Background: Increasing evidence indicates that Six2 contributes to tumorigenesis in various tumor in- cluding hepatocellular carcinoma (HCC). This study aimed to determine the role of Six2 in HCC and to elucidate the ...Background: Increasing evidence indicates that Six2 contributes to tumorigenesis in various tumor in- cluding hepatocellular carcinoma (HCC). This study aimed to determine the role of Six2 in HCC and to elucidate the association of Six2 with clinical pathological characteristics. Methods: The expressions of Six2 in HCC tumor, para-tumor tissue and portal vein tumor thrombus (PVTT) were detected by tissue microarray technique, immunohistochemistry, real-time RT-PCR and West- ern blotting. Chi-square and Kaplan-Meier analysis were used to analyze the correlation between Six2 expression and prognosis of HCC patients. Lentivirus mediated Six2 knockdown, spheroid formation as- say, proliferation assay and subcutaneous tumor implantation were performed to determine the function of Six2. Results: In 274 HCC samples, Six2 was strongly expressed. Kaplan-Meier analysis revealed that high ex- pression of Six2 was correlated with a shorter overall survival (OS) and disease-free survival (DFS). More- over, Six2 expression was associated with sex, alpha-fetoprotein, tumor size and portal vein invasion. Six2 was highly expressed in PVTT. Six2 knockdown inhibited HCC cell lines proliferation, migration, and self-renewal in vitro and in vivo. In addition, low-expression of Six2 weakened TGF-β induced Smad4 activation and epithelial-mesenchymal transition in HCC cell lines. Conclusions: Elevated Six2 expression in HCC tumor patients was associated with negative prognosis. Upregulated Six2 promoted tumor growth and facilitated HCC metastasis via TGF-β/Smad signal pathway.展开更多
The Wnt/β-catenin signaling pathway regulates many aspects of tumor biology,and many studies have focused on the role of this signaling pathway in tumor cells.However,it is now clear that tumor development and metast...The Wnt/β-catenin signaling pathway regulates many aspects of tumor biology,and many studies have focused on the role of this signaling pathway in tumor cells.However,it is now clear that tumor development and metastasis depend on the two-way interaction between cancer cells and their environment,thereby forming a tumor microenvironment(TME).In this review,we discuss how Wnt/β-catenin signaling regulates cross-interactions among different components of the TME,including immune cells,stem cells,tumor vasculature,and noncellular components of the TME in hepatocellular carcinoma.We also investigate their preclinical and clinical insights for primary liver cancer intervention,and explore the significance of using Wnt/β-catenin mutations as a biomarker to predict resistance in immunotherapy.展开更多
AIM To clone and identify the whole cDNA ofMXR7 gene and to find out its expression inhuman HCC,and normal tissues.METHODS The DNA primers were designed andsynthesized according to the whole cDNAsequence of MXR? gene....AIM To clone and identify the whole cDNA ofMXR7 gene and to find out its expression inhuman HCC,and normal tissues.METHODS The DNA primers were designed andsynthesized according to the whole cDNAsequence of MXR? gene.The cDNA of humanHCC was taken as the template while the cDNA ofMXR7 gene was synthesized by polymerasechain reaction（PCR）.Recombinant DNAconforming to reading frame was constructed byconnecting purified PCR product of the cDNA ofMXR? gene with expression vector pGEX-5X-1 offusion protein.The plasmid MXRT/pGEX-5X-1was identified by sequencing.Using <sup>32</sup>p labeledMXR? cDNA as probe,MXR7 mRNA expressionwas detected by Northern blot analysis in 12different human normal tissues,7 preoperativelyuntreated non-liver tumor tissues,30preoperatively untreated HCC,theparacancerous liver tissues and 12 normal livertissues samples.RESULTS Restriction enzyme and sequenceanalysis confirmed that the insertion sequence invector pGEX-5X-1 was the same as the cDNAsequence of MXR7 gene.Northern blot analysisshowed no expression of MXR? mRNA in 12 kindsof normal human tissues including liver,7 tumortissues in other sites and 12 normal livertissues,the frequencies of MXR7 mRNA expression in HCC and paracancerous livertissues were 76.6% and 13.3%,respectively.The frequency of MXR7 mRNA expression in HCCwithout elevation of serum AFP and in HCC【5cm was 90%（9/10）and 83.3%（5/6）,respectively.CONCLUSION MXR7 mRNA is highly expressedin human HCC,which is specific and occurs at anearly stage of HCC,suggesting MXR7 mRNA canbe a tumor biomarker for HCC.The detection ofMXR7 mRNA expression in the biopsied livertissue is helpful in discovering early subclinicalliver cancer in those with negative serum AFP.展开更多
AIM： To investigate the relationship between the expression of P120 and the clinicopathologic parameters in intrahepatic cholangiocarcinoma （ICC）. METHODS： An immunohistochemical study of E-cadherin and P120 caten...AIM： To investigate the relationship between the expression of P120 and the clinicopathologic parameters in intrahepatic cholangiocarcinoma （ICC）. METHODS： An immunohistochemical study of E-cadherin and P120 catenin was performed on 42 specimens of ICC with a Dako Envision kit. RESULTS： The expression of E-cadherin and P120 was reduced in 27 cases （64.3%） and 31 cases （73.8%）, respectively. Both E-cadherin and P120 expressions were significantly correlated with the tumor histological grade （χ^2 = 9.333, P = 009 and χ^= 11.71, P = 0.003）, TNM stage （χ^= 8.627, P = 0.035 and χ^= 13.123, P = 0.004）, intrahepatic metastasis （χ^= 7.292, P = 0.007 and χ^= 4.657, P = 0.041, respectively） and patients′ survival （χ^= 6.351, P = 0.002 and χ^= 4.023, P = 0.000, respectively）. In addition, the expression of P120 was in concordance with that of E-cadherin （χ^ = 13.797, P = 0.000）, indicating that the expression of P120 may be dependent on that of E-cadherin. Finally, only P120 expression was found to be an independent prognostic factor in Cox regression model （r = 0.088, P = 0.049）. CONCLUSION： Down-regulated expression of E-cadherin and P120 occurs frequently in ICC and contributes to the progression and development of tumor. Both of them may be valuable biologic markers for predicting tumor invasion, metastasis and patients′ survival, but only P120 is an independent prognostic factor for ICC.展开更多
