AIM: Expression of heat shock proteins (HSPs) is frequently up-regulated in hepatocellular carcinoma (HCC), which evolves from dysplastic nodule (DN) and early HCC to advanced HCC. However, little is known about the d...AIM: Expression of heat shock proteins (HSPs) is frequently up-regulated in hepatocellular carcinoma (HCC), which evolves from dysplastic nodule (DN) and early HCC to advanced HCC. However, little is known about the differential expression of HSPs in multistep hepatocarcinogenesis. It was the purpose of this study to monitor the expression of HSPs in multistep hepatocarcinogenesis and to evaluate their prognostic significance in hepatitis B virus (HBV)related HCC.METHODS: Thirty-eight HCC and 19 DN samples were obtained from 52 hepatitis B surface antigen-positive Korean patients. Immunohistochemical and dot immunoblot analyses of HSP27, HSP60, HSP70, HSP90, glucoseregulated protein (GRP)78, and GRP94 were performed and their expression at different stages of HCC development was statistically analyzed.RESULTS: Expression of HSP27, HSP70, HSP90, GRP78, and GRP94 increased along with the stepwise progression of hepatocarcinogenesis. Strong correlation was found only in GRP78 (Spearman's r= 0.802). There was a positive correlation between the expressions of GRP78, GRP94, HSP90, or HSP70 and prognostic factors of HCC. Specifically, the expression of GRP78, GRP94, or HSP90 was associated significantly with vascular invasion and intrahepatic metastasis.CONCLUSION: The expressions of HSPs are commonly up-regulated in HBV-related HCCs and GRP78 might play an important role in the stepwise progression of HBVrelated hepatocarcinogenesis. GRP78, GRP94, and HSP90 may be important prognostic markers of HBV-related HCC, strongly suggesting vascular invasion and intrahepatic metastasis.展开更多
Farnesoid X receptor （FXR） is a member of the nuclear receptor superfamily of ligand-activated transcription factors. As a metabolic regulator, FXR plays key roles in bile acid, cholesterol, lipid, and glucose metab...Farnesoid X receptor （FXR） is a member of the nuclear receptor superfamily of ligand-activated transcription factors. As a metabolic regulator, FXR plays key roles in bile acid, cholesterol, lipid, and glucose metabolism. Therefore, FXR is a potential drug target for a number of metabolic disorders, especially those related to the metabolic syndrome. More recently, our group and others have extended the functions of FXR to more than metabolic regulation, which include anti-bacterial growth in intestine, liver regeneration, and hepatocarcinogenesis. These new findings suggest that FXR has much broader roles than previously thought, and also higi.light FXR as a drug target for multiple diseases. This review summarizes the basic information of FXR but focuses on its new functions.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
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 an...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 of disease mechanisms. This review summarizes the role of HBV DNA integration in human carcinogenesis.展开更多
The chronic infection of hepatitis B virus(HBV) is closely related to the occurrence and development of hepatocellular carcinoma(HCC). Accumulated evidence has shown that HBV X protein(HBx protein) is a multifunctiona...The chronic infection of hepatitis B virus(HBV) is closely related to the occurrence and development of hepatocellular carcinoma(HCC). Accumulated evidence has shown that HBV X protein(HBx protein) is a multifunctional regulator with a crucial role in hepatocarcinogenesis. However, information on the mechanism by which HBV induces HCC is lacking. This review focuses on the pathological functions of HBx in HBV-induced hepatocarcinogenesis. As a transactivator, HBx can modulate nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB) and transcription factor AP-2. Moreover, HBx can affect regulatory non-coding RNAs(ncRNAs) including microRNAs and long ncRNAs(lncRNAs), such as miRNA-205 and highly upregulated in liver cancer(HULC), respectively. HBx is also involved in epigenetic modification, including methylation and acetylation. HBx interacts with various signal-transduction pathways, such as protein kinase B/Akt, Wnt/β-catenin, signal transducer and activator of transcription, and NF-κB pathways. Moreover, HBx affects cellular fate by shifting the balance toward cell survival. HBx may lead to the loss of apoptotic functions or directly contributes to oncogenesis by achieving transforming functions, which induce hepatocarcinogenesis. Additionally, HBx can modulate apoptosis and immune response by direct or indirect interaction with host factors. We conclude that HBx hastens the development of hepatoma.展开更多
