Background:The effective treatment for hepatocellular carcinoma(HCC)depends on early diagnosis.Previously,the abnormal expression of Wnt3a as the key signaling molecule in the Wnt/β-catenin pathway was found in HCC c...Background:The effective treatment for hepatocellular carcinoma(HCC)depends on early diagnosis.Previously,the abnormal expression of Wnt3a as the key signaling molecule in the Wnt/β-catenin pathway was found in HCC cells and could be released into the circulation.In this study,we used rat model of hepatocarcinogenesis to dynamically investigate the alteration of oncogenic Wnt3a and to explore its early monitor value for HCC.Methods:Sprague-Dawley rats(SD)were fed with diet 2-fluorenylacetamide(2-FAA,0.05%)for inducing hepatocarcinogenesis,and grouped based on liver morphological alteration by Hematoxylin&Eosin(H&E)staining;rats fed with normal chow were used as normal control(NC).Total RNA and protein were purified from rat livers.Differently expressed genes(DEGs)or Wnt3a m RNA,cellular distribution,and Wnt3a protein levels were analyzed by whole genome microarray with signal logarithm ratio(SLR log 2 cy5/cy3),immunohistochemistry,and enzyme-linked immunosorbent assay,respectively.Results:Models of rat hepatocarcinogenesis were successfully established based on liver histopathological H&E staining.Rats were divided into the cell degeneration(r Deg),precancerosis(r Pre-C)and HCC(r HCC)groups.Total numbers of the up-and down-regulated DEGs with SLR≥8 were 55 and 48 in the r Deg group,268 and 57 in the r Pre-C group,and 312 and 201 in the r HCC group,respectively.Significantly altered genes were involved in cell proliferation,signal transduction,tumor metastasis,and apoptosis.Compared with the NC group,Wnt3a m RNA was increased by 4.6 folds(P<0.001)in the r Deg group,7.4 folds(P<0.001)in the r Pre-C group,and 10.4 folds(P<0.001)in the r HCC group;the positive rates of liver Wnt3a were 66.7%(P=0.001)in the r Deg group,100%(P<0.001)in the r Pre-C group,and 100%(P<0.001)in the r HCC group,respectively.Also,there were significant differences of liver Wnt3a(P<0.001)or serum Wnt3a(P<0.001)among different groups.Conclusions:Overexpression of Wnt3a was associated with rat hepatocarcinogenesis and it should be expected to be a promising monitoring biomarker for HCC occurrence at early stage.展开更多
Liver cancer ranks sixth in cancer incidence,and is the third leading cause of cancer-related deaths worldwide.Hepatocellular carcinoma(HCC)is the most common type of liver cancer,which arises from hepatocytes and acc...Liver cancer ranks sixth in cancer incidence,and is the third leading cause of cancer-related deaths worldwide.Hepatocellular carcinoma(HCC)is the most common type of liver cancer,which arises from hepatocytes and accounts for approximately 70%-85%of cases.Hepatitis B virus(HBV)frequently causes liver inflammation,hepatic damage and subsequent cirrhosis.Integrated viral DNA is found in 85%-90%of HBV-related HCCs.Its presence in tumors from non-cirrhotic livers of children or young adults further supports the role of viral DNA integration in hepatocarcinogenesis.Integration of subgenomic HBV DNA fragments into different locations within the host DNA is a significant feature of chronic HBV infection.Integration has two potential consequences:(1)the host genome becomes altered("cis"effect);and(2)the HBV genome becomes altered("trans"effect).The cis effect includes insertional mutagenesis,which can potentially disrupt host gene function or alter host gene regulation.Tumor progression is frequently associated with rearrangement and partial gain or loss of both viral and host sequences.However,the role of integrated HBV DNA in hepatocarcinogenesis remains controversial.Modern technology has provided a new paradigm to further our understanding ofdisease mechanisms.This review summarizes the role of HBV DNA integration in human carcinogenesis.展开更多
Liver cancer is an aggressive disease with a high mortality rate. Management of liver cancer is strongly dependent on the tumor stage and underlying liver disease. Unfortunately, most cases are discovered when the can...Liver cancer is an aggressive disease with a high mortality rate. Management of liver cancer is strongly dependent on the tumor stage and underlying liver disease. Unfortunately, most cases are discovered when the cancer is already advanced, missing the opportunity for surgical resection. Thus, an improved understanding of the mechanisms responsible for liver cancer initiation and progression will facilitate the detection of more reliable tumor markers and the development of new small molecules for targeted therapy of liver cancer. Recently, there is increasing evidence for the "cancer stem cell hypothesis", which postulates that liver cancer originates from the malignant transformation of liver stem/progenitor cells(liver cancer stem cells). This cancer stem cell model has important significance for understanding the basic biology of liver cancer and has profound importance for the development of new strategies for cancer prevention and treatment. In this review, we highlight recent advances in the role of liver stem cells in hepatocarcinogenesis. Our review of the literature shows that identification of the cellular origin and the signaling pathways involved is challenging issues in liver cancer with pivotal implications in therapeutic perspectives. Although the dedifferentiation of mature hepatocytes/cholangiocytes in hepatocarcinogenesis cannot be excluded, neoplastic transformation of a stem cell subpopulation more easily explains hepatocarcinogenesis. Elimination of liver cancer stem cells in liver cancer could result in the degeneration of downstream cells, which makes them potential targets for liver cancer therapies. Therefore, liver stem cells could represent a new target for therapeutic approaches to liver cancer in the near future.展开更多
BACKGROUND Prevalence of nonalcoholic fatty liver disease(NAFLD)is rapidly increasing,and NAFLD has become one of the most common chronic liver diseases worldwide.With abnormal CD44 activation,the severe form of NAFLD...BACKGROUND Prevalence of nonalcoholic fatty liver disease(NAFLD)is rapidly increasing,and NAFLD has become one of the most common chronic liver diseases worldwide.With abnormal CD44 activation,the severe form of NAFLD can progress to liver cirrhosis and hepatocellular carcinoma(HCC).Thus,the molecular mechanism of CD44 in NAFLD needs to be identified.AIM To investigate the relationship between CD44 activation and malignant transformation of rat hepatocytes under nonalcoholic lipid accumulation.METHODS Sprague-Dawley rats were fed a high-fat(HF)for 12 wk to entice NAFLD and then with HF plus 2-fluorenylacetamide(0.05%)to induce HCC.Rats were sacrificed every 2 wk,and subsequently divided into the groups based on liver pathological examination(hematoxylin and eosin staining):NAFLD,denaturation,precancerosis,HCC,and control.Liver CD44 mRNA was detected by OneArray.Liver fat as assessed by Oil red O staining or CD44 by immunohistochemical assay was compared with their integral optic density.Serum CD44,alanine aminotransferase,aspartate aminotransferase,triglyceride,total cholesterol,and AFP levels were quantitatively tested.RESULTS Elevated CD44 was first reported in hepatocarcinogenesis,with increasing expression from NAFLD to HCC at the protein or mRNA level.The CD44 integral optic density values were significantly different between the control group and the NAFLD(t=25.433,P<0.001),denaturation(t=48.822,P<0.001),precancerosis(t=27.751,P<0.001),and HCC(t=16.239,P<0.001)groups,respectively.Hepatic CD44 can be secreted into the blood,and serum CD44 levels in HCC or precancerous rats were significantly higher(P<0.001)than those in any of the other rats.Positive correlations were found between liver CD44 and CD44 mRNA(rs=0.373,P=0.043)and serum CD44(rs=0.541,P=0.002)and between liver CD44 mRNA and serum CD44(rs=0.507,P=0.004).Moreover,significant correlations were found between liver CD44 and liver AFP(rs=0.572,P=0.001),between serum CD44 and serum AFP(rs=0.608,P<0.001),and between CD44 mRNA and AFP mRNA(rs=0.370,P=0.044).CONCLUSION The data suggested that increasing CD44 expression is associated with the malignant transformation of hepatocytes in NAFLD.展开更多