Objective： Portal vein metastasis of hepatocellular carcinoma（HCC） results in a poor prognosis and seriously affects the survival rate of patients. The mechanism underlying the formation of portal vein tumor throm...Objective： Portal vein metastasis of hepatocellular carcinoma（HCC） results in a poor prognosis and seriously affects the survival rate of patients. The mechanism underlying the formation of portal vein tumor thrombus（PVTT） is complex and is not yet fully understood. This study was conducted to investigate the impact of portal vein blood on the proliferation, metastasis, invasion and apoptosis of PVTT cells and to explore its possible mechanisms, which was expected to lay a foundation for ascertaining the mechanism underlying the portal vein metastasis of HCC.Methods： Peripheral blood and portal vein blood were collected from patients with HCC, and the sera from these two sources were used to culture the PVTT-originated HCC cell line CSQT-2. The cells were collected after 24 h, and flow cytometry was performed to detect cell proliferation, cell cycle stages and apoptosis. Transwell migration and invasion assays were applied to detect the metastasis and invasion of the cells in each group. The changes in the expression of MMP-2 and MMP-9 in cells were detected via Western blotting. The contents of IL-12, IFN-γ, IL-1β, IL-2 and TNF-α in the two groups of sera were quantified using corresponding kits. Results： Compared with the group of cells cultured with peripheral serum, the cells cultured with portal vein serum showed significantly lower apoptosis（P〈0.01）, significantly enhanced cell metastasis and invasion（P〈0.01）, whereas cell proliferation and the stages of the cell cycle did not differ significantly（P〉0.05）. A significantly increased expression level of MMP-2 has been observed in tumor cells treated portal vein serum. In addition, compared with peripheral serum, the content of IL-12 was significantly decreased in portal vein serum（P〈0.05）, while the contents of IFN-γ, IL-1β, IL-2, and TNF-α did not differ significantly（P〈0.05）. Conclusions： Portal vein serum from HCC patients could inhibit the apoptosis of PVTT-originated HCC cells and promote cell metastasis and invasion. This effect may be related to the lower level of IL-12 in portal vein serum.展开更多
Non-alcoholic fatty liver disease(NAFLD)is prevalent worldwide as a chronic liver disease that not only gives rise to hepatic complications,but leads to other chronic diseases such as type 2 diabetes and atheroscleros...Non-alcoholic fatty liver disease(NAFLD)is prevalent worldwide as a chronic liver disease that not only gives rise to hepatic complications,but leads to other chronic diseases such as type 2 diabetes and atherosclerosis.The aberrant accumulation of lipid droplets(LDs)in hepatocytes is a prominent signature of NAFLD.However,conventional techniques lack the capability to effectively monitor the dynamic changes in LD levels during NAFLD with living organisms.Hence,it is imperative to develop LD-specific long-wavelength fluorescent probes with high imaging contrast for the in-situ diagnosis of NAFLD.In this study,we synthesized a new LD-selective long-wavelength fluorescent probe,denoted as LD-1,based on the twisted intramolecular charge transfer(TICT)mechanism.The probe exhibits a large Stokes shift and intensive fluorescence emission in nonpolar and viscous solutions.By self-assembling LD-1 with bovine serum albumin(BSA),a biocompatible,long-wavelength fluorescent probe hybrid,LD-1@BSA,was formed,allowing for LDs to be selectively imaged in hepatocytes.Moreover,LD-1@BSA successfully discriminates NAFLD cells before and after drug treatment,and achieves non-invasive and real-time monitoring of LD accumulation in a mouse model of NAFLD.展开更多
Tumor-associated macrophages(TAMs)actively interact with the tumor microenvironment(TME).The dynamic communication between TAMs and the TME is closely associated with tumorigenesis,progression,metastasis,and drug resi...Tumor-associated macrophages(TAMs)actively interact with the tumor microenvironment(TME).The dynamic communication between TAMs and the TME is closely associated with tumorigenesis,progression,metastasis,and drug resistance.With the development of single-cell sequencing,specific TAMs have been identified,and their roles in the TME were explored.With the development of an under-standing of the interactions between TAMs and the TME,targeting TAMs has become a new treatment strategy for cancer therapy be-cause of their high plasticity.In this review,we highlight strategies for remodeling TAMs based on targeting specific genes involved in reg-ulating TAM phenotypes,blocking the crosstalk between TAMs and the TME,and targeting abnormal metabolic pathways.Moreover,we provided perspectives on the translational potential of targeting TAMs for cancer treatment,which could shed light on TAM-based thera-peutic strategy in the future.展开更多
Objective：To obtain information at the molecular level on the possible mechanism of MXR7 gene overexpressed in hepatocellular carcinoma （HCC） and also to provide a clue for further study. Methods：Genomic DNA was i...Objective：To obtain information at the molecular level on the possible mechanism of MXR7 gene overexpressed in hepatocellular carcinoma （HCC） and also to provide a clue for further study. Methods：Genomic DNA was isolated from 20 samples of hepatoma and paired non-HCC liver tissues, 2 cases of blood tumor and two types of cells （HepG2, MCF-7） and digested with two kinds of endonucleases （EcoR I and Eag I which is methylation sensitive endonuclease）. And the condition of MXR7 gene methylation was examined and analyzed by Southern blot. Results： MXR7 was unmethylated neither in tested tumorous liver samples nor in paired non HCC liver tissues. In addition, the same result was found in 2 blood tumor samples and HepG2. Only two paired samples had different methylation outcome, one was unmethylated and the other was partly methylated. Conclusion： MXR7 is unmethylated in HHC, suggesting methylation of MXR7 may have no relation with its expression and regulation.展开更多
The application of tumor antigen-based immunotherapy is hindered by the rarity of validated immunogenic peptides.In this study,we aimed to investigate the potential of circular RNAs(circRNAs)as a novel source of tumor...The application of tumor antigen-based immunotherapy is hindered by the rarity of validated immunogenic peptides.In this study,we aimed to investigate the potential of circular RNAs(circRNAs)as a novel source of tumor antigen peptides in hepatobiliary tumor organoids.Using RNA-sequencing(RNA-seq)with an algorithm-based score tool,3950 translated tumor-specific circRNAs were predicted to generate 18971 antigen peptides in 27 organoids.In view of the antigen landscape,11 amino acid length(mer)peptides and human leukocyte antigen(HLA)-A binding peptides harbored the highest immunogenicity-related scores.In three out of five analyzed organoids,13 predicted antigen peptides were directly confirmed as HLA-A,-B,and-C(HLA-ABC)binding peptides with mass spectrometry(MS)-based immunopeptidomics.CircRNA-derived tumor-specific peptides presented by the HLA-ABC molecules stimulated cluster of differentiation 8(CD8)T cells to exhibit increased CD107a interferonγ(IFNγ)co-expressions and IFNγsecretion in flow cytometry and enzyme-linked immunosorbent assay(ELISA).Cytotoxic T cell activity targeting the organoids,induced by the immunogenic circRNA-derived peptides,was verified in a killing assay.Notably,the antigen peptide YGFNEILKK from circTBC1D15 was not only recognized as an HLA-ABC-presented peptide of the organoids but also drastically reduced the tumor organoid survival rate.Our findings highlight a crucial subset for generating tumor antigens,which has implications for targeting tumor-specific circRNAs in cancers.展开更多
The development of cancer is a complex process that requires the participation of many factors,including mutations in genes, regulation of signaling pathways, disruption of homeostasis, and failure of self-monitoring ...The development of cancer is a complex process that requires the participation of many factors,including mutations in genes, regulation of signaling pathways, disruption of homeostasis, and failure of self-monitoring mechanisms. Sufficient evidence has展开更多