The striking gender disparity observed in the incidence of hepatocellutar carcinoma （HCC） suggests an important role of sex hormones in HCC pathogenesis. Though the studies began as early as in 1980s, the precise ro...The striking gender disparity observed in the incidence of hepatocellutar carcinoma （HCC） suggests an important role of sex hormones in HCC pathogenesis. Though the studies began as early as in 1980s, the precise role of sex hormones and the significance of their receptors in HCC still remain poorly understood and perhaps contribute to current controversies about the potential use of hormonal therapy in HCC. A comprehensive review of the existing literature revealed several shortcomings associated with the studies on estrogen receptor （ER） and androgen receptor （AR） in normal liver and HCC. These shortcomings include the use of less sensitive receptor ligand binding assays and immunohistochemistry studies for ERα alone until 1996 when ERβ isoform was identified. The animal models of HCC utilized for studies were primarily based on chemical-induced hepatocarcinogenesis with less similarity to virus-induced HCC pathogenesis. However, recent in vitro studies in hepatoma cells provide newer insights for hormonal regulation of key cellular processes including interaction of ER and AR with viral proteins. In light of the above facts, there is an urgent need for a detailed investigation of sex hormones and their receptors in normal liver and HCC. In this review, we systematically present the information currently available on androgens, estrogens and their receptors in normal liver and HCC obtained from in vitro, in vivo experimental models and clinical studies. This information will direct future basic and clinical research to bridge the gap in knowledge to explore the therapeutic potential of hormonal therapy in HCC.展开更多
AIM： To evaluate the effectiveness of ultrasonographic screening for early detection of hepatocellular carcinoma （HCC）. METHODS： The data of 14 968 patients who had ultrasonography （US） for chronic liver disease...AIM： To evaluate the effectiveness of ultrasonographic screening for early detection of hepatocellular carcinoma （HCC）. METHODS： The data of 14 968 patients who had ultrasonography （US） for chronic liver diseases were collected into a database program from June 1995 to June 2005. The risk factors for HCC were also studied. A total of 6089 patients who had repeated US were enrolled, 264 patients were diagnosed with HCC during follow-up （mean, 39 mo）. RESULTS： The detection rate of small HCC （≤ 3 cm in diameter） was 67.7%. The tumor size detected by screening at the intervals of 6 mo was significantly smaller than that at longer intervals. Only 29.3% of HCC patients had an elevated serum alpha fetoprotein （AFP） level above 400 ng/mL. The risk of HCC development during follow-up was higher in patients with liver cirrhosis （10.9%） and hepatitis C （9.0%） than in patients with chronic hepatitis （4.2%）, hepatitis B （4.9%） and non-B, non-C hepatitis （NBNC, 3.9%）. CONCLUSION： US screening at a interval of 6 mo is beneficial to high-risk patients over 40 years old and the early detection of HCC prolongs survival.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
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=0.04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
AIM： To identify the precise location of putative tumor suppressor genes （TSGs） on the short arm of chromosome 8 in patients with hepatocellular carcinoma （HCC）. METHODS： We used 16 microsatellite markers inform...AIM： To identify the precise location of putative tumor suppressor genes （TSGs） on the short arm of chromosome 8 in patients with hepatocellular carcinoma （HCC）. METHODS： We used 16 microsatellite markers informative in Japanese patients, which were selected from 61 pub- lished markers, on 81：）, to analyze the frequency of loss of heterozygosity （LOH） in each region in 33 cases （56 lesions） of HCC. RESULTS： The frequency of LOH at 8p23.2-21 with at least one marker was 63% （20/32） in the informative cases. More specifically, the frequency of LOH at 8p23.2, 8p23.1, 8p22, and 8p21 was 6%, 52%, 47%, and 13% in HCC cases. The LOH was significantly more frequent at 8p23.1 and 8p22 than the average （52% vs 220, P = 0.0008; and 47% vs 22%, P = 0.004, respectively） or others sites, such as 8p23.2 （52% vs 60, P = 0.003; 47% vs 220, P = 0.004） and 8p21 （52% vs 13%, P = 0.001; 47% vs 13%, P = 0.005） in liver cancer on the basis of cases. Notably, LOH frequency was significantly higher at D85277, DSS503, DSS1130, DSS552, DSS254 and D8S258 than at the other sites. However, no allelic loss was detected at any marker on 8p in the lesions of nontumor liver tissues. CONCLUSION： Deletion of 8p, especially the loss of 8p23.1-22, is an important event in the initiation or promotion of HCC. Our results should be useful in identi- fying critical genes that might lie at 8p23.1-22.展开更多