Hepatocellular carcinoma is on the rise and occurs in the setting of chronic liver disease and cirrhosis.Though treatment modalities are available,mortality from this cancer remains high.Medical therapy with the utili...Hepatocellular carcinoma is on the rise and occurs in the setting of chronic liver disease and cirrhosis.Though treatment modalities are available,mortality from this cancer remains high.Medical therapy with the utilization of biologic compounds such as the Food and Drug Administration approved sorafenib might be the only option that can increase survival.Immunotherapy,with modern pharmacologic developments,is a new frontier in cancer therapy and therefore the immunobiology of hepatocarcinogenesis is under investigation.This review will discuss current concepts of immunobiology in hepatocarcinogenesis along with current treatment modalities employing immunotherapy.The tumor microenvironment along with a variety of immune cells coexists and interplays to lead to tumorigenesis.Tumor infiltrating lymphocytes including CD8+ T cells,CD4+ T cells along with regulatory T cells,tumor associated macrophages,tumor associated neutrophils,myeloid derived suppressor cells,and natural killer cells interact to actively provide anti-tumor or pro-tumor effects.Furthermore,oncogenic pathways such as Raf/mitogenactivated protein kinase/extracellular-signal-regulated kinase pathway,phosphatidyl-3-kinase/AKT/mammalian target or rapamycin,Wnt/β-catenin,nuclear factor-κB and signal transducers and activators of transcription 3 may lead to activation and proliferation of tumor cells and are also considered cornerstones in tumorigenesis.Immunotherapy directed at this complex milieu of cells has been showned to be successful in cancer treatment.The use of vaccines,adoptive cell therapy and immune checkpoint inhibitor modulation are current options for therapy.Further translational research will shed light to concepts such as anti-tumor immunity which can add another alternative in the therapeutic armamentarium.展开更多
BACKGROUND: β-catenin has two distinct roles in E-cadherin mediated cell adhesion and carcinogenesis by activating the wnt/β-catenin signaling pathway. One occurs at the cell-adhesion site, where cadherins are linke...BACKGROUND: β-catenin has two distinct roles in E-cadherin mediated cell adhesion and carcinogenesis by activating the wnt/β-catenin signaling pathway. One occurs at the cell-adhesion site, where cadherins are linked to the actin-based cytoskeleton. The other takes place in the cytoplasm and nuclei and is thought to regulate cell transformation. We studied the role of β-catenin in hepatocarcinogenesis of rats. METHODS: Fresh liver specimens were obtained from normal rats. and atypical hyperplasia livers and hepatocarcinoma tissues from model rats. The changes of β-catenin in gene expression levels were detected by reverse transcriptase polymerase chain reaction (RT-PCR) in the different specimens separately. At the same time, their localization was observed immunohistochemically. RESULTS: In the normal liver specimens, β-catenin staining was seen in the cell membrane. In liver specimens of atypical byperplasia, β-catenin staining occurred in the cell cytoplasm of some cells as well as in the cell membrane of others. Immunohistochemically cancerous tissues showed the presence of β-catenin in the cytoplasm and nuclei. RTPCR revealed that the gene expression levels of β-catenin were same in all samples. CONCLUSIONS: The accumulation of β-catenin in the cytoplasm and/or nuclei frequently occurs in hepatocarcinogenesis of rats. It may be an early event in the development of hepatocarcinoma of rats.展开更多
Deregulated c-Myc expression is a hallmark of many human cancers. We have recently identified a role of mammalian homolog of yeast SPT-ADA-GCN5-acetyltransferas(SAGA) complex component, SAGAassociated factor 29(SGF29)...Deregulated c-Myc expression is a hallmark of many human cancers. We have recently identified a role of mammalian homolog of yeast SPT-ADA-GCN5-acetyltransferas(SAGA) complex component, SAGAassociated factor 29(SGF29), in regulating the c-Myc overexpression. Here, we discuss the molecular nature of SFG29 in SPT3-TAF9-GCN5-acetyltransferase complex, a counterpart of yeast SAGA complex, and the mechanism through which the elevated SGF29 expression contribute to oncogenic potential of c-Myc in hepatocellularcarcinoma(HCC). We propose that the upstream regulation of SGF29 elicited by sexdetermining region Y(Sry) is also augmented in HCC. We hypothesize that c-Myc elevation driven by the deregulated Sry and SGF29 pathway is implicated in the male specific acquisition of human HCCs.展开更多
Transgenic mouse technology has enabled the investigation of the pathogenic effects, including those on development, immunological reactions and carcinogenesis, of viral genes directly in living organism in a real-tim...Transgenic mouse technology has enabled the investigation of the pathogenic effects, including those on development, immunological reactions and carcinogenesis, of viral genes directly in living organism in a real-time manner. Although viral hepatocarcinogenesis comprises multiple sequences of pathological events, that is, chronic necroinflammation and the subsequent regeneration of hepatocytes that induces the accumulation of genetic alterations and hepatocellular carcinoma(HCC), the direct action of viral proteins also play significant roles. The pathogenesis of hepatitis B virus X and hepatitis C virus(HCV) core genes has been extensively studied by virtue of their functions as a transactivator and a steatosis inducer, respectively. In particular, the mechanism of steatosis in HCV infection and its possible association with HCC has been well studied using HCV core gene transgenic mouse models. Although transgenic mouse models have remarkable advantages, they are intrinsically accompanied by some drawbacks when used to study human diseases. Therefore, the results obtained from transgenic mouse studies should be carefully interpreted in the context of whether or not they are well associated with human pathogenesis.展开更多