Dear Editor,Hepatocellular carcinoma(HCC),the most common pathological type of primary liver cancer,ranks as the third deadliest cancer.Despite the progress of surgical resection in recent years,the 5-year survival of...Dear Editor,Hepatocellular carcinoma(HCC),the most common pathological type of primary liver cancer,ranks as the third deadliest cancer.Despite the progress of surgical resection in recent years,the 5-year survival of HCC patients is still unsatisfactory due to the frequent relapse and chemoresistance.Accumulating evidence has demonstrated that liver cancer stem cells(CSCs)are critical for HCC chemoresistance and recurrence.Nevertheless,the molecular mechanisms of liver CSC regulation remain unclear,which hampers the development of the therapeutic strategy that targets liver CSCs.展开更多
In recent decades, diseases concerning the gut microbiota have presented some of the most serious public health problems worldwide. The human host＇s physiological status is influenced by the intestinal microbiome, th...In recent decades, diseases concerning the gut microbiota have presented some of the most serious public health problems worldwide. The human host＇s physiological status is influenced by the intestinal microbiome, thus integrating external factors, such as diet, with genetic and immune signals. The notion that chronic inflammation drives carcinogenesis has been widely established for various tissues. It is surprising that the role of the microbiota in tumorigenesis has only recently been recognized, given that the presence of bacteria at tumor sites was first described more than a century ago. Extensive epidemiological studies have revealed that there is a strong link between the gut microbiota and some common cancers. However, the exact molecular mechanisms linking the gut microbiota and cancer are not yet fully understood. Changes to the gut microbiota are instrumental in determining the occurrence and progression of hepatocarcinoma, chronic liver diseases related to alcohol, nonalcoholic fatty liver disease （NAFLD）, and cirrhosis. To be specific, the gut milieu may play an important role in systemic inflammation, endotoxemia, and vasodilation, which leads to complications such as spontaneous bacterial peritonitis and hepatic encephalopathy. Relevant animal studies involving gut microbiota manipulations, combined with observational studies on patients with NAFLD, have provided ample evidence pointing to the contribution of dysbiosis to the pathogenesis of NAFLD. Given the poor prognosis of these clinical events, their prevention and early management are essential. Studies of the composition and function of the gut microbiota could shed some light on understanding the prognosis because the microbiota serves as an essential component of the gut milieu that can impact the aforementioned clinical events. As far as disease management is concerned, probiotics may provide a novel direction for therapeutics for hepatocellular carcinoma （HCC） and NAFLD, given that probiotics function as a type of medicine that can improve human health by regulating the immune system. Here, we provide an overview of the relationships among the gut microbiota, tumors, and liver diseases. In addition, considering the significance of bacterial homeostasis, we discuss probiotics in this article in order to guide treatments for related diseases.展开更多
Hepatitis B virus(HBV)is the most common cause of hepatocellular carcinoma(HCC),which is the predominant liver cancer type in Southeast Asia.Approximately 350 million individuals suffer from persistent hepatitis B inf...Hepatitis B virus(HBV)is the most common cause of hepatocellular carcinoma(HCC),which is the predominant liver cancer type in Southeast Asia.Approximately 350 million individuals suffer from persistent hepatitis B infection worldwide.HBV promotes HCC development through direct and indirect mechanisms.HBV DNA integrates into the host genome during the initial stages of tumorigenesis,causing insertional mutagenesis of cancer-related genes and genomic instability.Extrachromosomal circular DNA(ecDNA)is formed,which is efficiently amplified in large quantities to express viral genes and host oncogenes.Moreover,virus-associated proteins,such as the regulatory HBV X(HBx)protein and/or the modified preS/S envelope protein,alter the expression of genes associated with multiple functions in host cells.In this review,we summarize the role of the HBx and preS/S proteins in promoting tumorigenesis.In addition to summarizing the specific mechanism of HBV-related tumorigenesis,the concerns and perspectives for future study are discussed.展开更多
Zinc-dependent histone deacetylases(HDACs)are pivotal enzymes governing the epigenetic modulation of gene expression through chromatin remodeling.The dysregulated expression of HDACs is intricately linked to various p...Zinc-dependent histone deacetylases(HDACs)are pivotal enzymes governing the epigenetic modulation of gene expression through chromatin remodeling.The dysregulated expression of HDACs is intricately linked to various pathological conditions,including cancer and inflammation.Histone deacetylase inhibitors(HDACi)have shown therapeutic potential in certain hematologic malignancies.However,the clinical performance of HDACi in solid tumors remains unsatisfactory,and the precise mechanisms of its therapeutic effect in solid tumors has not been fully elucidated.In this study,we identified nucleus-localized PFKL(Liver-type phosphofructokinase),as a key regulator of HDACi efficacy and intracellular epigenetic dynamics.Nuclear PFKL directly binds to classⅠHDACs through interacting with zinc-binding sites,thereby inhibiting HDAC enzymatic activity and promoting intracellular histone acetylation.In addition,the Thr562 residue within PFKL enhances the chelation effect between the zinc-binding group(ZBG)of the HDACi romidepsin and the zinc within the HDACs,further promoting drug efficacy.Based on the mechanism of PFKL facilitates the efficacy of romidepsin,we developed a therapeutic peptide,PFKL-552-572-R8,which significantly enhances the antitumor effect of romidepsin both in vitro and in vivo.Our findings reveal that spatiotemporal regulation confers a moonlight function to PFKL as an endogenous HDAC inhibitor to maintain the stability of epigenetic modifications and highlight PFKL as a promising therapeutic target for enhancing the clinical utility of HDACi in solid tumors.展开更多