Patients with chronic hepatitis B are at significant risk for hepatocellular carcinoma(HCC). Globally,over half a million people each year are diagnosed with HCC,with marked geographical variations. Despite overwhelmi...Patients with chronic hepatitis B are at significant risk for hepatocellular carcinoma(HCC). Globally,over half a million people each year are diagnosed with HCC,with marked geographical variations. Despite overwhelming evidence for a causal role of hepatitis B virus(HBV) infection in the development of HCC and a well-established relationship between high baseline hepatitis B viral load and cumulative risk of HCC,the molecular basis for this association has not been fully elucidated. In addition,a beneficial role for antiviral therapy in preventing the development of HCC has been difficult to establish. This review examines the biological and molecular mechanisms of HBV-related hepatocarcinogenesis,recent results on the effect of modern nucleos(t)ides on the rate of HCC development in high risk HBV cohorts and the potential mechanisms by which long-term antiviral therapy with potent inhibitors of HBV replication might reduce the risk of HCC in patients with chronic hepatitis B. Although evidence from randomized controlled trials shows the favourable effects of antiviral agentsin achieving profound and durable suppression of HBV DNA levels while improving liver function and histology,robust evidence of other long-term clinical outcomes,such as prevention of HCC,are limited.展开更多
To study the inhibitory effect of Huqi San （Qi- protecting powder） on rat prehepatocarcinoma induced by diethylinitrosamine （DEN） by analyzing the mutational activation of c-fos proto-oncogene and over-expression ...To study the inhibitory effect of Huqi San （Qi- protecting powder） on rat prehepatocarcinoma induced by diethylinitrosamine （DEN） by analyzing the mutational activation of c-fos proto-oncogene and over-expression of c-jun and c-myc oncogenes. METHODS： A Solt-Farber two-step test model of prehepatocarcinoma was induced in rats by DEN and 2-acetylaminofluorene （AAF） to investigate the modifying effects of Huqi San on the expression of c-jun, c-fos and c-myc in DEN-mediated hepatocarcinogenesis. Huqi San was made of eight medicinal herbs containing glycoprival granules, in which each milliliter contains 0.38 g crude drugs. T-glutamy-transpeptidase-isoenzyme （T-GTase） was determined with histochemical methods. Level of 8-hydroxydeoxyguanosine （OHdG） formed in liver and c-jun, c-fos and c-myc proto-oncogenes were detected by immunohistochemical methods. RESULTS： The level of 8-OHdG, a mark of oxidative DNA damage, was significantly decreased in the liver of rats with prehepatocarcinoma induced by DEN who received 8 g/kg body weight or 4 g/kg body weight Huqi San before （1 wk） and after DEN exposure （4 wk）. Huqi San- treated rats showed a significant decrease in number of T-GT positive foci （P 〈 0.001, prevention group： 4.96-0.72 vs 29.46-2.17; large dose therapeutic group： 7.53-0.88 vs 29.46-2.17）. On the other hand, significant changes in expression of c-jun, c-fos and c-myc were found in Huqi San-treated rats. CONCLUSION： Activation of c-jun, c-fos and c-myc plays a crucial role in the pathogenesis of liver cancer.Huqi San can inhibit the over-expression of c-jun, c-fos and c-myc oncogenes and liver preneolastic lesions induced by DEN.展开更多
AIM To explore the relationship between dynamic expression of high mobility group box-3(HMGB3) and malignant transformation of hepatocytes.METHODS Expression of HMGB family proteins were observed in rat hepatocarcinog...AIM To explore the relationship between dynamic expression of high mobility group box-3(HMGB3) and malignant transformation of hepatocytes.METHODS Expression of HMGB family proteins were observed in rat hepatocarcinogenesis models induced with 2-acetylaminofluorene. Alterations of HMGB3 were analyzed at the m RNA level by reverse transcription-quantitative polymerase chain reaction(RT-q PCR) and at the protein level by immunohistochemistry or Western blotting. HMGB3 in human liver cancer tissues were evaluated using bioinformatics databases from GEO, TCGA, and Oncomine. A specific HMGB3-sh RNA was used to knockdown HMGB3 expression in order to investigate its effects on proliferation and cell cycle in vitro and in vivo.RESULTS Elevated HMGB3 