Liver fibrosis and hepatocellular carcinoma(HCC)have been worldwide threats nowadays.Liver fibrosis is reversible in early stages but will develop precancerosis of HCC in cirrhotic stage.In pathological liver,excessiv...Liver fibrosis and hepatocellular carcinoma(HCC)have been worldwide threats nowadays.Liver fibrosis is reversible in early stages but will develop precancerosis of HCC in cirrhotic stage.In pathological liver,excessive H_(2)O_(2) is generated and accumulated,which impacts the functionality of hepatocytes,Kupffer cells(KCs)and hepatic stellate cells(HSCs),leading to genesis of fibrosis and HCC.H_(2)O_(2) accumulation is associated with overproduction of superoxide anion(O_(2)^(·-))and abolished antioxidant enzyme systems.Plenty of therapeutics focused on H_(2)O_(2) have shown satisfactory effects against liver fibrosis or HCC in different ways.This review summarized the reasons of liver H_(2)O_(2) accumulation,and the role of H_(2)O_(2) in genesis of liver fibrosis and HCC.Additionally,nanotherapeutics targeting H_(2)O_(2) were summarized for further consideration of antifibrotic or antitumor therapy.展开更多
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. There are two major challenges for HCC, the first being that early detection is generally not applicable, and secondly, it...Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. There are two major challenges for HCC, the first being that early detection is generally not applicable, and secondly, it is usually fatal within several months after diagnosis. HCC is an inflammation-induced cancer. It is known that chronic inflammation leads to oxidative/nitrosative stress and lipid peroxidation, generating excess oxidative stress, together with aldehydes which can react with DNA bases to form promutagenic DNA adducts. In this review, the evidence between oxidative stress and liver carcinogenesis is summarized. We focused on the potential of using DNA adducts as oxidative stress biomarkers for liver carcinogenesis.展开更多
It has been generally accepted that about 85% of cancers are caused by chemical factors and the chemically induced carcinogenic process can be divided into two or three stages, i. e. initiation and promotion, or toge...It has been generally accepted that about 85% of cancers are caused by chemical factors and the chemically induced carcinogenic process can be divided into two or three stages, i. e. initiation and promotion, or together with further progression. The initiation is usually considered to be an irreversible process, but it can be blocked to further progress to cancer. For this reason, searching of objective markers for identifying initiated cells has played an important role in defining the preneoplastic lesion. So far, a large number of studies have been carried out on this object, including biochemistry, histopathology, histochemistry, immunohistochemistry, etc., and nearly thirty histochemical and other phenotypic changes have been found associated with the putative preneoplastic liver展开更多
Objective: To study whether the ethanol extract of Phellinus merrillii(EPM) has chemopreventive potential against liver carcinogenesis. Methods: Thirty male Spraque-Dawley rats were randomly divided into control group...Objective: To study whether the ethanol extract of Phellinus merrillii(EPM) has chemopreventive potential against liver carcinogenesis. Methods: Thirty male Spraque-Dawley rats were randomly divided into control group, EPM control group, hepatocarcinoma control group, low-dose EPM group and high-dose EPM group, 6 in each group. Using the Solt and Farber protocol in a rat model of hepatocarcinogenesis, the chemopreventive effect of EPM on diethylnitrosamine(DEN)-initiated, 2-acetylaminofluorene(2-AAF) and partial hepatectomy(PH)-promoted liver carcinogenesis in rats was evaluated. Basic pathophysiological and histological examinations, together with the serum levels of glutamic oxaloacetic transaminase(s GOT), glutamic pyruvic transaminase(s GPT) and gamma-glutamyl transpeptidase(γ-GT) were measured. Results: Treatment of EPM at the concentration of 2 g/kg body weight in the diet for 8 weeks clearly prevented the development of carcinogenesis and reduced the levels of s GOT, s GPT, and serum γ-GT of rats as compared with the hepatocarcinoma control group(P<0.05 or P<0.01). These phenotypes were accompanied by a significant increase in natural killer cell activity. Conclusion: EPM showed a strong liver preventive effect against DEN+2-AAF+PH-induced hepatocarcinogenesis in a rat model.展开更多
Objective To investigate the effects of herbal compound 861 (Cpd861) on hepatocarcinogenesis induced by diethylntrosamine and 2-acetylaminofluorene (DEN-AAF) in female Sprague Dawley rats. Methods Liver preneoplastic ...Objective To investigate the effects of herbal compound 861 (Cpd861) on hepatocarcinogenesis induced by diethylntrosamine and 2-acetylaminofluorene (DEN-AAF) in female Sprague Dawley rats. Methods Liver preneoplastic foci were induced using the DEN-AAF method in female Sprague Dawley rats, which were then treated with Cpd861. For quantitative assessment of liver preneoplastic foci, the placental form of glutathione-S-transferase (GST-P) positive foci were measured using immunohistochemical staining and image analysis. GST-P protein expression was measured by Western blotting, mRNA expression was assessed by Northern blotting. Results Treatment using DEN-AAF caused a significant decrease in body weight and increase in liver weight compared to the control group. Oral Cpd861 administration essentially prevented DEN-AAF-induced body weight loss and liver weight increase. When 2-AAF was followed by treatment with Cpd861, there was a decrease in the number of large foci as compared to 2-AAF alone. However, there were still considerable numbers of small mixed clear/vacuolated cell foci, some of which were positive for GST-P. Significant increase in GST-P protein and mRNA expression were observed in the DEN-AAF group, while treatment with Cpd861 inhibited the increase. The effect of Cpd861 on hepatocarcinogenesis occurred in a concentration-dependent manner. Conclusion Chinese herbal compound Cpd861 prevents hepatocarcinogenesis in DEN-AAF-induced liver preneoplastic lesions in rats.展开更多
Liver cancer is the second leading cause of cancer deaths in men worldwide,and the 6th and 7th cause of cancer deaths in men and women in developed countries.70%-90%of primary liver cancer is hepatocellular carcinoma....Liver cancer is the second leading cause of cancer deaths in men worldwide,and the 6th and 7th cause of cancer deaths in men and women in developed countries.70%-90%of primary liver cancer is hepatocellular carcinoma.Hepatitis B or C viruses and chronic inflammation due to alcohol intake are the main risk factors for hepatocellular carcinoma.One of the key approaches for the early detection of hepatocellular carcinoma is to understand the specific imaging findings of liver nodules in the multi-step hepatocrcinogenesis process.In this article,we review the imaging findings of multistep hepatocarcinogenesis,with a focus on the early detection of malignant,cirrhotic nodules with CT and MRI.展开更多