Background and Aims:Given the high burden of hepatocellular carcinoma(HCC),risk stratification in patients with cirrhosis is critical but remains inadequate.In this study,we aimed to develop and validate an HCC predic...Background and Aims:Given the high burden of hepatocellular carcinoma(HCC),risk stratification in patients with cirrhosis is critical but remains inadequate.In this study,we aimed to develop and validate an HCC prediction model by integrating radiomics and deep learning features from liver and spleen computed tomography(CT)images into the established age-male-ALBI-platelet(aMAP)clinical model.Methods:Patients were enrolled between 2018 and 2023 from a Chinese multicenter,prospective,observational cirrhosis cohort,all of whom underwent 3-phase contrast-enhanced abdominal CT scans at enrollment.The aMAP clinical score was calculated,and radiomic(PyRadiomics)and deep learning(ResNet-18)features were extracted from liver and spleen regions of interest.Feature selection was performed using the least absolute shrinkage and selection operator.Results:Among 2,411 patients(median follow-up:42.7 months[IQR:32.9–54.1]),118 developed HCC(three-year cumulative incidence:3.59%).Chronic hepatitis B virus infection was the main etiology,accounting for 91.5%of cases.The aMAP-CT model,which incorporates CT signatures,significantly outperformed existing models(area under the receiver-operating characteristic curve:0.809–0.869 in three cohorts).It stratified patients into high-risk(three-year HCC incidence:26.3%)and low-risk(1.7%)groups.Stepwise application(aMAPaMAP-CT)further refined stratification(three-year incidences:1.8%[93.0%of the cohort]vs.27.2%[7.0%]).Conclusions:The aMAP-CT model improves HCC risk prediction by integrating CT-based liver and spleen signatures,enabling precise identification of high-risk cirrhosis patients.This approach personalizes surveillance strategies,potentially facilitating earlier detection and improved outcomes.展开更多
Berberine has been shown to reduce acute liver injury although the underlying mechanism is not fully understood. Because of the anatomic connection, the liver is constantly exposed to gut-derived bacterial products an...Berberine has been shown to reduce acute liver injury although the underlying mechanism is not fully understood. Because of the anatomic connection, the liver is constantly exposed to gut-derived bacterial products and metabolites. In this study, we showed that berberine has beneficial effects on both hepatotoxicity and intestinal damage in a rat model of chronic or acute liver injury. Microbiota transplantation from the rats with chronic hepatotoxicity could aggravate acute hepatotoxicity in mice treated with diethylnitrosamine(DEN). In rat models with gut homeostasis disruption induced by penicillin or dextran sulfate sodium(DSS), their fecal microbiota could also cause an enhanced hepatotoxicity of recipient mice. When treated with berberine,the DSS-induced enteric dysbacteriosis could be mitigated and their fecal bacteria were able to reduce acute hepatotoxicity in recipient mice. This study indicates that berberine could improve intestinal dysbacteriosis, which reduces the hepatotoxicity caused by pathological or pharmacological intervention. Fecal microbiota transplantation might be a useful method to directly explore homeostatic alteration in gut microbiota.展开更多
Tumor immune microenvironment is closely related to tumor initiation,prognosis,and response to immunotherapy.The immune landscapes,number of infiltrating immune cells,and the localization of lymphocytes in the tumor v...Tumor immune microenvironment is closely related to tumor initiation,prognosis,and response to immunotherapy.The immune landscapes,number of infiltrating immune cells,and the localization of lymphocytes in the tumor vary in across different types of tumors.The immune contexture in cancer,which is determined by the density,composition,functional state and organization of the leukocyte infiltrate of the tumor,can yield information relevant to the prediction of treatment response and patients’prognosis.Better understanding of the immune atlas in human tumors have been achieved with the development and application of single-cell analysis technology,which has provided a reference for prognosis,and insights on new targets for immunotherapy.In this review,we summarized the different characteristics of immune contexture in cancer defined by a variety of single-cell techniques,which have enhanced our understanding on the pathophysiology of the tumor microenvironment.We believe that there are much more to be uncovered in this rapidly developing field of medicine,and they will predict the prognosis of cancer patients and guide the rational design of immunotherapies for success in cancer eradication.展开更多
Liver cancer is one of the most common causes of cancer-related death worldwide and mainly includes hepatocellular carcinoma(HCC)and cholangiocarcinoma(CCA).Extracellular vesicles(EVs)are membrane-derived nanometer-si...Liver cancer is one of the most common causes of cancer-related death worldwide and mainly includes hepatocellular carcinoma(HCC)and cholangiocarcinoma(CCA).Extracellular vesicles(EVs)are membrane-derived nanometer-sized vesicles that can be released by different cell types under normal and pathological conditions and thus play important roles in the transmission of biological information between cells.Increasing evidence suggests that liver cancer cell-derived EVs may help establish a favorable microenvironment to support the proliferation,invasion and metastasis of cancer cells.In this review,we summarized the role of EVs in the tumor microenvironment(TME)during the development and progression of liver cancer.As messenger carriers,EVs are loaded by various biomolecules,such as proteins,RNA,DNA,lipids and metabolites,making them potential liquid biopsy biomarkers for the diagnosis and prognosis of liver cancer.We also highlighted the progress of EVs as antigen carriers and EV-based therapeutics in preclinical studies of liver cancer.展开更多
基金supported by grants from the State Key Project for Liver Cancer(2017ZX10203206)the National Key Research and Development Program(2017YFC0906900)+2 种基金the National Natural Science Foundation of China(813700 6 6,81670516)the Funds for Creative Research Groups of China(81521091)the Precision Medicine Project of Second Military Medical University(2017JZ30)
文摘Background: Increasing evidence indicates that Six2 contributes to tumorigenesis in various tumor in- cluding hepatocellular carcinoma (HCC). This study aimed to determine the role of Six2 in HCC and to elucidate the association of Six2 with clinical pathological characteristics. Methods: The expressions of Six2 in HCC tumor, para-tumor tissue and portal vein tumor thrombus (PVTT) were detected by tissue microarray technique, immunohistochemistry, real-time RT-PCR and West- ern blotting. Chi-square and Kaplan-Meier analysis were used to analyze the correlation between Six2 expression and prognosis of HCC patients. Lentivirus mediated Six2 knockdown, spheroid formation as- say, proliferation assay and subcutaneous tumor implantation were performed to determine the function of Six2. Results: In 274 HCC samples, Six2 was strongly expressed. Kaplan-Meier analysis revealed that high ex- pression of Six2 was correlated with a shorter overall survival (OS) and disease-free survival (DFS). More- over, Six2 expression was associated with sex, alpha-fetoprotein, tumor size and portal vein invasion. Six2 was highly expressed in PVTT. Six2 knockdown inhibited HCC cell lines proliferation, migration, and self-renewal in vitro and in vivo. In addition, low-expression of Six2 weakened TGF-β induced Smad4 activation and epithelial-mesenchymal transition in HCC cell lines. Conclusions: Elevated Six2 expression in HCC tumor patients was associated with negative prognosis. Upregulated Six2 promoted tumor growth and facilitated HCC metastasis via TGF-β/Smad signal pathway.
