[Show abstract][Hide abstract] ABSTRACT: We previously demonstrated that the enhancer of rudimentary homolog (ERH) gene is required for the expression of multiple cell cycle and DNA damage response (DDR) genes. The present study investigated the role of ERH and its target DNA damage repair genes in hepatocellular carcinoma cells. We observed positive correlation between ERH and ataxia telangiectasia and Rad3 related (ATR) expression in liver tissues. Expression of ERH, ATR as well as checkpoint kinase 1 (CHK1) were higher in HCCs than in normal liver tissues. Knocking-down ERH augmented ultraviolet light induced DNA damage in HepG2 cells. ATR protein level is reduced upon ERH depletion as a result of defect in the splicing of ATR mRNA. Consequently, the ATR effector kinase Chk1 failed to be phosphorylated upon ultraviolet light or hydroxyurea treatment in ERH knocked-down HepG2 cells. Finally, we observed Chk1 inhibitor AZD7762 enhanced the effect of doxorubicin on inhibiting growth of HCC cells in vitro and in vivo. This study suggested that ERH regulates the splicing of the DNA damage response proteins ATR in HCC cells, and targeting DNA damage response by Chk1 inhibitor augments chemotherapy to treat HCC cells.
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma (HCC) is associated with a poor prognosis and remains one of the leading causes of cancer death worldwide. Tumor-associated antigens (TAAs) and autoantibodies have been reported as potential markers in different cancers. Here, we employed an immunoproteomic approach to identify TAAs in the sera of patients with hepatitis B virus-related HCC (HBV-HCC). Immunoreactive spots were excised from 2-DE and analyzed by nano-LC-MS/MS. This analysis identified 16 HCC-associated antigens, including hnRNP L. The antigenicity of hnRNP L was further validated by immunoblotting using recombinant proteins. Autoantibodies against hnRNP L were found in 60% patients with HBV-HCC. Using sera from hnRNP L-positive patients, we found that most of these antibodies recognized glycine-rich region in the N-terminus of hnRNP L. In addition, high titers of autoantibodies against hnRNP L were found in HBV-HCC patients' sera and were associated with increased tumor size and reduced survival rate. hnRNP L protein was also found highly expressed in HCC tissue. Knockdown of hnRNP L significantly suppressed cell growth, migration, and invasion in vitro. Our results indicate that an N-terminal epitope of hnRNP L is a potential biomarker for the diagnosis of HBV-HCC and show that hnRNP L contributes to HCC progression.
In this paper, we employed an immunoproteomic approach to identify TAAs in the sera of patients with hepatitis B virus-related HCC (HBV-HCC). We identified hnRNP L as a tumor-associated antigen in HBV-relative HCC patients. Glycine-rich region located at the N-terminus of hnRNP L constitute the major epitope. We also demonstrated that hnRNP L is involved in cell proliferation and metastasis.
Journal of proteomics 10/2013; 94. DOI:10.1016/j.jprot.2013.10.003 · 3.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study aimed to investigate the association between serum adiponectin and chronic hepatitis B virus (HBV) infection.
We conducted a campus-based cross-sectional study in Northern Taiwan, an HBV-endemic country. A total of 506 participants, including 147 chronic HBV-infected individuals and 359 healthy controls, were assessed for anthropometric indices, serum adiponectin levels, serum HBV viral load and markers, serum alanine aminotransferase levels and metabolic factors.
Older age, male gender, higher alanine aminotransferase, higher body mass index, greater waist circumference, lower fasting glucose, higher triglycerides, and higher adiponectin were associated with chronic HBV infection in univariate analyses. In multivariate analysis, the presence of chronic HBV infection was positively associated with serum adiponectin levels (P < 0.0001) and high adiponectin levels over the 75th percentile (odds ratio, 4.25; 95% confidence interval, 2.36-7.66; P < 0.0001) after adjusting for age, gender, body mass index, and insulin resistance index. Furthermore, serum adiponectin levels were positively associated with HBV viral load in overweight to obese HBV-infected subjects (P = 0.018).