Background: Intestinal microbial dysbiosis is involved in liver disease pathogenesis. However, its role in primary liver cancer(PLC), particularly in hepatocarcinogenesis remains unclear. The present study aimed to st...Background: Intestinal microbial dysbiosis is involved in liver disease pathogenesis. However, its role in primary liver cancer(PLC), particularly in hepatocarcinogenesis remains unclear. The present study aimed to study the changes in intestinal flora at various stages of PLC and clarify the relationship between intestinal microbes and PLC. Methods: Twenty-four patients with PLC(PLC group), 24 patients with liver cirrhosis(LC group), and 23 healthy control individuals(HC group) were enrolled from October 2016 to October 2017. Stool specimens of the participants were collected and the genomic DNA of fecal bacteria was isolated. High-throughput pyrosequencing of 16 S r DNA was used to identify differences in gut bacterial diversity among HC, LC, and PLC groups. We also analyzed the relationship between clinical factors and intestinal microorganisms in LC and PLC groups. Results: Diversity of Firmicutes tended to decrease from the HC to LC and PLC groups at the phylum level. Among species, Enterobacter ludwigii displayed an increasing trend in the PLC group, wherein the relative abundance of Enterobacter ludwigii in the PLC group was 100 times greater than that in the HC and LC groups. The ratio of Firmicutes/Bacteroidetes was significantly decreased with the disease progression. In addition, the linear discriminant analysis effect size method indicated that Clostridia were predominant in the gut microbiota of the HC group, whereas Enterococcaceae, Lactobacillales, Bacilli and Gammaproteobacteria may be used as diagnostic markers of PLC. Redundancy analysis showed a correlation between intestinal microbial diversity and clinical factors AST, ALT, and AFP. Veillonella showed a significant positive correlation with AFP in the PLC group, whereas Subdoligranulum showed a negative correlation with AFP. Conclusions: This study indicates that dysbiosis of the gut microbiota might be involved in PLC development and progression.展开更多
Hepatocellular carcinoma (HCC) is the most common malignant hepatobiliary disease; it is responsible for about 1 million deaths per year. Risk factors include hepatitis B and C, hepatic cirrhosis, including alcohol re...Hepatocellular carcinoma (HCC) is the most common malignant hepatobiliary disease; it is responsible for about 1 million deaths per year. Risk factors include hepatitis B and C, hepatic cirrhosis, including alcohol related hepatitis, metabolic and nutritional hepatic damage. The main modality of diffusion is intrahepatic in the natural course of the disease. There are two leading types of treatment: local and systemic. Surgical resection and liver transplantation constitute the most appropriate local treatments and are considered the only real possibility for recovery. Other local approaches include: radiofrequency ablation, percutaneous ethanol ablation, hepatic endoarterial chemoembolization and intrahepatic radiotherapy (SIRT: selective internal radiation therapy). These last treatments are used to control the disease when surgery or transplantation is not achievable; in some cases they are able to prolong survival while theyconstitute mainly a palliative treatment. Systemic treatments include: chemotherapy, immunological and hormonal therapies and, more recently, the introduction of new specific molecular target drugs. At the moment, in this group, the only drug that has given positive results during phase trials (SHARP study) is Sorafenib.Sorafenib represents the only primary systemic therapy that has demonstrated, unlike the other treatments previously described, an increase in survival rate in patients affected with advanced HCC. Currently, other studies are taking place that are further developing the potential of this drug. These studies, including phase trials, aredirected in order to test the activity and safety of new emerging drugs with targeted activity. Examples of these new agents are: Sunitinib, Gef itinib, Cetuximab, Bevacizumab and Erlotinib.展开更多
We describe a 77-year-old woman with chronic hepatitis B who became resistant to lamivudine.She was started on adefovir(10 mg daily)while still continuing lamivudine therapy.Four mo later her liver function improved a...We describe a 77-year-old woman with chronic hepatitis B who became resistant to lamivudine.She was started on adefovir(10 mg daily)while still continuing lamivudine therapy.Four mo later her liver function improved and serum Hepatitis B virus(HBV)-DNA level became undetectable.Three years after the start of additional adefovir treatment,hepatocellular carcinoma (HCC)was detected and the patient underwent a successful hepa-tectomy.Our findings suggest tha-t the addition of adefovir to ongoing lamivudine therapy cannot completely suppress hepatocarcinogenesis,but is useful for improving liver function in patients with lamivudine-resistant HBV-related cirrhosis,allowing HCC surgery.展开更多
The prognosis for patients who are diagnosed with advanced stage hepatocellular carcinoma(HCC)is poor because there are few treatment options.Recent research has focused on the identification of novel molecular entiti...The prognosis for patients who are diagnosed with advanced stage hepatocellular carcinoma(HCC)is poor because there are few treatment options.Recent research has focused on the identification of novel molecular entities that can be targeted to inhibit oncogenic signals that are involved in the carcinogenesis,proliferation and progression of HCC.Among all of the pathways that are involved in the development of HCC,Hedgehog(HH)signalling has demonstrated a substantial role in hepatocarcinogenesis and HCC progression.HH plays a physiological role in embryogenesis,through the induction of the differentiation of hepatocytes from endodermal progenitors.The re-activation of the HH pathway in chronic damaged liver is a mechanism of fibrotic degeneration and is implicated in various stages of HCC development.HH activation sustains the subpopulation of immature liver epithelial cells that are involved in the pathogenesis of cirrhosis and HCC,and HH itself is a mediator of the alcohol-derived malignant transformation of liver cells.High levels of expression of HH protein markers in liver tumour tissues are correlated with aggressive histological and biological features and a poor clinical outcome.In vitro and in vivo inhibition models of the HH pathway confirm that HH is essential in maintaining tumour growth,metastasis and a mesenchymal phenotype.展开更多
Objective: To investigate the inhibitory effect ofBoschniakia rossica(BR) on rat precancerous hepatic fociinduced by diethylnitrosamine (DEN) and its antioxidativeaedvities. Methods: The expression of tumor markerPlac...Objective: To investigate the inhibitory effect ofBoschniakia rossica(BR) on rat precancerous hepatic fociinduced by diethylnitrosamine (DEN) and its antioxidativeaedvities. Methods: The expression of tumor markerPlacental form glutathione S-transferase (GST-P), p53 andp21 protein were investigated by immunohistochendstrytechniques using ABC method. TNF-α was measured byELISA and antioxidative activities of SOD, MDA, GSH-Px,GST and CAT were investigated by colorimetric method inrat serum and mitochondria of liver cells. Results: The500mg/kg of BR-H2O extract fraction from BR-methanolextract had inhibitory effect on the formation of DENinduced GST-P-positive foci in rat liver and the expressionof mutant p53 and p21 protein was lower than that ofhepatic precancerous lesions. The serum TNF-α wasincreased by the administration of BR extract in the earlystage of chemical hepatocarcinogenesis in rat livers. Thesertun and liver cells mitochondria activities of SOD andGSH-Px rose again in rats administered with BR-H2Oextract and the increasing activity 0f GST and content ofMDA in the hepatic precancerous were decreased by theBR-H2O extract. Conclusion: These results indicated thatBR-H2O extract has inhibitory effect on DEN-inducedprecancerous hepatic foci in rats and induced TNF-αproduction in rats. The antioxidative action was exhibitedby the administration of BR-H2O extract in the early stageof chemical bepatocarcinogenesis in rat livers.展开更多