基金supported by the National Research Program of China(Grant Nos.2017YFA0505803 and 2017YFC0908100)the State Key Project for Infectious Diseases(Grant Nos.2018ZX10732202-001 and 2018ZX10302207-004)the National Natural Science Foundation of China(Grant Nos.81790633,61922047,and 81902412).
文摘The Wnt/β-catenin signaling pathway regulates many aspects of tumor biology,and many studies have focused on the role of this signaling pathway in tumor cells.However,it is now clear that tumor development and metastasis depend on the two-way interaction between cancer cells and their environment,thereby forming a tumor microenvironment(TME).In this review,we discuss how Wnt/β-catenin signaling regulates cross-interactions among different components of the TME,including immune cells,stem cells,tumor vasculature,and noncellular components of the TME in hepatocellular carcinoma.We also investigate their preclinical and clinical insights for primary liver cancer intervention,and explore the significance of using Wnt/β-catenin mutations as a biomarker to predict resistance in immunotherapy.
基金the National Natural Science Foundation of China,No.39770379the National Basic Research Project("973")SUGEN,USA.
文摘AIM To clone and identify the whole cDNA ofMXR7 gene and to find out its expression inhuman HCC,and normal tissues.METHODS The DNA primers were designed andsynthesized according to the whole cDNAsequence of MXR? gene.The cDNA of humanHCC was taken as the template while the cDNA ofMXR7 gene was synthesized by polymerasechain reaction（PCR）.Recombinant DNAconforming to reading frame was constructed byconnecting purified PCR product of the cDNA ofMXR? gene with expression vector pGEX-5X-1 offusion protein.The plasmid MXRT/pGEX-5X-1was identified by sequencing.Using <sup>32</sup>p labeledMXR? cDNA as probe,MXR7 mRNA expressionwas detected by Northern blot analysis in 12different human normal tissues,7 preoperativelyuntreated non-liver tumor tissues,30preoperatively untreated HCC,theparacancerous liver tissues and 12 normal livertissues samples.RESULTS Restriction enzyme and sequenceanalysis confirmed that the insertion sequence invector pGEX-5X-1 was the same as the cDNAsequence of MXR7 gene.Northern blot analysisshowed no expression of MXR? mRNA in 12 kindsof normal human tissues including liver,7 tumortissues in other sites and 12 normal livertissues,the frequencies of MXR7 mRNA expression in HCC and paracancerous livertissues were 76.6% and 13.3%,respectively.The frequency of MXR7 mRNA expression in HCCwithout elevation of serum AFP and in HCC【5cm was 90%（9/10）and 83.3%（5/6）,respectively.CONCLUSION MXR7 mRNA is highly expressedin human HCC,which is specific and occurs at anearly stage of HCC,suggesting MXR7 mRNA canbe a tumor biomarker for HCC.The detection ofMXR7 mRNA expression in the biopsied livertissue is helpful in discovering early subclinicalliver cancer in those with negative serum AFP.
文摘AIM： To investigate the relationship between the expression of P120 and the clinicopathologic parameters in intrahepatic cholangiocarcinoma （ICC）. METHODS： An immunohistochemical study of E-cadherin and P120 catenin was performed on 42 specimens of ICC with a Dako Envision kit. RESULTS： The expression of E-cadherin and P120 was reduced in 27 cases （64.3%） and 31 cases （73.8%）, respectively. Both E-cadherin and P120 expressions were significantly correlated with the tumor histological grade （χ^2 = 9.333, P = 009 and χ^= 11.71, P = 0.003）, TNM stage （χ^= 8.627, P = 0.035 and χ^= 13.123, P = 0.004）, intrahepatic metastasis （χ^= 7.292, P = 0.007 and χ^= 4.657, P = 0.041, respectively） and patients′ survival （χ^= 6.351, P = 0.002 and χ^= 4.023, P = 0.000, respectively）. In addition, the expression of P120 was in concordance with that of E-cadherin （χ^ = 13.797, P = 0.000）, indicating that the expression of P120 may be dependent on that of E-cadherin. Finally, only P120 expression was found to be an independent prognostic factor in Cox regression model （r = 0.088, P = 0.049）. CONCLUSION： Down-regulated expression of E-cadherin and P120 occurs frequently in ICC and contributes to the progression and development of tumor. Both of them may be valuable biologic markers for predicting tumor invasion, metastasis and patients′ survival, but only P120 is an independent prognostic factor for ICC.
基金supported by the China National Funds for the Science Fund for Creative Research Groups (No: 81221061)The State Key Project on Infections Diseases of China (2012zx10002016016003)+4 种基金China National Funds for the Distinguished Young Scientists (No: 81125018)National Natural Science Foundation(No: 81071750, 81101831, 81101511)New Excellent Talents Program of Shanghai Municipal Health Bureau (No:XBR2011025)Shanghai Scienceand Technology Committee (No. 134119a020010JC1417600)
文摘Objective： Portal vein metastasis of hepatocellular carcinoma（HCC） results in a poor prognosis and seriously affects the survival rate of patients. The mechanism underlying the formation of portal vein tumor thrombus（PVTT） is complex and is not yet fully understood. This study was conducted to investigate the impact of portal vein blood on the proliferation, metastasis, invasion and apoptosis of PVTT cells and to explore its possible mechanisms, which was expected to lay a foundation for ascertaining the mechanism underlying the portal vein metastasis of HCC.Methods： Peripheral blood and portal vein blood were collected from patients with HCC, and the sera from these two sources were used to culture the PVTT-originated HCC cell line CSQT-2. The cells were collected after 24 h, and flow cytometry was performed to detect cell proliferation, cell cycle stages and apoptosis. Transwell migration and invasion assays were applied to detect the metastasis and invasion of the cells in each group. The changes in the expression of MMP-2 and MMP-9 in cells were detected via Western blotting. The contents of IL-12, IFN-γ, IL-1β, IL-2 and TNF-α in the two groups of sera were quantified using corresponding kits. Results： Compared with the group of cells cultured with peripheral serum, the cells cultured with portal vein serum showed significantly lower apoptosis（P〈0.01）, significantly enhanced cell metastasis and invasion（P〈0.01）, whereas cell proliferation and the stages of the cell cycle did not differ significantly（P〉0.05）. A significantly increased expression level of MMP-2 has been observed in tumor cells treated portal vein serum. In addition, compared with peripheral serum, the content of IL-12 was significantly decreased in portal vein serum（P〈0.05）, while the contents of IFN-γ, IL-1β, IL-2, and TNF-α did not differ significantly（P〈0.05）. Conclusions： Portal vein serum from HCC patients could inhibit the apoptosis of PVTT-originated HCC cells and promote cell metastasis and invasion. This effect may be related to the lower level of IL-12 in portal vein serum.