levels were first reported in hepatocarcinogenesis, with increasing expression from normal liver to cancer. Bioinformatic databases showed that HMGB3 expression in hepatocellular carcinoma tissues was significantly higher than that in normal liver tissues. Higher HMGB3 expression was discovered in liver cancer cells compared with LO2 cells in vitro. According to gene set enrichment analysis, HMGB3 m RNA levels were correlated with cell cycle and DNA replication pathways. Knocking down HMGB3 by specific sh RNA significantly inhibited proliferation of Hep G2 cells by cell cycle arrest and downregulating DNA replication related genes(cyclin B1, FEN1, and PCNA) at the m RNA and protein level. Furthermore, silencing HMGB3 significantly inhibited xenograft tumor growth(measured by Ki67) in vivo.CONCLUSION HMGB3 is involved in malignant transformation of hepatocytes and could be a useful biomarker for diagnosis and a potential target for therapy of liver cancer.展开更多
Objective: To investigate the inhibitory effect of Boschniakia rossica (BR) on rat precancerous hepatic foci induced by diethylnitrosamine (DEN) and its antioxidative activities. Methods: The expression of tumor marke...Objective: To investigate the inhibitory effect of Boschniakia rossica (BR) on rat precancerous hepatic foci induced by diethylnitrosamine (DEN) and its antioxidative activities. Methods: The expression of tumor marker—placental form glutathione S-transferase (GST-P), p53 and p21 protein were investigated by immunohistochemistry techniques using ABC method. TNF-α was measured by ELISA and antioxidative activities of SOD, MDA, GSH-Px, GST and CAT were investigated by colorimetric method in rat serum and mitochondria of liver cells. Results: The 500 mg/kg of BR-H2O extract fraction from BR-methanol extract had inhibitory effect on the formation of DEN-induced GST-P-positive foci in rat liver and the expression of mutant p53 and p21 protein was lower than that of hepatic precancerous lesions. The serum TNF-α was increased by the administration of BR extract in the early stage of chemical hepatocarcinogenesis in rat livers. The serum and liver cells mitochondria activities of SOD and GSH-Px rose again in rats administered with BR-H2O extract and the increasing activity of GST and content of MDA in the hepatic precancerous were decreased by the BH-H2O extract. Conclusion: These results indicated that BR-H2O extract has inhibitory effect on DEN-induced precancerous hepatic foci in rats and induced TNF-α production in rats. The antioxidative action was exhibited by the administration of BR-H2O extract in the early stage of chemical hepatocarcinogenesis in rat livers.展开更多
AIM: To investigate H<sub>2</sub>O<sub>2</sub>-induced promotion proliferation and malignant transformation in WB-F344 cells and anti-tumor effects of ursolic acid (UA) and oleanolic acid (OA).
基金Supported by the fund from the Korea Science and Engineering Foundation (Grant No. R01-2001-00098). Seung Oe Lim was supported by BK21 Research Fellowship from the Ministry of Education and Human Resources Development
文摘AIM: Expression of heat shock proteins (HSPs) is frequently up-regulated in hepatocellular carcinoma (HCC), which evolves from dysplastic nodule (DN) and early HCC to advanced HCC. However, little is known about the differential expression of HSPs in multistep hepatocarcinogenesis. It was the purpose of this study to monitor the expression of HSPs in multistep hepatocarcinogenesis and to evaluate their prognostic significance in hepatitis B virus (HBV)related HCC.METHODS: Thirty-eight HCC and 19 DN samples were obtained from 52 hepatitis B surface antigen-positive Korean patients. Immunohistochemical and dot immunoblot analyses of HSP27, HSP60, HSP70, HSP90, glucoseregulated protein (GRP)78, and GRP94 were performed and their expression at different stages of HCC development was statistically analyzed.RESULTS: Expression of HSP27, HSP70, HSP90, GRP78, and GRP94 increased along with the stepwise progression of hepatocarcinogenesis. Strong correlation was found only in GRP78 (Spearman's r= 0.802). There was a positive correlation between the expressions of GRP78, GRP94, HSP90, or HSP70 and prognostic factors of HCC. Specifically, the expression of GRP78, GRP94, or HSP90 was associated significantly with vascular invasion and intrahepatic metastasis.CONCLUSION: The expressions of HSPs are commonly up-regulated in HBV-related HCCs and GRP78 might play an important role in the stepwise progression of HBVrelated hepatocarcinogenesis. GRP78, GRP94, and HSP90 may be important prognostic markers of HBV-related HCC, strongly suggesting vascular invasion and intrahepatic metastasis.
