is one of the most common forms of resistance that has emerged in many types of cancers.Here,we aimed to systematically identify the genetic interactions underlying MAPKi resistance,and to further investigate the mechanisms that produce the genetic interactions that generate synergistic MAPKi resistance.Methods:We conducted a comprehensive pair-wise sgRNA-based high-throughput screening assay to identify synergistic interactions that sensitized cancer cells to MAPKi,and validated 3 genetic combinations through competitive growth,cell viability,and spheroid formation assays.We next conducted Kaplan-Meier survival analysis based on The Cancer Genome Atlas database and conducted immunohistochemistry to determine the clinical relevance of these synergistic combinations.We also investigated the MAPKi resistance mechanisms of these validated synergistic combinations by using co-immunoprecipitation,Western blot,qRTPCR,and immunofluorescence assays.Results:We constructed a systematic interaction network of MAPKi resistance and identified 3 novel synergistic combinations that effectively targeted MAPKi resistance(ITGB3+IGF1R,ITGB3+JNK,and HDGF+LGR5).We next analyzed their clinical relevance and the mechanisms by which they sensitized cancer cells to MAPKi exposure.Specifically,we discovered a novel protein complex,HDGF-LGR5,that adaptively responded to MAPKi to enhance cancer cell stemness,which was up-or downregulated by the inhibitors of ITGB3+JNK or ITGB3+IGF1R.Conclusions:Pair-wise sgRNA library screening provided systematic insights into elucidating MAPKi resistance in cancer cells.ITGB3-+IGF1R-targeting drugs(cilengitide+linsitinib)could be used as an effective therapy for suppressing the adaptive formation of the HDGF-LGR5 protein complex,which enhanced cancer stemness during MAPKi stress.
文摘Metastasis is responsible for the majority of deaths related to cancer and results from several interconnected processes including cell proliferation,angiogenesis,chemotaxis,cell adhesion,migration,and invasion into the surrounding tissue.SDF-1αinduced chemotaxis plays an important role in cancer chemotaxis and metastasis.Binding of SDF-1α(CXCL12)to CXCR4 triggers activation of heterotrimeric G proteins that regulate actin polymerization and migration of cancer cells.
文摘Background: Hepatocellular carcinoma (HCC) has a poor prognosis. Selective internal radiation therapy (SIRT) with microspheres is a treatment option for HCC. This study aimed to assess safety and survival (OS) in patients with HCC treated with SIRT, to stratify patients with tumor vascularization and analyze the impact of sequential sorafenib treatment. Methods: Thirty-nine patients who received SIRT for HCC between 2010 and 2013 at our center were included in this retrospective analysis. Tumor vascularization was assessed using a combination of MRI, MAA-scintigraphy and angiography. Tumor vascularization was correlated with survival. Subgroups are treated with two commercially available 90Y-labeled products SIR-Spheres (n = 16) and TheraSpheres (n = 23) and sequential therapy with sorafenib compared to SIRT only was analyzed. Results: Adverse events occurred in 49% of patients with only four grade 3 and no grade 4 event. Median survival for all patients was 12.5 months (95% CI: 8.7 - 16.3). No significant differences were detectable between Thera Spheres or SIR Spheres. Survival was shorter in patients with low tumor vascularization score (OS: 3.8 months (95% CI 0 - 15.0), p = 0.043). Survival was longer with sorafenib upon progression after SIRT (n=16) with an OS of 17.4 months (95% CI: 12.1 – 22.7) compared to no sorafenib (n = 13;9.1 months;95% CI: 3.0 - 15.1) or progression upon sorafenib before SIRT (n = 10;8.6 months;95% CI: 5.5 - 11.7). Conclusions: SIRT is safe in HCC patients. Tumor vascularization by radiography and scintigraphy may predict survival benefit. Sorafenib is active after SIRT and significantly prolongs survival.
文摘Laparoscopic liver resection(LLR)for liver tumors has increased dramatically in the past two decades with less complications,blood loss,packed red blood cell(pRBC)transfusions,and shorter length of stay(LOS)compared to open liver resection(OLR)(1-5).Specifically for colorectal cancer liver metastases(CRLM),multiple studies consisting of case-match series,propensity score analyses,and meta-analyses have shown clinical benefits with improved short-term outcomes and comparable long-term survival comparing LLR to OLR(6-15).Another benefit is that LLR for CRLM allows for quicker recovery with earlier initiation of adjuvant systemic chemotherapy compared to OLR(16-18).