Although chronic HBV-infected individuals were heavier than healthy controls, they had significantly higher serum adiponectin levels than healthy counterparts. Additionally, adiponectin levels were positively associated with HBV viral load in overweight to obese HBV-infected subjects. Future research should focus on elucidating adiponectin pathways, which may contribute to the development of adjuvant treatments for chronic HBV infection.
[Show abstract][Hide abstract] ABSTRACT: Cancers with Ras mutations represent a major therapeutic problem. Recent RNAi screens have uncovered multiple nononcogene addiction pathways that are necessary for the survival of Ras mutant cells. Here, we identify the evolutionarily conserved gene enhancer of rudimentary homolog (ERH), in which depletion causes greater toxicity in cancer cells with mutations in the small GTPase KRAS compared with KRAS WT cells. ERH interacts with the spliceosome protein SNRPD3 and is required for the mRNA splicing of the mitotic motor protein CENP-E. Loss of ERH leads to loss of CENP-E and consequently, chromosome congression defects. Gene expression profiling indicates that ERH is required for the expression of multiple cell cycle genes, and the gene expression signature resulting from ERH down-regulation inversely correlates with KRAS signatures. Clinically, tumor ERH expression is inversely associated with survival of colorectal cancer patients whose tumors harbor KRAS mutations. Together, these findings identify a role of ERH in mRNA splicing and mitosis, and they provide evidence that KRAS mutant cancer cells are dependent on ERH for their survival.
Proceedings of the National Academy of Sciences 12/2012; 109(52). DOI:10.1073/pnas.1207673110 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To (a) explore changes in physical and psychological distress and quality of life (QOL) and (b) identify the significant pre- and postdischarge factors related to changes in physical and mental domains of QOL over a period of 2 months in patients with hepatocellular carcinoma receiving one course of transarterial chemoembolization (TACE) treatment.
A longitudinal prospective design was used, with participants recruited from a teaching hospital in Northern Taiwan. Data were collected three times: within 3 days prior to discharge (T0) and at the fourth (T1) and eighth (T2) weeks after discharge. A set of structured questionnaires was used to assess participants' QOL, symptom distress, anxiety, and depression. Changes in QOL and associated factors were examined using generalized estimating equations.
Eighty-nine patients were included in this study. Fatigue was reported to be the most distressful symptom after treatment. Overall QOL improved monthly after discharge. Change in physical QOL 2 months after TACE treatment was associated with age, diagnosis status, level of symptom distress, and depression after discharge. Change in mental QOL was significantly associated with gender, diagnosis status, and anxiety and depression after discharge.
Health care providers should pay special attention to patients of older age, those who are male, and those who have higher levels of depression and anxiety after discharge. Designing personalized education programs before discharge for patients with newly diagnosed cancer versus those who have recurrent disease is suggested to help patients maintain a better QOL after discharge.