文摘Farnesoid X receptor （FXR） is a member of the nuclear receptor superfamily of ligand-activated transcription factors. As a metabolic regulator, FXR plays key roles in bile acid, cholesterol, lipid, and glucose metabolism. Therefore, FXR is a potential drug target for a number of metabolic disorders, especially those related to the metabolic syndrome. More recently, our group and others have extended the functions of FXR to more than metabolic regulation, which include anti-bacterial growth in intestine, liver regeneration, and hepatocarcinogenesis. These new findings suggest that FXR has much broader roles than previously thought, and also higi.light FXR as a drug target for multiple diseases. This review summarizes the basic information of FXR but focuses on its new functions.
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 of disease mechanisms. This review summarizes the role of HBV DNA integration in human carcinogenesis.
文摘The chronic infection of hepatitis B virus(HBV) is closely related to the occurrence and development of hepatocellular carcinoma(HCC). Accumulated evidence has shown that HBV X protein(HBx protein) is a multifunctional regulator with a crucial role in hepatocarcinogenesis. However, information on the mechanism by which HBV induces HCC is lacking. This review focuses on the pathological functions of HBx in HBV-induced hepatocarcinogenesis. As a transactivator, HBx can modulate nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB) and transcription factor AP-2. Moreover, HBx can affect regulatory non-coding RNAs(ncRNAs) including microRNAs and long ncRNAs(lncRNAs), such as miRNA-205 and highly upregulated in liver cancer(HULC), respectively. HBx is also involved in epigenetic modification, including methylation and acetylation. HBx interacts with various signal-transduction pathways, such as protein kinase B/Akt, Wnt/β-catenin, signal transducer and activator of transcription, and NF-κB pathways. Moreover, HBx affects cellular fate by shifting the balance toward cell survival. HBx may lead to the loss of apoptotic functions or directly contributes to oncogenesis by achieving transforming functions, which induce hepatocarcinogenesis. Additionally, HBx can modulate apoptosis and immune response by direct or indirect interaction with host factors. We conclude that HBx hastens the development of hepatoma.
文摘The striking gender disparity observed in the incidence of hepatocellutar carcinoma （HCC） suggests an important role of sex hormones in HCC pathogenesis. Though the studies began as early as in 1980s, the precise role of sex hormones and the significance of their receptors in HCC still remain poorly understood and perhaps contribute to current controversies about the potential use of hormonal therapy in HCC. A comprehensive review of the existing literature revealed several shortcomings associated with the studies on estrogen receptor （ER） and androgen receptor （AR） in normal liver and HCC. These shortcomings include the use of less sensitive receptor ligand binding assays and immunohistochemistry studies for ERα alone until 1996 when ERβ isoform was identified. The animal models of HCC utilized for studies were primarily based on chemical-induced hepatocarcinogenesis with less similarity to virus-induced HCC pathogenesis. However, recent in vitro studies in hepatoma cells provide newer insights for hormonal regulation of key cellular processes including interaction of ER and AR with viral proteins. In light of the above facts, there is an urgent need for a detailed investigation of sex hormones and their receptors in normal liver and HCC. In this review, we systematically present the information currently available on androgens, estrogens and their receptors in normal liver and HCC obtained from in vitro, in vivo experimental models and clinical studies. This information will direct future basic and clinical research to bridge the gap in knowledge to explore the therapeutic potential of hormonal therapy in HCC.
文摘AIM： To evaluate the effectiveness of ultrasonographic screening for early detection of hepatocellular carcinoma （HCC）. METHODS： The data of 14 968 patients who had ultrasonography （US） for chronic liver diseases were collected into a database program from June 1995 to June 2005. The risk factors for HCC were also studied. A total of 6089 patients who had repeated US were enrolled, 264 patients were diagnosed with HCC during follow-up （mean, 39 mo）. RESULTS： The detection rate of small HCC （≤ 3 cm in diameter） was 67.7%. The tumor size detected by screening at the intervals of 6 mo was significantly smaller than that at longer intervals. Only 29.3% of HCC patients had an elevated serum alpha fetoprotein （AFP） level above 400 ng/mL. The risk of HCC development during follow-up was higher in patients with liver cirrhosis （10.9%） and hepatitis C （9.0%） than in patients with chronic hepatitis （4.2%）, hepatitis B （4.9%） and non-B, non-C hepatitis （NBNC, 3.9%）. CONCLUSION： US screening at a interval of 6 mo is beneficial to high-risk patients over 40 years old and the early detection of HCC prolongs survival.