AIM: To investigate H2O2-induced promotion proliferation and malignant transformation in WB-F344 cells and anti-tumor effects of ursolic acid(UA) and oleanolic acid(OA). METHODS: WB-F344 cells were continuously expose...AIM: To investigate H2O2-induced promotion proliferation and malignant transformation in WB-F344 cells and anti-tumor effects of ursolic acid(UA) and oleanolic acid(OA). METHODS: WB-F344 cells were continuously exposed to 7 x 10-7mol/L H2 O2 for 21 d. Observations of cell morphology, colony formation rates, flow cytometric analysis of cell cycle changes and aneuploidy formation indicated that H2 O2 was able to induce malignant transformation of WB-F344 cells. We treated malignantly transformed WB-F344 cells with 4 μmol/L OA or 8 μmol/L UA for 72 h and analyzed the cell cycle distribution by flow cytometry. RESULTS: MTT assay showed that 7 x 10-7mol/L H2 O2 decreased G1 phase subpopulation from 73.8% to 49.6% compared with the control group, and increased S phase subpopulation from 14.5% to 31.8%(P < 0.05 vs control group). Cell morphology showed that nucleus to cytoplasm ratio increased, many mitotic cells, prokaryotes and even tumor giant cells were shown in H2 O2-induced WB-F344 cells. Fluorescence activated cell sorting analysis showed that WB-F344 cell aneuploidy increased to 12% following H2 O2 treatment. Flow cytometric analysis of the transformed WB-F344 cells following treatment with OA(4 μmol/L) and UA(8 μmol/L) showed that OA increased G1 subpopulation to 68.6%, compared to 49.7% in unexposed cells. UA increased G1 subpopulation to 67.4% compared to 49.7% in unexposed cells(P < 0.05 vs H2 O2 model group). CONCLUSION: H2O2 causes the malignant transformation of WB-F344 cells. OA and UA exert anti-tumor effects by inhibiting the proliferation in malignantly transformed WB-F344 cells.展开更多
基金supported by grants from the Natural Science Foundation of China(81873915,31872738 and 81673241)Nantong S&T Key Plan(MS12019021)NTU Medical Program of China(TDYX2021010)。
文摘Background:The effective treatment for hepatocellular carcinoma(HCC)depends on early diagnosis.Previously,the abnormal expression of Wnt3a as the key signaling molecule in the Wnt/β-catenin pathway was found in HCC cells and could be released into the circulation.In this study,we used rat model of hepatocarcinogenesis to dynamically investigate the alteration of oncogenic Wnt3a and to explore its early monitor value for HCC.Methods:Sprague-Dawley rats(SD)were fed with diet 2-fluorenylacetamide(2-FAA,0.05%)for inducing hepatocarcinogenesis,and grouped based on liver morphological alteration by Hematoxylin&Eosin(H&E)staining;rats fed with normal chow were used as normal control(NC).Total RNA and protein were purified from rat livers.Differently expressed genes(DEGs)or Wnt3a m RNA,cellular distribution,and Wnt3a protein levels were analyzed by whole genome microarray with signal logarithm ratio(SLR log 2 cy5/cy3),immunohistochemistry,and enzyme-linked immunosorbent assay,respectively.Results:Models of rat hepatocarcinogenesis were successfully established based on liver histopathological H&E staining.Rats were divided into the cell degeneration(r Deg),precancerosis(r Pre-C)and HCC(r HCC)groups.Total numbers of the up-and down-regulated DEGs with SLR≥8 were 55 and 48 in the r Deg group,268 and 57 in the r Pre-C group,and 312 and 201 in the r HCC group,respectively.Significantly altered genes were involved in cell proliferation,signal transduction,tumor metastasis,and apoptosis.Compared with the NC group,Wnt3a m RNA was increased by 4.6 folds(P<0.001)in the r Deg group,7.4 folds(P<0.001)in the r Pre-C group,and 10.4 folds(P<0.001)in the r HCC group;the positive rates of liver Wnt3a were 66.7%(P=0.001)in the r Deg group,100%(P<0.001)in the r Pre-C group,and 100%(P<0.001)in the r HCC group,respectively.Also,there were significant differences of liver Wnt3a(P<0.001)or serum Wnt3a(P<0.001)among different groups.Conclusions:Overexpression of Wnt3a was associated with rat hepatocarcinogenesis and it should be expected to be a promising monitoring biomarker for HCC occurrence at early stage.
文摘Liver cancer ranks sixth in cancer incidence,and is the third leading cause of cancer-related deaths worldwide.Hepatocellular carcinoma(HCC)is the most common type of liver cancer,which arises from hepatocytes and accounts for approximately 70%-85%of cases.Hepatitis B virus(HBV)frequently causes liver inflammation,hepatic damage and subsequent cirrhosis.Integrated viral DNA is found in 85%-90%of HBV-related HCCs.Its presence in tumors from non-cirrhotic livers of children or young adults further supports the role of viral DNA integration in hepatocarcinogenesis.Integration of subgenomic HBV DNA fragments into different locations within the host DNA is a significant feature of chronic HBV infection.Integration has two potential consequences:(1)the host genome becomes altered("cis"effect);and(2)the HBV genome becomes altered("trans"effect).The cis effect includes insertional mutagenesis,which can potentially disrupt host gene function or alter host gene regulation.Tumor progression is frequently associated with rearrangement and partial gain or loss of both viral and host sequences.However,the role of integrated HBV DNA in hepatocarcinogenesis remains controversial.Modern technology has provided a new paradigm to further our understanding ofdisease mechanisms.This review summarizes the role of HBV DNA integration in human carcinogenesis.
基金Supported by The Special Research Foundation of the National Natural Science Foundation of China,No.81172068
文摘Liver cancer is an aggressive disease with a high mortality rate. Management of liver cancer is strongly dependent on the tumor stage and underlying liver disease. Unfortunately, most cases are discovered when the cancer is already advanced, missing the opportunity for surgical resection. Thus, an improved understanding of the mechanisms responsible for liver cancer initiation and progression will facilitate the detection of more reliable tumor markers and the development of new small molecules for targeted therapy of liver cancer. Recently, there is increasing evidence for the "cancer stem cell hypothesis", which postulates that liver cancer originates from the malignant transformation of liver stem/progenitor cells(liver cancer stem cells). This cancer stem cell model has important significance for understanding the basic biology of liver cancer and has profound importance for the development of new strategies for cancer prevention and treatment. In this review, we highlight recent advances in the role of liver stem cells in hepatocarcinogenesis. Our review of the literature shows that identification of the cellular origin and the signaling pathways involved is challenging issues in liver cancer with pivotal implications in therapeutic perspectives. Although the dedifferentiation of mature hepatocytes/cholangiocytes in hepatocarcinogenesis cannot be excluded, neoplastic transformation of a stem cell subpopulation more easily explains hepatocarcinogenesis. Elimination of liver cancer stem cells in liver cancer could result in the degeneration of downstream cells, which makes them potential targets for liver cancer therapies. Therefore, liver stem cells could represent a new target for therapeutic approaches to liver cancer in the near future.