The Oncologist 04/2012; 17(5):732-9. DOI:10.1634/theoncologist.2011-0368 · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Significant hepatitis B viral load (≥10,000 copies/mL) was established to increase risk of advanced liver diseases. The aim of this study was to explore the metabolic risk factors for significant hepatitis B viral load. A campus-based cohort consisting of 146 participants of chronic hepatitis B virus (HBV) infection in Northern Taiwan was investigated in 2009. Clinical profiles including serum levels of deoxyribonucleic acid of hepatitis B virus (HBV DNA) were collected. Hepatitis B e antigen (HBeAg) serostatus, high alanine aminotransferase level, body mass index (BMI) ranges, and insulin resistance were related to significant HBV DNA levels in univariate analysis. Compared to individuals with BMI 23-24.9 kg/m(2) in multivariate analysis, those with BMI ≥25 kg/m(2) (OR = 3.86, 95% CI = 1.38-10.8, P = 0.010) and those with BMI <23 kg/m(2) (OR = 4.47, 95% CI = 1.32-15.2, P = 0.016) were at higher risk for significant HBV DNA levels. This phenomenon was also manifest in HBeAg seronegatives, who contributed to a majority of significant viral load in our study. Furthermore, insulin resistance and BMI ≥25 kg/m(2) had positive additive effects on significant HBV DNA levels (adjusted OR = 9.34, 95% CI = 1.74-50.3, P = 0.009). In conclusion, having certain BMI ranges (BMI ≥25 kg/m(2) or BMI <23 kg/m(2)) could be a risk factor of significant HBV DNA levels.:
Obesity Research & Clinical Practice 01/2012; 6(1):e1-e90. DOI:10.1016/j.orcp.2011.04.005 · 1.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several viral factors are associated with disease progression in hepatitis B virus (HBV) carriers. Compared with Taiwanese Han Chinese, Taiwanese aborigines have a higher prevalence of chronic HBV infection and a higher standardized mortality rate of chronic liver diseases but a lower standardized mortality rate of hepatocellular carcinoma (HCC). The aim of this study was to investigate whether aboriginal Taiwanese HBV carriers have more favorable viral factors which reduce the risk for HCC than Han Chinese carriers. Blood samples from 3,488 HBV carriers (1,527 aborigines and 1,961 Han Chinese) were assayed for aminotransferases, hepatitis B e antigen (HBeAg), HBV DNA, and HBV genotype. Aboriginal HBV carriers had a lower HBeAg-positive rate (5.3% vs. 10.2%, P < 0.0001) and a lower viral load of HBV DNA > 2,000 IU/ml (27.4% vs. 36.7%, P < 0.0001) but a higher rate of alcohol consumption (40.0% vs. 19.3%, P < 0.0001) than Han Chinese carriers. The prevalence of HBV genotype B in aboriginal carriers (92.7%) was significantly higher than that in Han Chinese carriers (72.7%) in all age groups (P < 0.05). In addition, patients with rare genotype D infections were clustered in a township in southern Taiwan. In conclusion, aboriginal Taiwanese HBV carriers have more favorable viral factors than Han Chinese carriers, which may be partly responsible for the lower standardized mortality rate of HCC in Taiwanese aborigines.
Journal of Medical Virology 08/2011; 83(8):1326-31. DOI:10.1002/jmv.22135 · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths in Taiwan. HCC with duodenal involvement are rare and are associated with a poor prognosis. The purpose of this retrospective study was to collect clinical information and data regarding survival following various treatments.
Between 1996 and 2009, 21 cases (17 men) were diagnosed with HCC and duodenal invasion and metastases by diagnostic imaging, endoscopy with biopsy, or surgically collected specimens sent to pathology. The clinical course was analyzed from the patients' medical records.
Gastrointestinal bleeding was reported in 18/21 patients. Diagnostic imaging showed that the majority of cases involved direct tumor invasion (predominantly from the right liver lobe) and six cases from metastasis. Tumor mass and ulcerations were the most common features noted on endoscopy. In addition to the component therapy and medication treatment, panendoscopic hemostasis, surgery, transcatheter arterial embolization, and radiotherapy were performed for the management of duodenal involvement and gastrointestinal bleeding. Survival duration after duodenal involvement ranged from 0.2 to 57.8 months (mean 10.5 months).
Gastrointestinal bleeding in advanced HCC should raise suspicions of duodenal involvement. HCC can involve the duodenum by direct invasion (from either the left or right liver lobes) or metastasis. The prognosis for HCC patients with duodenal involvement is poor, but is improved by supportive care and application of various treatment modalities.
Journal of Gastroenterology and Hepatology 07/2011; 27(4):677-83. DOI:10.1111/j.1440-1746.2011.06869.x · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PurposeThe proportion of B-HCC cases in Taiwan has progressively decreased over the last 20years. It was not really due to an overall
decrease in B-HCC but due to an increase in HCV-related HCC. The identification of potential HCV endemic areas in Taiwan has
consequently become important.