基金supported by the National Natural Science Foundation of China(Nos.82372818 to Xiaodong Zhang,82103066 to Guang Yang,82302887 to Hongfeng Yuan,82303210 to Yufei Wang)The China Postdoctoral Science Foundation(No.2022M712389 to Hongfeng Yuan,No.2023M732624 to Yufei Wang,No.2023M742621 to Lina Zhao)+1 种基金Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-009A to W.Lu,China)“14th Five-Year Plan”Tumor Prevention and Treatment Research Project of Tianjin Medical University Cancer Institute and Hospital(No.YZ-03,China).
文摘Protein arginine methyltransferase 5(PRMT5)acts as an oncogene in liver cancer,yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined.Here,we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8^(+)T-cell-mediated antitumor immunity both in vivo and in vitro.Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule,fibrinogen-like protein 1(FGL1).Mechanistically,PRMT5 catalyzed symmetric dimethylation of transcription factor 12(TCF12)at arginine 554(R554),prompting the binding of TCF12 to FGL1 promoter region,which transcriptionally activated FGL1 in tumor cells.Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression,which promoted CD8^(+)T-cell-mediated antitumor immunity.Notably,combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice.Collectively,our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.
基金supported by the National Natural Science Foundation of China(grants 82373365 and 82173317)the Tianjin Key Medical Discipline Construction Project(TJYXZDXK-009A).
文摘Intrahepatic cholangiocarcinoma(ICC)poses a significant threat to human health owing to its high malignancy rate and poor prognosis.Sur-gery is the most effective treatment option for ICC.However,the prognosis remains unfavorable even after surgical resection.Therefore,neo-adjuvant therapy has emerged as a potential treatment option for patients with ICC.Neoadjuvant therapy can improve patient prognosis by reducing the tumor size and eliminating tiny lesions that are not visible to the naked eye.Nevertheless,specific treatment options for neoad-juvant therapy are unavailable.This review summarizes the studies on neoadjuvant therapy for ICC in the last decade,including chemotherapy,radiotherapy,interventional therapy,targeted therapy,and immunotherapy,with the aim of providing suggestions for the selection of clinical treatment options for patients with ICC.Current reports suggest that chemotherapy is the most effective neoadjuvant treatment option.How-ever,radiotherapy and interventional therapies require further investigation to obtain conclusive recommendations.Although targeted thera-pies and immunotherapies have been studied less extensively,several ongoing clinical trials are investigating these promising approaches.
文摘Background Antitumor drugs(such as chemotherapy,targeted therapy,immunotherapy,etc.)and local treatments like surgery and radiotherapy are widely used in cancer treatment,but they often carry the risk of liver injury,which seriously affects the prognosis and quality of life of patients.Therefore,liver protection is of crucial importance in cancer treatment.Methods Relevant experts organized by the Oncology Hepatology Committee of China Anti-Cancer Association Association formulated this guideline based on the latest research achievements and clinical practice experience at home and abroad,aiming to provide comprehensive and systematic guidance for clinicians on liver protection.Results This guideline elaborates on the importance of liver protection during cancer treatment,comprehensively introduces the pathophysiological mechanisms,diagnosis,treatment,and preventive measures of antitumor treatment-related liver injury.Conclusion This guideline is helpful for clinicians to formulate individualized treatment plans,improve the treatment outcome and quality of life of cancer patients,and provides an important reference for the clinical practice of liver protection in cancer treatment.
文摘Liver metastases pose a serious challenge in the field of systemic cancer treatment,as this organ has a particular microenvironment that favours malignant cells disseminating to settle there.We outline major steps of liver immune tolerance in metastasis including pre-metastatic niche formation,immune evasion during circulation,establishment of an intrahepatic immune desert and metabolism,myeloid cell networks and gut microbiome-mediated coordinated tolerance.We then combine new combination and integrative therapies that are intended to break this tolerance;these include immunochemotherapy regimens,synergistic antiangiogenics and immunotherapies,dual immune checkpoint blockade and myeloid-cell reprogramming,combined locoregional and systemic therapies and new microenvironmental targeting.Each strategy is assessed with regard to its potential disruption of hepatic immune quiescence,improved clinical translation and durable antitumour activity.We suggest a proposed solution termed Liver-metastasis-oriented shared-mechanism therapeutic strategy,which may target multiple metastatic bottlenecks due to similarities.This framework provides a basis for personalizing combination therapies and designing future clinical trials for treating liver metastases,with organ-specific considerations and will be the subject of a commentary.