基金National Natural Science Foundation of China(Nos.22107029,22377135,22305178,92253306 and 82130099)the Taishan Scholars Program(No.tsqn202312305)+7 种基金the Young Elite Scientists Sponsorship Program by Chinese Chemical Societythe Fundamental Research Projects of Science&Technology Innovation and development Plan in Yantai City(No.2023JCYJ059)the Shandong Laboratory Program(No.SYS202205)the Fundamental Research Funds for the Central Universities(No.222201717003)the Programme of Introducing Talents of Discipline to Universities(No.B16017)the Open Funding Project of the State Key Laboratory of Bioreactor Engineeringthe State Key Laboratory of Drug Research(No.SKLDR-2023-KF-10)the Ministry of Education Key Laboratory on signaling Regulation and Targeting Therapy of Liver Cancer(Naval Medical University)(No.2023-MEKLLCMS/ZD-00*)。
文摘Non-alcoholic fatty liver disease(NAFLD)is prevalent worldwide as a chronic liver disease that not only gives rise to hepatic complications,but leads to other chronic diseases such as type 2 diabetes and atherosclerosis.The aberrant accumulation of lipid droplets(LDs)in hepatocytes is a prominent signature of NAFLD.However,conventional techniques lack the capability to effectively monitor the dynamic changes in LD levels during NAFLD with living organisms.Hence,it is imperative to develop LD-specific long-wavelength fluorescent probes with high imaging contrast for the in-situ diagnosis of NAFLD.In this study,we synthesized a new LD-selective long-wavelength fluorescent probe,denoted as LD-1,based on the twisted intramolecular charge transfer(TICT)mechanism.The probe exhibits a large Stokes shift and intensive fluorescence emission in nonpolar and viscous solutions.By self-assembling LD-1 with bovine serum albumin(BSA),a biocompatible,long-wavelength fluorescent probe hybrid,LD-1@BSA,was formed,allowing for LDs to be selectively imaged in hepatocytes.Moreover,LD-1@BSA successfully discriminates NAFLD cells before and after drug treatment,and achieves non-invasive and real-time monitoring of LD accumulation in a mouse model of NAFLD.
基金supported by the National Natural Science Foundation of China(no.82173146)the Shanghai Science and Technology Committee Rising-Star Program(no.21QA1411700).
文摘Tumor-associated macrophages(TAMs)actively interact with the tumor microenvironment(TME).The dynamic communication between TAMs and the TME is closely associated with tumorigenesis,progression,metastasis,and drug resistance.With the development of single-cell sequencing,specific TAMs have been identified,and their roles in the TME were explored.With the development of an under-standing of the interactions between TAMs and the TME,targeting TAMs has become a new treatment strategy for cancer therapy be-cause of their high plasticity.In this review,we highlight strategies for remodeling TAMs based on targeting specific genes involved in reg-ulating TAM phenotypes,blocking the crosstalk between TAMs and the TME,and targeting abnormal metabolic pathways.Moreover,we provided perspectives on the translational potential of targeting TAMs for cancer treatment,which could shed light on TAM-based thera-peutic strategy in the future.
文摘Objective：To obtain information at the molecular level on the possible mechanism of MXR7 gene overexpressed in hepatocellular carcinoma （HCC） and also to provide a clue for further study. Methods：Genomic DNA was isolated from 20 samples of hepatoma and paired non-HCC liver tissues, 2 cases of blood tumor and two types of cells （HepG2, MCF-7） and digested with two kinds of endonucleases （EcoR I and Eag I which is methylation sensitive endonuclease）. And the condition of MXR7 gene methylation was examined and analyzed by Southern blot. Results： MXR7 was unmethylated neither in tested tumorous liver samples nor in paired non HCC liver tissues. In addition, the same result was found in 2 blood tumor samples and HepG2. Only two paired samples had different methylation outcome, one was unmethylated and the other was partly methylated. Conclusion： MXR7 is unmethylated in HHC, suggesting methylation of MXR7 may have no relation with its expression and regulation.
基金the National Natural Science Foundation of China(U21A20376,82102871,81988101,81903184,81790633,and 81830054)the Innovation Program of Shanghai Municipal Education Commission(2019-01-07-00-07E00065)+1 种基金the National Science Foundation of Shanghai(21XD1404600,21JC1406600,and 22140901000)the China Postdoctoral Science Foundation(2020M671007).
文摘The application of tumor antigen-based immunotherapy is hindered by the rarity of validated immunogenic peptides.In this study,we aimed to investigate the potential of circular RNAs(circRNAs)as a novel source of tumor antigen peptides in hepatobiliary tumor organoids.Using RNA-sequencing(RNA-seq)with an algorithm-based score tool,3950 translated tumor-specific circRNAs were predicted to generate 18971 antigen peptides in 27 organoids.In view of the antigen landscape,11 amino acid length(mer)peptides and human leukocyte antigen(HLA)-A binding peptides harbored the highest immunogenicity-related scores.In three out of five analyzed organoids,13 predicted antigen peptides were directly confirmed as HLA-A,-B,and-C(HLA-ABC)binding peptides with mass spectrometry(MS)-based immunopeptidomics.CircRNA-derived tumor-specific peptides presented by the HLA-ABC molecules stimulated cluster of differentiation 8(CD8)T cells to exhibit increased CD107a interferonγ(IFNγ)co-expressions and IFNγsecretion in flow cytometry and enzyme-linked immunosorbent assay(ELISA).Cytotoxic T cell activity targeting the organoids,induced by the immunogenic circRNA-derived peptides,was verified in a killing assay.Notably,the antigen peptide YGFNEILKK from circTBC1D15 was not only recognized as an HLA-ABC-presented peptide of the organoids but also drastically reduced the tumor organoid survival rate.Our findings highlight a crucial subset for generating tumor antigens,which has implications for targeting tumor-specific circRNAs in cancers.