MethodsData were collected retrospectively from eight Taiwan medical centers from 1981 to 2001, the geographical variations of male
C-HCC townships in Taiwan were illustrated on maps. Goodness of fit was used to compare the anti-HCV prevalence in townships
and cities, with the mean anti-HCV prevalence for Taiwan as a whole. Township-, city-, and county-specific prevalence of anti-HCV
was presented as the median, ranges, and SMRs.
ResultsGeographic variation can be analyzed in only 263 townships and cities. The maps were designed on the basis of different SMRs.
The mean anti-HCV prevalence for male HCC patients in Taiwan was 31.9% (95% confidence interval: 30.7–33.0). Twenty-five townships
distributed throughout central-western and south-western Taiwan have significantly higher prevalence (P<0.05) (12 townships SMR≥2; 13 townships 1.5≤SMR<2). Twenty-two townships have significantly lower prevalence (P<0.05) (6 townships 0.5≤SMR<1; 16 townships SMR<0.5). Four different patterns of geographic variation in different counties
were also noted and demonstrated.
ConclusionWe successfully highlighted some potential high HCV endemic townships in Taiwan.
Hepatology International 12/2009; 3(4):537-543. DOI:10.1007/s12072-009-9146-x · 1.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antemortem diagnosis of hepatocellular carcinoma (HCC) with cardiac metastasis is uncommon. To clarify the clinical manifestation and survival of HCC patients with cardiac metastases, we initiated the present study.
We retrospectively analyzed 48 HCC patients with metastases into cardiac cavity diagnosed antemortem. The baseline clinical characteristics, echocardiogram, treatment modality and the outcome data were collected.
The most common symptoms of cardiac metastasis included asymptomatic in 19 cases (39.5%), bilateral lower leg edema in 18 cases (37.5%) and exertional dyspnea in 15 cases (31.3%). The median and mean survival times from the time of diagnosis of cardiac metastasis were 102 days and 161 days, respectively. Compared with another cohort of 48 patients with age-, gender-, and stage-matched HCC patients without cardiac metastasis, the median survival in the cardiac metastasis group was similar to the control group (68 days) (P = 0.67). The cause of death was HCC in 29, hepatic failure in seven, multiple organ failure in four, gastrointestinal bleeding in three, sepsis in two, pulmonary embolism in one, respiratory failure in one, and acute myocardial infarction in one.
Hepatocellular carcinoma patients with cardiac metastases were in the advanced stages. These patients had limited survival from the diagnosis of cardiac metastases. The most common cause of death was related to HCC per se or the underlying liver disease. Only a few patients expired because of cardiac metastases.
Journal of Gastroenterology and Hepatology 11/2009; 25(1):150-5. DOI:10.1111/j.1440-1746.2009.06036.x · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Liver progenitors, so-called oval cells, proliferate remarkably from periportal areas after severe liver injury when hepatocyte regeneration is compromised. These cells invade far into the liver parenchyma. Molecular mechanisms underlying these behaviors of oval cells remain poorly understood. In this study, we treated rats with 2-acetylaminofluorene/carbon tetrachloride to induce hepatic oval cells. By expression microarray analysis, we investigated global gene expression profiles in liver tissue, with an emphasis on adhesion molecules, extracellular matrix proteins, matrix metalloproteinases (MMPs), growth factors/cytokines, and receptors that might contribute to the distinct behaviors of oval cells. Genes upregulated at least twofold were selected. We then performed immunostaining to verify the microarray results and identified expression of MMP-7 and CD44 in oval cells. Staining of cytokeratin (CK)-19, an oval-cell marker, was similar between oval cells located next to periportal areas and those located far within the parenchyma. In contrast, CD44 staining was more intense in the parenchyma than in periportal areas, suggesting a role of CD44 in oval-cell invasion. Moreover, newly differentiated CK-19+ hepatocytes within foci did not show CD44 staining, suggesting that CD44 is related to the undifferentiated oval-cell phenotype. We then investigated oval-cell reactivity in CD44-deficient mice fed an oval cell-inducing diet of 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Results showed significantly reduced oval-cell reactivity in CD44-deficient mice. Thus, oval cells express MMP-7 and CD44, and CD44 appears to play critical roles in the proliferation, invasion, and differentiation of hepatic oval cells in rodents.