基金Supported by the Projects of the Ministry of S.and T.National Key Research and Development Program,No.2018YFC0116902the National Natural Science Foundation of China,No.31872738+3 种基金the National Natural Science Foundation of China,No.81673241the National Natural Science Foundation of China,No.81702419the National Natural Science Foundation of China,No.81873915the Jiangsu Medical Science of China,No.BE2016698
文摘BACKGROUND Prevalence of nonalcoholic fatty liver disease(NAFLD)is rapidly increasing,and NAFLD has become one of the most common chronic liver diseases worldwide.With abnormal CD44 activation,the severe form of NAFLD can progress to liver cirrhosis and hepatocellular carcinoma(HCC).Thus,the molecular mechanism of CD44 in NAFLD needs to be identified.AIM To investigate the relationship between CD44 activation and malignant transformation of rat hepatocytes under nonalcoholic lipid accumulation.METHODS Sprague-Dawley rats were fed a high-fat(HF)for 12 wk to entice NAFLD and then with HF plus 2-fluorenylacetamide(0.05%)to induce HCC.Rats were sacrificed every 2 wk,and subsequently divided into the groups based on liver pathological examination(hematoxylin and eosin staining):NAFLD,denaturation,precancerosis,HCC,and control.Liver CD44 mRNA was detected by OneArray.Liver fat as assessed by Oil red O staining or CD44 by immunohistochemical assay was compared with their integral optic density.Serum CD44,alanine aminotransferase,aspartate aminotransferase,triglyceride,total cholesterol,and AFP levels were quantitatively tested.RESULTS Elevated CD44 was first reported in hepatocarcinogenesis,with increasing expression from NAFLD to HCC at the protein or mRNA level.The CD44 integral optic density values were significantly different between the control group and the NAFLD(t=25.433,P<0.001),denaturation(t=48.822,P<0.001),precancerosis(t=27.751,P<0.001),and HCC(t=16.239,P<0.001)groups,respectively.Hepatic CD44 can be secreted into the blood,and serum CD44 levels in HCC or precancerous rats were significantly higher(P<0.001)than those in any of the other rats.Positive correlations were found between liver CD44 and CD44 mRNA(rs=0.373,P=0.043)and serum CD44(rs=0.541,P=0.002)and between liver CD44 mRNA and serum CD44(rs=0.507,P=0.004).Moreover,significant correlations were found between liver CD44 and liver AFP(rs=0.572,P=0.001),between serum CD44 and serum AFP(rs=0.608,P<0.001),and between CD44 mRNA and AFP mRNA(rs=0.370,P=0.044).CONCLUSION The data suggested that increasing CD44 expression is associated with the malignant transformation of hepatocytes in NAFLD.
文摘Hepatocellular carcinoma is on the rise and occurs in the setting of chronic liver disease and cirrhosis.Though treatment modalities are available,mortality from this cancer remains high.Medical therapy with the utilization of biologic compounds such as the Food and Drug Administration approved sorafenib might be the only option that can increase survival.Immunotherapy,with modern pharmacologic developments,is a new frontier in cancer therapy and therefore the immunobiology of hepatocarcinogenesis is under investigation.This review will discuss current concepts of immunobiology in hepatocarcinogenesis along with current treatment modalities employing immunotherapy.The tumor microenvironment along with a variety of immune cells coexists and interplays to lead to tumorigenesis.Tumor infiltrating lymphocytes including CD8+ T cells,CD4+ T cells along with regulatory T cells,tumor associated macrophages,tumor associated neutrophils,myeloid derived suppressor cells,and natural killer cells interact to actively provide anti-tumor or pro-tumor effects.Furthermore,oncogenic pathways such as Raf/mitogenactivated protein kinase/extracellular-signal-regulated kinase pathway,phosphatidyl-3-kinase/AKT/mammalian target or rapamycin,Wnt/β-catenin,nuclear factor-κB and signal transducers and activators of transcription 3 may lead to activation and proliferation of tumor cells and are also considered cornerstones in tumorigenesis.Immunotherapy directed at this complex milieu of cells has been showned to be successful in cancer treatment.The use of vaccines,adoptive cell therapy and immune checkpoint inhibitor modulation are current options for therapy.Further translational research will shed light to concepts such as anti-tumor immunity which can add another alternative in the therapeutic armamentarium.
文摘BACKGROUND: β-catenin has two distinct roles in E-cadherin mediated cell adhesion and carcinogenesis by activating the wnt/β-catenin signaling pathway. One occurs at the cell-adhesion site, where cadherins are linked to the actin-based cytoskeleton. The other takes place in the cytoplasm and nuclei and is thought to regulate cell transformation. We studied the role of β-catenin in hepatocarcinogenesis of rats. METHODS: Fresh liver specimens were obtained from normal rats. and atypical hyperplasia livers and hepatocarcinoma tissues from model rats. The changes of β-catenin in gene expression levels were detected by reverse transcriptase polymerase chain reaction (RT-PCR) in the different specimens separately. At the same time, their localization was observed immunohistochemically. RESULTS: In the normal liver specimens, β-catenin staining was seen in the cell membrane. In liver specimens of atypical byperplasia, β-catenin staining occurred in the cell cytoplasm of some cells as well as in the cell membrane of others. Immunohistochemically cancerous tissues showed the presence of β-catenin in the cytoplasm and nuclei. RTPCR revealed that the gene expression levels of β-catenin were same in all samples. CONCLUSIONS: The accumulation of β-catenin in the cytoplasm and/or nuclei frequently occurs in hepatocarcinogenesis of rats. It may be an early event in the development of hepatocarcinoma of rats.
基金Supported by The "Academic Frontier" project for Private University:a matching fund subsidy from MEXT(Ministry of Education,Culture,Sports,Science and Technology),2006-2010(to Tashiro F)
文摘Deregulated c-Myc expression is a hallmark of many human cancers. We have recently identified a role of mammalian homolog of yeast SPT-ADA-GCN5-acetyltransferas(SAGA) complex component, SAGAassociated factor 29(SGF29), in regulating the c-Myc overexpression. Here, we discuss the molecular nature of SFG29 in SPT3-TAF9-GCN5-acetyltransferase complex, a counterpart of yeast SAGA complex, and the mechanism through which the elevated SGF29 expression contribute to oncogenic potential of c-Myc in hepatocellularcarcinoma(HCC). We propose that the upstream regulation of SGF29 elicited by sexdetermining region Y(Sry) is also augmented in HCC. We hypothesize that c-Myc elevation driven by the deregulated Sry and SGF29 pathway is implicated in the male specific acquisition of human HCCs.
文摘Transgenic mouse technology has enabled the investigation of the pathogenic effects, including those on development, immunological reactions and carcinogenesis, of viral genes directly in living organism in a real-time manner. Although viral hepatocarcinogenesis comprises multiple sequences of pathological events, that is, chronic necroinflammation and the subsequent regeneration of hepatocytes that induces the accumulation of genetic alterations and hepatocellular carcinoma(HCC), the direct action of viral proteins also play significant roles. The pathogenesis of hepatitis B virus X and hepatitis C virus(HCV) core genes has been extensively studied by virtue of their functions as a transactivator and a steatosis inducer, respectively. In particular, the mechanism of steatosis in HCV infection and its possible association with HCC has been well studied using HCV core gene transgenic mouse models. Although transgenic mouse models have remarkable advantages, they are intrinsically accompanied by some drawbacks when used to study human diseases. Therefore, the results obtained from transgenic mouse studies should be carefully interpreted in the context of whether or not they are well associated with human pathogenesis.
基金This work was financially supported by the National Natural Science Foundation of China(Nos.52003246,81922073 and 81973481)the Traditional Chinese Medicine Key Scientific Research Fund Project of Zhejiang Province(Nos.2018ZY004,2022ZQ032 and 2021ZZ009)the Youth Natural Science Program of Zhejiang Chinese Medical University(2021JKZKTS007A).