基金supported by the grants from the Outstanding Academic Leaders Plan of Shanghai [Grant No.2018BR07]the National Science Foundation of China [Grant No.81572061]+1 种基金Program for Young Medical Technicians(Clinical Examination)in Shanghai [2016]05Shanghai Health and Family Planning Commission Clinical Research Project for Health Industry [Grant No.20184Y0199]
文摘The development of cancer is a complex process that requires the participation of many factors,including mutations in genes, regulation of signaling pathways, disruption of homeostasis, and failure of self-monitoring mechanisms. Sufficient evidence has
基金This work was supported by the grants from the National Key Research and Developm ent Program of China 2017YFA0504503National Natural Science Foundation of China(NSFC)81972777 and 82003161+3 种基金Program of Shanghai Academ ic Research Leader(18XD1405400)Natural Science Foundation of Shanghai(20ZR145770)the Shanghai Key Laboratory of Cell Engineering(14DZ2272300)Shanghai Sailing Project(20YF1459600)from the Science and Technology Commission of Shanghai Municipality.
文摘Dear Editor,Hepatocellular carcinoma(HCC),the most common pathological type of primary liver cancer,ranks as the third deadliest cancer.Despite the progress of surgical resection in recent years,the 5-year survival of HCC patients is still unsatisfactory due to the frequent relapse and chemoresistance.Accumulating evidence has demonstrated that liver cancer stem cells(CSCs)are critical for HCC chemoresistance and recurrence.Nevertheless,the molecular mechanisms of liver CSC regulation remain unclear,which hampers the development of the therapeutic strategy that targets liver CSCs.
基金This research was supported by grants from National Natural Science Foundation of China （81521091）, the Shanghai Key Laboratory of Hepatobiliary Tumor Biology, and the Ministry of Education （MOE） Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer.
文摘In recent decades, diseases concerning the gut microbiota have presented some of the most serious public health problems worldwide. The human host＇s physiological status is influenced by the intestinal microbiome, thus integrating external factors, such as diet, with genetic and immune signals. The notion that chronic inflammation drives carcinogenesis has been widely established for various tissues. It is surprising that the role of the microbiota in tumorigenesis has only recently been recognized, given that the presence of bacteria at tumor sites was first described more than a century ago. Extensive epidemiological studies have revealed that there is a strong link between the gut microbiota and some common cancers. However, the exact molecular mechanisms linking the gut microbiota and cancer are not yet fully understood. Changes to the gut microbiota are instrumental in determining the occurrence and progression of hepatocarcinoma, chronic liver diseases related to alcohol, nonalcoholic fatty liver disease （NAFLD）, and cirrhosis. To be specific, the gut milieu may play an important role in systemic inflammation, endotoxemia, and vasodilation, which leads to complications such as spontaneous bacterial peritonitis and hepatic encephalopathy. Relevant animal studies involving gut microbiota manipulations, combined with observational studies on patients with NAFLD, have provided ample evidence pointing to the contribution of dysbiosis to the pathogenesis of NAFLD. Given the poor prognosis of these clinical events, their prevention and early management are essential. Studies of the composition and function of the gut microbiota could shed some light on understanding the prognosis because the microbiota serves as an essential component of the gut milieu that can impact the aforementioned clinical events. As far as disease management is concerned, probiotics may provide a novel direction for therapeutics for hepatocellular carcinoma （HCC） and NAFLD, given that probiotics function as a type of medicine that can improve human health by regulating the immune system. Here, we provide an overview of the relationships among the gut microbiota, tumors, and liver diseases. In addition, considering the significance of bacterial homeostasis, we discuss probiotics in this article in order to guide treatments for related diseases.
基金supported by the National Natural Science Foundation of China(grant numbers:81988101,82173146,U21A20376,82425038,and 82421005)the Natural Science Foundation of Shanghai(grant numbers:22140901000 and 21XD1404600)the National Key R&D Program of China(grant numbers:2023YFC2507500).
文摘Hepatitis B virus(HBV)is the most common cause of hepatocellular carcinoma(HCC),which is the predominant liver cancer type in Southeast Asia.Approximately 350 million individuals suffer from persistent hepatitis B infection worldwide.HBV promotes HCC development through direct and indirect mechanisms.HBV DNA integrates into the host genome during the initial stages of tumorigenesis,causing insertional mutagenesis of cancer-related genes and genomic instability.Extrachromosomal circular DNA(ecDNA)is formed,which is efficiently amplified in large quantities to express viral genes and host oncogenes.Moreover,virus-associated proteins,such as the regulatory HBV X(HBx)protein and/or the modified preS/S envelope protein,alter the expression of genes associated with multiple functions in host cells.In this review,we summarize the role of the HBx and preS/S proteins in promoting tumorigenesis.In addition to summarizing the specific mechanism of HBV-related tumorigenesis,the concerns and perspectives for future study are discussed.
基金supported by grants from the National Key R&D Program of China(2022YFC2503704 to L.-W.D.)the National Natural Science Foundation of China(81988101and 91859205 to H.-Y.W.,82473208 to L.-W.D.,92253306 to Y.-X.T.,and 32270814 and 92359301 to T.-Y.J.)+1 种基金Open Project of State Key Laboratory of Systems Medicine for Cancer(KF2125-93 to L.-W.D.)Shanghai Science and Technology Committee Rising-Star Program(24QA2711800 to T.-Y.J.).