[Show abstract][Hide abstract] ABSTRACT: Although the mechanism remains obscure, two histological subtypes of gastric carcinoma (GC), the diffuse and intestinal types, differ drastically in epidemiological, clinical, pathological and biological characteristics. We investigated whether the genetic alterations of several oncogenes and tumour suppressor genes could be correlated with the two histological subtypes. In 60 patients with GC, the overexpression of mutant p53 and c-erbB-2 oncoproteins was studied using immunohistochemical stains. Mutations of the p15 and p16 tumour suppressor genes were assessed by polymerase chain reaction, Southern blotting, and direct DNA sequencing. Overexpression of c-erbB-2 and p53 was found in 21 (35.0%) and 27 (45.0%) patients, respectively. Overexpression of the c-erbB-2 oncoprotein was more common in the intestinal type (15/32, 46.9%) and the advanced stage (19/45, 42.2%) than in the diffuse type (6/28, 21.4%) and the early stage (2/15, 13.3%) of GC (P<0.05). Similarly, p53 overexpression was more frequently found in the intestinal type (19/32, 59.4%) and the advanced stage (24/45, 53.3%) than in the diffuse type (8/28, 28.6%) and the early stage (3/15, 20.0%) of GC (P<0.05). Homozygous deletions of p16 in exon 1 were found in six (10.0%) patients. Five of them had the intestinal-type advanced GC. Neither point mutations of p16 nor alterations of p15 were detected. The frequency of alterations of p53, c-erbB-2, and p16 was not related to sex and Helicobacter pylori infection. No correlation of genetic changes between any two genes was observed. Our preliminary results indicate alterations in the p15 gene were not important in gastric tumorigenesis, while infrequent homozygous deletions in the p16 gene play a limited role in tumour progression of intestinal-type GC. Moreover, overexpression of c-erbB-2 and p53 is frequently encountered in the intestinal-type advanced GC. Alterations of p53, c-erbB-2 and p16 genes may function independently of each other in gastric carcinogenesis. The association between genetic alterations and histological subtypes supports the notion that a distinct pathogenesis may exist in different histological subtypes.
Journal of Gastroenterology and Hepatology 08/2009; 13(3):305 - 310. DOI:10.1111/j.1440-1746.1998.01560.x · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Peritoneal metastasis is an uncommon manifestation of hepatocellular carcinoma (HCC). The aim of the present paper was to investigate the characteristics and survival of HCC patients with peritoneal metastases.
From January 1985 to December 2004, we retrospectively reviewed the records of 53 Taiwanese HCC patients with peritoneal metastases.
Peritoneal metastases were detected at the time of HCC diagnosis (synchronously) in 10 patients and after the initial therapy for the primary tumors (metachronously) in 43 patients. The mean time for development of the metachronous peritoneal metastases was similar whether the primary cancer was treated with surgery (24 months) or transarterial chemoembolization (22.2 months). The single patient whose primary cancer was treated with supportive care alone developed peritoneal metastasis only 7.5 months after detection of the primary cancer. Surgical resection of the peritoneal metastases was possible in two-thirds of the 43 metachronous patients. The median survival for those who received surgery for these metastases was 12.5 months vs. 2.1 months for those without surgery (P = 0.0013). However, there was no difference in survival if patients were stratified to Child-Pugh grade.
Peritoneal metastases of HCC are rare and can occur synchronously or metachronously. Though increased long-term survival was found in patients who had surgical removal of peritoneal metastases, the main determinant of better survival is Child-Pugh grade.