文摘Liver fibrosis and hepatocellular carcinoma(HCC)have been worldwide threats nowadays.Liver fibrosis is reversible in early stages but will develop precancerosis of HCC in cirrhotic stage.In pathological liver,excessive H_(2)O_(2) is generated and accumulated,which impacts the functionality of hepatocytes,Kupffer cells(KCs)and hepatic stellate cells(HSCs),leading to genesis of fibrosis and HCC.H_(2)O_(2) accumulation is associated with overproduction of superoxide anion(O_(2)^(·-))and abolished antioxidant enzyme systems.Plenty of therapeutics focused on H_(2)O_(2) have shown satisfactory effects against liver fibrosis or HCC in different ways.This review summarized the reasons of liver H_(2)O_(2) accumulation,and the role of H_(2)O_(2) in genesis of liver fibrosis and HCC.Additionally,nanotherapeutics targeting H_(2)O_(2) were summarized for further consideration of antifibrotic or antitumor therapy.
文摘Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. There are two major challenges for HCC, the first being that early detection is generally not applicable, and secondly, it is usually fatal within several months after diagnosis. HCC is an inflammation-induced cancer. It is known that chronic inflammation leads to oxidative/nitrosative stress and lipid peroxidation, generating excess oxidative stress, together with aldehydes which can react with DNA bases to form promutagenic DNA adducts. In this review, the evidence between oxidative stress and liver carcinogenesis is summarized. We focused on the potential of using DNA adducts as oxidative stress biomarkers for liver carcinogenesis.
基金Project supported by the National Natural Science Foundation of China
文摘It has been generally accepted that about 85% of cancers are caused by chemical factors and the chemically induced carcinogenic process can be divided into two or three stages, i. e. initiation and promotion, or together with further progression. The initiation is usually considered to be an irreversible process, but it can be blocked to further progress to cancer. For this reason, searching of objective markers for identifying initiated cells has played an important role in defining the preneoplastic lesion. So far, a large number of studies have been carried out on this object, including biochemistry, histopathology, histochemistry, immunohistochemistry, etc., and nearly thirty histochemical and other phenotypic changes have been found associated with the putative preneoplastic liver
基金Supported by China Medical University Tsuzuki Institute for Traditional Medicine(No.CMU95-PH-11 and No.CMU97-232)the National Science Council(No.NSC 95-2320-B-182-059-MY3)Chang Gung University(No.CMRPD160271),Taiwan,China
文摘Objective: To study whether the ethanol extract of Phellinus merrillii(EPM) has chemopreventive potential against liver carcinogenesis. Methods: Thirty male Spraque-Dawley rats were randomly divided into control group, EPM control group, hepatocarcinoma control group, low-dose EPM group and high-dose EPM group, 6 in each group. Using the Solt and Farber protocol in a rat model of hepatocarcinogenesis, the chemopreventive effect of EPM on diethylnitrosamine(DEN)-initiated, 2-acetylaminofluorene(2-AAF) and partial hepatectomy(PH)-promoted liver carcinogenesis in rats was evaluated. Basic pathophysiological and histological examinations, together with the serum levels of glutamic oxaloacetic transaminase(s GOT), glutamic pyruvic transaminase(s GPT) and gamma-glutamyl transpeptidase(γ-GT) were measured. Results: Treatment of EPM at the concentration of 2 g/kg body weight in the diet for 8 weeks clearly prevented the development of carcinogenesis and reduced the levels of s GOT, s GPT, and serum γ-GT of rats as compared with the hepatocarcinoma control group(P<0.05 or P<0.01). These phenotypes were accompanied by a significant increase in natural killer cell activity. Conclusion: EPM showed a strong liver preventive effect against DEN+2-AAF+PH-induced hepatocarcinogenesis in a rat model.
文摘Objective To investigate the effects of herbal compound 861 (Cpd861) on hepatocarcinogenesis induced by diethylntrosamine and 2-acetylaminofluorene (DEN-AAF) in female Sprague Dawley rats. Methods Liver preneoplastic foci were induced using the DEN-AAF method in female Sprague Dawley rats, which were then treated with Cpd861. For quantitative assessment of liver preneoplastic foci, the placental form of glutathione-S-transferase (GST-P) positive foci were measured using immunohistochemical staining and image analysis. GST-P protein expression was measured by Western blotting, mRNA expression was assessed by Northern blotting. Results Treatment using DEN-AAF caused a significant decrease in body weight and increase in liver weight compared to the control group. Oral Cpd861 administration essentially prevented DEN-AAF-induced body weight loss and liver weight increase. When 2-AAF was followed by treatment with Cpd861, there was a decrease in the number of large foci as compared to 2-AAF alone. However, there were still considerable numbers of small mixed clear/vacuolated cell foci, some of which were positive for GST-P. Significant increase in GST-P protein and mRNA expression were observed in the DEN-AAF group, while treatment with Cpd861 inhibited the increase. The effect of Cpd861 on hepatocarcinogenesis occurred in a concentration-dependent manner. Conclusion Chinese herbal compound Cpd861 prevents hepatocarcinogenesis in DEN-AAF-induced liver preneoplastic lesions in rats.
文摘Liver cancer is the second leading cause of cancer deaths in men worldwide,and the 6th and 7th cause of cancer deaths in men and women in developed countries.70%-90%of primary liver cancer is hepatocellular carcinoma.Hepatitis B or C viruses and chronic inflammation due to alcohol intake are the main risk factors for hepatocellular carcinoma.One of the key approaches for the early detection of hepatocellular carcinoma is to understand the specific imaging findings of liver nodules in the multi-step hepatocrcinogenesis process.In this article,we review the imaging findings of multistep hepatocarcinogenesis,with a focus on the early detection of malignant,cirrhotic nodules with CT and MRI.
基金supported by grants from National Natural Science Foundation of China(31570509 and 31770536)
文摘Background: Intestinal microbial dysbiosis is involved in liver disease pathogenesis. However, its role in primary liver cancer(PLC), particularly in hepatocarcinogenesis remains unclear. The present study aimed to study the changes in intestinal flora at various stages of PLC and clarify the relationship between intestinal microbes and PLC. Methods: Twenty-four patients with PLC(PLC group), 24 patients with liver cirrhosis(LC group), and 23 healthy control individuals(HC group) were enrolled from October 2016 to October 2017. Stool specimens of the participants were collected and the genomic DNA of fecal bacteria was isolated. High-throughput pyrosequencing of 16 S r DNA was used to identify differences in gut bacterial diversity among HC, LC, and PLC groups. We also analyzed the relationship between clinical factors and intestinal microorganisms in LC and PLC groups. Results: Diversity of Firmicutes tended to decrease from the HC to LC and PLC groups at the phylum level. Among species, Enterobacter ludwigii displayed an increasing trend in the PLC group, wherein the relative abundance of Enterobacter ludwigii in the PLC group was 100 times greater than that in the HC and LC groups. The ratio of Firmicutes/Bacteroidetes was significantly decreased with the disease progression. In addition, the linear discriminant analysis effect size method indicated that Clostridia were predominant in the gut microbiota of the HC group, whereas Enterococcaceae, Lactobacillales, Bacilli and Gammaproteobacteria may be used as diagnostic markers of PLC. Redundancy analysis showed a correlation between intestinal microbial diversity and clinical factors AST, ALT, and AFP. Veillonella showed a significant positive correlation with AFP in the PLC group, whereas Subdoligranulum showed a negative correlation with AFP. Conclusions: This study indicates that dysbiosis of the gut microbiota might be involved in PLC development and progression.