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.
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=0.04
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AIM： To identify the precise location of putative tumor suppressor genes （TSGs） on the short arm of chromosome 8 in patients with hepatocellular carcinoma （HCC）. METHODS： We used 16 microsatellite markers informative in Japanese patients, which were selected from 61 pub- lished markers, on 81：）, to analyze the frequency of loss of heterozygosity （LOH） in each region in 33 cases （56 lesions） of HCC. RESULTS： The frequency of LOH at 8p23.2-21 with at least one marker was 63% （20/32） in the informative cases. More specifically, the frequency of LOH at 8p23.2, 8p23.1, 8p22, and 8p21 was 6%, 52%, 47%, and 13% in HCC cases. The LOH was significantly more frequent at 8p23.1 and 8p22 than the average （52% vs 220, P = 0.0008; and 47% vs 22%, P = 0.004, respectively） or others sites, such as 8p23.2 （52% vs 60, P = 0.003; 47% vs 220, P = 0.004） and 8p21 （52% vs 13%, P = 0.001; 47% vs 13%, P = 0.005） in liver cancer on the basis of cases. Notably, LOH frequency was significantly higher at D85277, DSS503, DSS1130, DSS552, DSS254 and D8S258 than at the other sites. However, no allelic loss was detected at any marker on 8p in the lesions of nontumor liver tissues. CONCLUSION： Deletion of 8p, especially the loss of 8p23.1-22, is an important event in the initiation or promotion of HCC. Our results should be useful in identi- fying critical genes that might lie at 8p23.1-22.
文摘Patients with chronic hepatitis B are at significant risk for hepatocellular carcinoma(HCC). Globally,over half a million people each year are diagnosed with HCC,with marked geographical variations. Despite overwhelming evidence for a causal role of hepatitis B virus(HBV) infection in the development of HCC and a well-established relationship between high baseline hepatitis B viral load and cumulative risk of HCC,the molecular basis for this association has not been fully elucidated. In addition,a beneficial role for antiviral therapy in preventing the development of HCC has been difficult to establish. This review examines the biological and molecular mechanisms of HBV-related hepatocarcinogenesis,recent results on the effect of modern nucleos(t)ides on the rate of HCC development in high risk HBV cohorts and the potential mechanisms by which long-term antiviral therapy with potent inhibitors of HBV replication might reduce the risk of HCC in patients with chronic hepatitis B. Although evidence from randomized controlled trials shows the favourable effects of antiviral agentsin achieving profound and durable suppression of HBV DNA levels while improving liver function and histology,robust evidence of other long-term clinical outcomes,such as prevention of HCC,are limited.
基金Supported by The Chinese Medicine Technology Item of Peking City (No.JJ2005-10)Beijing Municipal Commission of Education (No. M200610025003)
文摘To study the inhibitory effect of Huqi San （Qi- protecting powder） on rat prehepatocarcinoma induced by diethylinitrosamine （DEN） by analyzing the mutational activation of c-fos proto-oncogene and over-expression of c-jun and c-myc oncogenes. METHODS： A Solt-Farber two-step test model of prehepatocarcinoma was induced in rats by DEN and 2-acetylaminofluorene （AAF） to investigate the modifying effects of Huqi San on the expression of c-jun, c-fos and c-myc in DEN-mediated hepatocarcinogenesis. Huqi San was made of eight medicinal herbs containing glycoprival granules, in which each milliliter contains 0.38 g crude drugs. T-glutamy-transpeptidase-isoenzyme （T-GTase） was determined with histochemical methods. Level of 8-hydroxydeoxyguanosine （OHdG） formed in liver and c-jun, c-fos and c-myc proto-oncogenes were detected by immunohistochemical methods. RESULTS： The level of 8-OHdG, a mark of oxidative DNA damage, was significantly decreased in the liver of rats with prehepatocarcinoma induced by DEN who received 8 g/kg body weight or 4 g/kg body weight Huqi San before （1 wk） and after DEN exposure （4 wk）. Huqi San- treated rats showed a significant decrease in number of T-GT positive foci （P 〈 0.001, prevention group： 4.96-0.72 vs 29.46-2.17; large dose therapeutic group： 7.53-0.88 vs 29.46-2.17）. On the other hand, significant changes in expression of c-jun, c-fos and c-myc were found in Huqi San-treated rats. CONCLUSION： Activation of c-jun, c-fos and c-myc plays a crucial role in the pathogenesis of liver cancer.Huqi San can inhibit the over-expression of c-jun, c-fos and c-myc oncogenes and liver preneolastic lesions induced by DEN.