Journal of Gastroenterology and Hepatology 06/2009; 24(5):815-20. DOI:10.1111/j.1440-1746.2009.05848.x · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: According to current guidelines of hepatocellular carcinoma (HCC) treatment, multiple HCCs are usually not suitable for surgical resection. However, surgical resection is still possible for patients with multiple HCCs. The role of hepatic resection vs transarterial chemoembolization (TACE) for multiple HCCs should be further clarified.
We retrospectively enrolled 1065 patients with multiple HCCs. Among them, 294 received surgical resection, 367 received transarterial chemoembolization (TACE), and 404 received chemotherapy or supportive care. Three staging systems (TNM, CLIP, and BCLC) were used for comparison of stage-specific survival between different treatment modalities.
The median survival of multiple HCC patients who received surgical resection was 37.9 months, while it was 17.3 months in TACE group, and 2.8 months in supportive group (P < .001). The 1-year, 3-year, 5-year survival rates for surgical group were 77.4%, 51.9%, and 36.6%, respectively. Kaplan-Meier survival analysis demonstrated that patients who received surgical resections had the best survival, followed by TACE and supportive care. For patients of the same stage, surgical resection yields better results than TACE. Surgery could offer better survival than TACE for patients either within or beyond Milan's criteria.
Our results indicate that if patients have preserved liver functions, hepatic resection is helpful, even for patients with multiple HCCs.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to compare six prognostic staging systems (Okuda stage, TNM stage, CLIP score, BCLC stage, JIS score and Tokyo score) in predicting survival in patients with hepatocellular carcinoma (HCC). A total of 2010 Taiwanese HCC patients were included. Demographic, laboratory and tumour characteristics were determined at diagnosis. Predictors of survival included serum levels of albumin, total bilirubin, alkaline phosphatase, alpha-fetoprotein, ascites, tumour size and portal vein invasion. The Tokyo score was the most informative one for predicting the survival of HCC patients as a whole, receiving surgical resection, or receiving transarterial chemoembolisation. CLIP score was the best fit system for HCC patients receiving chemotherapy or supportive care. Each staging system showed a significant difference in predicting the probability of survival across different stages. The applicability of staging systems for patients with HCC was dependent on treatment methods.
European journal of cancer (Oxford, England: 1990) 02/2009; 45(9):1630-9. DOI:10.1016/j.ejca.2008.12.025 · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Severe intrahepatic cholestasis with low serum gamma-glutamyltranspeptidase (gamma-GT) activity is exceptionally rare in adult patients, and its association with multi-genetic alterations of bile salt transporters has not been reported. We investigated a 25-year-old man presenting with a four-year history of jaundice. Laboratory and radiographic examinations revealed clinical pictures of progressive intrahepatic cholestasis with low gamma-GT. Serial liver histopathology demonstrated cirrhosis resulting from progressive persistent cholestatic injury. Genetic sequencing studies for the entire coding exons of ATP8B1 and ABCB11 uncovered a heterozygous missense mutation 1798 C->T (R600W) in ATP8B1, and a homozygous nucleotide substitution 1331 T->C (V444A) in ABCB11. In conclusion, this is a rare case of adult onset progressive intrahepatic cholestasis with low gamma-GT associated with heterozygous ATP8B1 mutation and homozygous ABCB11 polymorphism. Further studies are necessary to investigate the impact of heterozygous R600W mutation and whether other cholestatic disorders are multi-genetic.
Hepatology Research 02/2009; 39(6):625-31. DOI:10.1111/j.1872-034X.2009.00499.x · 2.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We recently reported the successful use of the loop-mediated isothermal amplification (LAMP) reaction for hepatitis B virus (HBV) DNA amplification and its optimal primer design method. In this study, we report the development of an integrated isothermal device for both amplification and detection of targeted HBV DNA. It has two major components, a disposable polymethyl methacrylate (PMMA) micro-reactor and a temperature-regulated optical detection unit (base apparatus) for real-time monitoring of the turbidity changes due to the precipitation of DNA amplification by-product, magnesium pyrophosphate. We have established a correlation curve (R2 = 0.99) between the concentration of pyrophosphate ions and the level of turbidity by using a simulated chemical reaction to evaluate the characteristics of our device. For the applications of rapid pathogens detection, we also have established a standard curve (R2 = 0.96) by using LAMP reaction with a standard template in our device. Moreover, we also have successfully used the device on seven clinical serum specimens where HBV DNA levels have been confirmed by real-time PCR. The result indicates that different amounts of HBV DNA can be successfully detected by using this device within 1 h.