文摘Hepatocellular carcinoma (HCC) is the most common malignant hepatobiliary disease; it is responsible for about 1 million deaths per year. Risk factors include hepatitis B and C, hepatic cirrhosis, including alcohol related hepatitis, metabolic and nutritional hepatic damage. The main modality of diffusion is intrahepatic in the natural course of the disease. There are two leading types of treatment: local and systemic. Surgical resection and liver transplantation constitute the most appropriate local treatments and are considered the only real possibility for recovery. Other local approaches include: radiofrequency ablation, percutaneous ethanol ablation, hepatic endoarterial chemoembolization and intrahepatic radiotherapy (SIRT: selective internal radiation therapy). These last treatments are used to control the disease when surgery or transplantation is not achievable; in some cases they are able to prolong survival while theyconstitute mainly a palliative treatment. Systemic treatments include: chemotherapy, immunological and hormonal therapies and, more recently, the introduction of new specific molecular target drugs. At the moment, in this group, the only drug that has given positive results during phase trials (SHARP study) is Sorafenib.Sorafenib represents the only primary systemic therapy that has demonstrated, unlike the other treatments previously described, an increase in survival rate in patients affected with advanced HCC. Currently, other studies are taking place that are further developing the potential of this drug. These studies, including phase trials, aredirected in order to test the activity and safety of new emerging drugs with targeted activity. Examples of these new agents are: Sunitinib, Gef itinib, Cetuximab, Bevacizumab and Erlotinib.
文摘We describe a 77-year-old woman with chronic hepatitis B who became resistant to lamivudine.She was started on adefovir(10 mg daily)while still continuing lamivudine therapy.Four mo later her liver function improved and serum Hepatitis B virus(HBV)-DNA level became undetectable.Three years after the start of additional adefovir treatment,hepatocellular carcinoma (HCC)was detected and the patient underwent a successful hepa-tectomy.Our findings suggest tha-t the addition of adefovir to ongoing lamivudine therapy cannot completely suppress hepatocarcinogenesis,but is useful for improving liver function in patients with lamivudine-resistant HBV-related cirrhosis,allowing HCC surgery.
文摘The prognosis for patients who are diagnosed with advanced stage hepatocellular carcinoma(HCC)is poor because there are few treatment options.Recent research has focused on the identification of novel molecular entities that can be targeted to inhibit oncogenic signals that are involved in the carcinogenesis,proliferation and progression of HCC.Among all of the pathways that are involved in the development of HCC,Hedgehog(HH)signalling has demonstrated a substantial role in hepatocarcinogenesis and HCC progression.HH plays a physiological role in embryogenesis,through the induction of the differentiation of hepatocytes from endodermal progenitors.The re-activation of the HH pathway in chronic damaged liver is a mechanism of fibrotic degeneration and is implicated in various stages of HCC development.HH activation sustains the subpopulation of immature liver epithelial cells that are involved in the pathogenesis of cirrhosis and HCC,and HH itself is a mediator of the alcohol-derived malignant transformation of liver cells.High levels of expression of HH protein markers in liver tumour tissues are correlated with aggressive histological and biological features and a poor clinical outcome.In vitro and in vivo inhibition models of the HH pathway confirm that HH is essential in maintaining tumour growth,metastasis and a mesenchymal phenotype.
文摘Objective: To investigate the inhibitory effect ofBoschniakia rossica(BR) on rat precancerous hepatic fociinduced by diethylnitrosamine (DEN) and its antioxidativeaedvities. Methods: The expression of tumor markerPlacental form glutathione S-transferase (GST-P), p53 andp21 protein were investigated by immunohistochendstrytechniques using ABC method. TNF-α was measured byELISA and antioxidative activities of SOD, MDA, GSH-Px,GST and CAT were investigated by colorimetric method inrat serum and mitochondria of liver cells. Results: The500mg/kg of BR-H2O extract fraction from BR-methanolextract had inhibitory effect on the formation of DENinduced GST-P-positive foci in rat liver and the expressionof mutant p53 and p21 protein was lower than that ofhepatic precancerous lesions. The serum TNF-α wasincreased by the administration of BR extract in the earlystage of chemical hepatocarcinogenesis in rat livers. Thesertun and liver cells mitochondria activities of SOD andGSH-Px rose again in rats administered with BR-H2Oextract and the increasing activity 0f GST and content ofMDA in the hepatic precancerous were decreased by theBR-H2O extract. Conclusion: These results indicated thatBR-H2O extract has inhibitory effect on DEN-inducedprecancerous hepatic foci in rats and induced TNF-αproduction in rats. The antioxidative action was exhibitedby the administration of BR-H2O extract in the early stageof chemical bepatocarcinogenesis in rat livers.
基金Supported by The Natural Science Foundation of Beijing Municipality,China,No.7112010the National Natural Science Foundation of China,No.81272757the Education Commission Research Program of Beijing Municipality,China,No.KM201010025004
文摘AIM: To investigate H2O2-induced promotion proliferation and malignant transformation in WB-F344 cells and anti-tumor effects of ursolic acid(UA) and oleanolic acid(OA). METHODS: WB-F344 cells were continuously exposed to 7 x 10-7mol/L H2 O2 for 21 d. Observations of cell morphology, colony formation rates, flow cytometric analysis of cell cycle changes and aneuploidy formation indicated that H2 O2 was able to induce malignant transformation of WB-F344 cells. We treated malignantly transformed WB-F344 cells with 4 μmol/L OA or 8 μmol/L UA for 72 h and analyzed the cell cycle distribution by flow cytometry. RESULTS: MTT assay showed that 7 x 10-7mol/L H2 O2 decreased G1 phase subpopulation from 73.8% to 49.6% compared with the control group, and increased S phase subpopulation from 14.5% to 31.8%(P < 0.05 vs control group). Cell morphology showed that nucleus to cytoplasm ratio increased, many mitotic cells, prokaryotes and even tumor giant cells were shown in H2 O2-induced WB-F344 cells. Fluorescence activated cell sorting analysis showed that WB-F344 cell aneuploidy increased to 12% following H2 O2 treatment. Flow cytometric analysis of the transformed WB-F344 cells following treatment with OA(4 μmol/L) and UA(8 μmol/L) showed that OA increased G1 subpopulation to 68.6%, compared to 49.7% in unexposed cells. UA increased G1 subpopulation to 67.4% compared to 49.7% in unexposed cells(P < 0.05 vs H2 O2 model group). CONCLUSION: H2O2 causes the malignant transformation of WB-F344 cells. OA and UA exert anti-tumor effects by inhibiting the proliferation in malignantly transformed WB-F344 cells.