基金Supported by the National Natural Science Foundation of China,No.81673241 and No.81702419Projects of Jiangsu MedicalScience,No.BE2016698+2 种基金Jiangsu Graduate Innovation,No.KYCX17_1934Nantong Health and Family Planning Commission,No.WQ2016083National Int S&T Cooperation Program,No.2013DFA32150
文摘AIM To explore the relationship between dynamic expression of high mobility group box-3(HMGB3) and malignant transformation of hepatocytes.METHODS Expression of HMGB family proteins were observed in rat hepatocarcinogenesis models induced with 2-acetylaminofluorene. Alterations of HMGB3 were analyzed at the m RNA level by reverse transcription-quantitative polymerase chain reaction(RT-q PCR) and at the protein level by immunohistochemistry or Western blotting. HMGB3 in human liver cancer tissues were evaluated using bioinformatics databases from GEO, TCGA, and Oncomine. A specific HMGB3-sh RNA was used to knockdown HMGB3 expression in order to investigate its effects on proliferation and cell cycle in vitro and in vivo.RESULTS Elevated HMGB3 levels were first reported in hepatocarcinogenesis, with increasing expression from normal liver to cancer. Bioinformatic databases showed that HMGB3 expression in hepatocellular carcinoma tissues was significantly higher than that in normal liver tissues. Higher HMGB3 expression was discovered in liver cancer cells compared with LO2 cells in vitro. According to gene set enrichment analysis, HMGB3 m RNA levels were correlated with cell cycle and DNA replication pathways. Knocking down HMGB3 by specific sh RNA significantly inhibited proliferation of Hep G2 cells by cell cycle arrest and downregulating DNA replication related genes(cyclin B1, FEN1, and PCNA) at the m RNA and protein level. Furthermore, silencing HMGB3 significantly inhibited xenograft tumor growth(measured by Ki67) in vivo.CONCLUSION HMGB3 is involved in malignant transformation of hepatocytes and could be a useful biomarker for diagnosis and a potential target for therapy of liver cancer.
文摘Objective: To investigate the inhibitory effect of Boschniakia rossica (BR) on rat precancerous hepatic foci induced by diethylnitrosamine (DEN) and its antioxidative activities. Methods: The expression of tumor marker—placental form glutathione S-transferase (GST-P), p53 and p21 protein were investigated by immunohistochemistry techniques using ABC method. TNF-α was measured by ELISA and antioxidative activities of SOD, MDA, GSH-Px, GST and CAT were investigated by colorimetric method in rat serum and mitochondria of liver cells. Results: The 500 mg/kg of BR-H2O extract fraction from BR-methanol extract had inhibitory effect on the formation of DEN-induced GST-P-positive foci in rat liver and the expression of mutant p53 and p21 protein was lower than that of hepatic precancerous lesions. The serum TNF-α was increased by the administration of BR extract in the early stage of chemical hepatocarcinogenesis in rat livers. The serum and liver cells mitochondria activities of SOD and GSH-Px rose again in rats administered with BR-H2O extract and the increasing activity of GST and content of MDA in the hepatic precancerous were decreased by the BH-H2O extract. Conclusion: These results indicated that BR-H2O extract has inhibitory effect on DEN-induced precancerous hepatic foci in rats and induced TNF-α production in rats. The antioxidative action was exhibited by the administration of BR-H2O extract in the early stage of chemical hepatocarcinogenesis 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 H<sub>2</sub>O<sub>2</sub>-induced promotion proliferation and malignant transformation in WB-F344 cells and anti-tumor effects of ursolic acid (UA) and oleanolic acid (OA).