Sensors and Actuators B Chemical 08/2008; 133(2-133):493-501. DOI:10.1016/j.snb.2008.03.008 · 4.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatitis delta virus (HDV) encodes two isoforms of delta antigens (HDAgs). The small form of HDAg (SHDAg) is required for HDV RNA replication, while the large form of HDAg (LHDAg) is required for viral assembly. Using tandem affinity purification method combined with mass spectrometry, we found that linker histone H1e bound to SHDAg. The binding domain of SHDAg to histone H1e was mapped to the N-terminal 67 amino acids. Oligomerization of SHDAg was required for its interaction with histone H1e. LHDAg barely bound to histone H1e and was masked at N-terminus. The binding domain of histone H1e to SHDAg was mapped to its central globular domain. HDV replication was inhibited by N- or C-terminal deletion mutants of histone H1e and was rescued by wild-type histone H1e. We conclude that histone H1e plays a significant role in HDV replication through forming protein complex with SHDAg.
[Show abstract][Hide abstract] ABSTRACT: Based on observations of a limited number of patients, delta (δ) infection has been reported to be infrequent in Taiwan. To further evaluate the role of δ-infection in patients with hepatitis B virus (HBV) infection, serum samples of 493 subjects with acute and chronic HBV infections collected in 1976–85 were studied for anti-δ by radioimmunoassay. Intrahepatic δ-antigen was also studied by immunofluorescence in 12 anti-δ-positive patients. The overall prevalence of δ-infection was 4.7%, consistent with previous studies. δ-Infection had an even yearly distribution in the last decade. However, there were four groups with significantly higher frequencies: (i) 24% of 41 anti-HBe-positive patients with chronic active hepatitis (CAH); (ii) 21% of 14 HBsAg carriers with prominent lobular hepatitis; (iii) two of three HBsAg carriers with intravenous drug abuse; and (iv) two of seven with fulminant hepatitis. On the other hand, δ-infection was uncommon in patients with chronic persistent hepatitis, cirrhosis, hepatocellular carcinoma, classical type B hepatitis, submassive necrosis and asymptomatic HBsAg carriers. δ-Antigen was found in only two patients with CAH; one progressed to cirrhosis, and the other had disease regression on follow-up. Overall, at least half of the δ-superinfected HBsAg-positive patients had a non-progressive course on follow-up.
It was concluded that δ-agent was introduced to Taiwan before 1976. Although it has played a role in some clinical settings of HBV infections, it is generally infrequent in Taiwan. The δ-superinfection apparent in half the patients studied seems to have a non-progressive course.
Journal of Gastroenterology and Hepatology 03/2008; 2(1):1 - 8. DOI:10.1111/j.1440-1746.1987.tb00142.x · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate whether the tumour suppressor gene, PPP2R1B, is involved in pathogenesis of hepatocellular carcinoma (HCC), reverse transcription-polymerase chain reaction (RT-PCR) and cDNA sequencing were performed. Eleven of 38 (29%) tumours and 1 of 34 (3%) corresponding non-tumour tissues showed coexpression of wild-type and aberrant mRNA. Various deletions were found in aberrant transcripts. Southern blot analysis did not show gene deletion in tumours, suggesting abnormal RNA splicing may be involved. These data suggest the possibility that aberrant transcripts of PPP2R1B might be associated with the development of HCC.
Cancer Letters 09/2007; 253(1):138-43. DOI:10.1016/j.canlet.2007.01.016 · 5.62 Impact Factor