文摘Zinc-dependent histone deacetylases(HDACs)are pivotal enzymes governing the epigenetic modulation of gene expression through chromatin remodeling.The dysregulated expression of HDACs is intricately linked to various pathological conditions,including cancer and inflammation.Histone deacetylase inhibitors(HDACi)have shown therapeutic potential in certain hematologic malignancies.However,the clinical performance of HDACi in solid tumors remains unsatisfactory,and the precise mechanisms of its therapeutic effect in solid tumors has not been fully elucidated.In this study,we identified nucleus-localized PFKL(Liver-type phosphofructokinase),as a key regulator of HDACi efficacy and intracellular epigenetic dynamics.Nuclear PFKL directly binds to classⅠHDACs through interacting with zinc-binding sites,thereby inhibiting HDAC enzymatic activity and promoting intracellular histone acetylation.In addition,the Thr562 residue within PFKL enhances the chelation effect between the zinc-binding group(ZBG)of the HDACi romidepsin and the zinc within the HDACs,further promoting drug efficacy.Based on the mechanism of PFKL facilitates the efficacy of romidepsin,we developed a therapeutic peptide,PFKL-552-572-R8,which significantly enhances the antitumor effect of romidepsin both in vitro and in vivo.Our findings reveal that spatiotemporal regulation confers a moonlight function to PFKL as an endogenous HDAC inhibitor to maintain the stability of epigenetic modifications and highlight PFKL as a promising therapeutic target for enhancing the clinical utility of HDACi in solid tumors.
基金supported by the National Key Research and Development Program of China(2022YFC2304800,2022YFC2303600,2023YFC2507500)the National Natural Science Foundation of China(82170610,92359304)the Guangdong Basic and Applied Basic Research Foundation(2023A1515011211).
文摘Background and Aims:Given the high burden of hepatocellular carcinoma(HCC),risk stratification in patients with cirrhosis is critical but remains inadequate.In this study,we aimed to develop and validate an HCC prediction model by integrating radiomics and deep learning features from liver and spleen computed tomography(CT)images into the established age-male-ALBI-platelet(aMAP)clinical model.Methods:Patients were enrolled between 2018 and 2023 from a Chinese multicenter,prospective,observational cirrhosis cohort,all of whom underwent 3-phase contrast-enhanced abdominal CT scans at enrollment.The aMAP clinical score was calculated,and radiomic(PyRadiomics)and deep learning(ResNet-18)features were extracted from liver and spleen regions of interest.Feature selection was performed using the least absolute shrinkage and selection operator.Results:Among 2,411 patients(median follow-up:42.7 months[IQR:32.9–54.1]),118 developed HCC(three-year cumulative incidence:3.59%).Chronic hepatitis B virus infection was the main etiology,accounting for 91.5%of cases.The aMAP-CT model,which incorporates CT signatures,significantly outperformed existing models(area under the receiver-operating characteristic curve:0.809–0.869 in three cohorts).It stratified patients into high-risk(three-year HCC incidence:26.3%)and low-risk(1.7%)groups.Stepwise application(aMAPaMAP-CT)further refined stratification(three-year incidences:1.8%[93.0%of the cohort]vs.27.2%[7.0%]).Conclusions:The aMAP-CT model improves HCC risk prediction by integrating CT-based liver and spleen signatures,enabling precise identification of high-risk cirrhosis patients.This approach personalizes surveillance strategies,potentially facilitating earlier detection and improved outcomes.
基金supported by the projects of the National Key Research Program of China (2016YFC1101402)the National Natural Science Foundation of China (31371440, 31571477)Program of Shanghai Academic/Technology Research Leader (16XD1403300)
文摘Berberine has been shown to reduce acute liver injury although the underlying mechanism is not fully understood. Because of the anatomic connection, the liver is constantly exposed to gut-derived bacterial products and metabolites. In this study, we showed that berberine has beneficial effects on both hepatotoxicity and intestinal damage in a rat model of chronic or acute liver injury. Microbiota transplantation from the rats with chronic hepatotoxicity could aggravate acute hepatotoxicity in mice treated with diethylnitrosamine(DEN). In rat models with gut homeostasis disruption induced by penicillin or dextran sulfate sodium(DSS), their fecal microbiota could also cause an enhanced hepatotoxicity of recipient mice. When treated with berberine,the DSS-induced enteric dysbacteriosis could be mitigated and their fecal bacteria were able to reduce acute hepatotoxicity in recipient mice. This study indicates that berberine could improve intestinal dysbacteriosis, which reduces the hepatotoxicity caused by pathological or pharmacological intervention. Fecal microbiota transplantation might be a useful method to directly explore homeostatic alteration in gut microbiota.
基金This work was supported by the State Key Project for Liver Cancer(2018ZX10732202-001)the National Research Program of China(2017YFA0505803,2017YFC0908100)+1 种基金National Natural Science Foundation of China(81790633,91729303,81672860,81702298 and 81422032)National Natural Science Foundation of Shanghai(17ZR143800)
文摘Tumor immune microenvironment is closely related to tumor initiation,prognosis,and response to immunotherapy.The immune landscapes,number of infiltrating immune cells,and the localization of lymphocytes in the tumor vary in across different types of tumors.The immune contexture in cancer,which is determined by the density,composition,functional state and organization of the leukocyte infiltrate of the tumor,can yield information relevant to the prediction of treatment response and patients’prognosis.Better understanding of the immune atlas in human tumors have been achieved with the development and application of single-cell analysis technology,which has provided a reference for prognosis,and insights on new targets for immunotherapy.In this review,we summarized the different characteristics of immune contexture in cancer defined by a variety of single-cell techniques,which have enhanced our understanding on the pathophysiology of the tumor microenvironment.We believe that there are much more to be uncovered in this rapidly developing field of medicine,and they will predict the prognosis of cancer patients and guide the rational design of immunotherapies for success in cancer eradication.
基金supported by the National Natural Science Foundation of China(81802878,81722034,81572896,and 81773077)Shanghai Sailing Program(18YF1400200)+1 种基金National Major Scientific and Technological Special Project for“Significant New Drugs Development”&"Prevention and Control of Infectious Diseases"(2018ZX09101002)Shanghai Pujiang Program(2019PJD059).
文摘Liver cancer is one of the most common causes of cancer-related death worldwide and mainly includes hepatocellular carcinoma(HCC)and cholangiocarcinoma(CCA).Extracellular vesicles(EVs)are membrane-derived nanometer-sized vesicles that can be released by different cell types under normal and pathological conditions and thus play important roles in the transmission of biological information between cells.Increasing evidence suggests that liver cancer cell-derived EVs may help establish a favorable microenvironment to support the proliferation,invasion and metastasis of cancer cells.In this review,we summarized the role of EVs in the tumor microenvironment(TME)during the development and progression of liver cancer.As messenger carriers,EVs are loaded by various biomolecules,such as proteins,RNA,DNA,lipids and metabolites,making them potential liquid biopsy biomarkers for the diagnosis and prognosis of liver cancer.We also highlighted the progress of EVs as antigen carriers and EV-based therapeutics in preclinical studies of liver cancer.
