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1.
World J Surg Oncol ; 13: 36, 2015 Feb 12.
Article in English | MEDLINE | ID: mdl-25889416

ABSTRACT

BACKGROUND: Prognostic factors are useful for determination of the therapeutic strategy and follow-up examination after curative operation in cancer treatment. The immunological state of the host can influence the prognosis for cancer patients as well as the features of the cancer. Human lymphocyte antigen (HLA) class I molecules have a central role in the anti-cancer immune system. Therefore, we focused on the HLA class I expression level in cancer cells to investigate its prognostic value in patients with colorectal cancer. METHODS: We reviewed the clinical pathology archives of 97 consecutive patients with stage II colorectal cancer who underwent curative operation at the Sapporo Medical University, Japan, from February 1994 to January 2005. Fifty-six high-risk patients had adjuvant chemotherapy. The cancer cell membrane immunoreactivity level for HLA class I expressed by EMR8-5 was classified into three categories (positive, dull, and negative). In this study, the cases were divided into two groups: "positive" and "dull/negative". HLA class I expression level and clinicopathological parameters were evaluated with the Pearson χ (2) test. Survival analysis was assessed by the Kaplan-Meier methods, and the differences between survival curves were analyzed using the log-rank test. RESULTS: Immunohistochemical study of HLA class I revealed the following. There were 51 cases that were positive, 40 were dull, and six negative. The HLA class I expression level had no significant correlation with other clinicopathological parameters, except for gender. Univariate and multivariate analyses related to disease-free survival (DFS) revealed that tumor location, HLA expression level, and venous invasion were significant independent prognostic factors (P < 0.05). The 5-year DFS rates in HLA class I positive group and in the dull/negative group were 89% and 70%, respectively. For high-risk patients with adjuvant chemotherapy, the 5-year DFS rates in the HLA class I positive group and in the dull/negative group were 84% and 68%, respectively. For low-risk patients without the chemotherapy, the 5-year DFS rates in the HLA class I positive group and in the dull/negative group were 100% and 71%, respectively. CONCLUSIONS: Our study concluded that the HLA class I expression level might be a very sensitive prognostic factor in colorectal cancer patients with stage II disease.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/metabolism , Colorectal Neoplasms/metabolism , Histocompatibility Antigens Class I/metabolism , Adult , Aged , Aged, 80 and over , Cisplatin/administration & dosage , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Immunoenzyme Techniques , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Invasiveness , Neoplasm Staging , Prognosis , Survival Rate
2.
Scand J Gastroenterol ; 43(5): 574-80, 2008.
Article in English | MEDLINE | ID: mdl-18415750

ABSTRACT

OBJECTIVE: Although commonly practiced in Japan, the effectiveness of regular screening with upper gastrointestinal (UGI) endoscopy against gastric cancer has not been well evidenced. The aim of the study was to investigate if gastric cancer-related mortality can be reduced by regular endoscopy. MATERIAL AND METHODS: The medical records of 833 patients with gastric ulcer (GU) and 2547 without ulcer (NU) were analyzed; these patients received long-term, repeated endoscopic examinations between 1969 and 2004. Gastric cancer incidence, death by gastric cancer, and overall survival were compared with those in a Japanese general population by calculating the standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs). RESULTS: The interval between UGI endoscopic examinations was 1.4 +/- 1.4 years in the GU group and 1.8 +/- 1.5 years in the NU group. During follow-up, 32 patients with GU and 61 in the NU group developed gastric cancer, showing annual incidence rates of 0.40% (95% CI: 0.24-0.56%) and 0.38% (0.28-0.48%), and SIRs of 2.21 (1.44-2.98) and 1.72 (1.29-2.15), respectively. The 5-year survival rate exceeded 80% among patients who developed gastric cancer. SMRs for gastric cancer and overall deaths were 0.50 (0.01-0.99) and 1.05 (0.87-1.23) in GU patients, and 0.45 (0.15-0.74) and 0.78 (0.69-0.88) in NU patients. There were no significant differences between the two groups in gastric cancer incidence, mortality from gastric cancer, and overall survival. CONCLUSIONS: Mortality from gastric cancer could be reduced by regular UGI endoscopy in a population with a high incidence of gastric cancer.


Subject(s)
Gastroscopy , Stomach Neoplasms/mortality , Female , Humans , Japan/epidemiology , Male , Middle Aged , Stomach Neoplasms/diagnosis , Stomach Neoplasms/pathology , Survival Rate
3.
J Gastroenterol ; 41(7): 693-701, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16933008

ABSTRACT

BACKGROUND: Long-term lamivudine treatment induces the emergence of lamivudine-resistant hepatitis B virus (HBV). The objective of this study was to develop a fluorescent biprobe hybridization (FBH) assay for the detection and quantification of HBV mutants in the clinical course of lamivudine-treated patients and to evaluate its clinical usefulness. METHODS: We developed an FBH assay to detect mutations in the HBV DNA polymerase gene. The assay's detection sensitivity was determined using a dilution series of wild-type/mutant plasmid DNA. Blood samples obtained from 27 lamivudine-treated patients were analyzed. RESULTS: Mutant DNA levels as low as 10% of total HBV DNA were detected (sensitivity = 100%, specificity = 80%). HBV mutants were detected in five of the 27 patients during an average follow-up of 20 months after lamivudine administration. In one of the five patients, the YIDD mutant was detected at the initiation of lamivudine treatment, while the remaining four patients were identified as having YIDD mutants within 3 months after beginning lamivudine administration. Of the five patients with an HBV mutant, four developed breakthrough hepatitis more than 10 months after the detection of HBV mutants, following the reappearance or a re-increase of HBV DNA, characterized by a predominance of the mutant. The YIDD mutant was detected in one patient, even when the titer of the serum HBV DNA was below the detection limit of commercially available quantitative polymerase chain reaction. CONCLUSIONS: The FBH assay is an efficient method for detecting and quantifying HBV mutants, as early as 3 months after lamivudine administration.


Subject(s)
Antiviral Agents/pharmacology , Drug Resistance, Viral/genetics , Hepatitis B virus/drug effects , Hepatitis B, Chronic/drug therapy , Lamivudine/pharmacology , Mutation , Adult , Antiviral Agents/administration & dosage , Antiviral Agents/therapeutic use , DNA Probes , DNA-Directed DNA Polymerase/genetics , Female , Fluorometry , Hepatitis B virus/genetics , Hepatitis B, Chronic/virology , Humans , Lamivudine/administration & dosage , Lamivudine/therapeutic use , Male , Middle Aged , Nucleic Acid Hybridization/methods , Sensitivity and Specificity , Transition Temperature
4.
Gastrointest Endosc ; 64(1): 73-8, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16813806

ABSTRACT

BACKGROUND: Hemorrhage is among the most serious complications of colorectal polypectomy and may occur after a longer postprocedure interval. OBJECTIVE: We aimed to elucidate the risk factors for delayed postpolypectomy hemorrhage, including both polyp characteristics and the general condition of the patients. DESIGN: Retrospective cohort study. PATIENTS: A total of 6617 cases of colorectal polypectomy was performed in 3138 consecutive patients in Japan. MAIN OUTCOME MEASUREMENTS: The risk factors for delayed postpolypectomy hemorrhage were assessed among polyp characteristics (form, size, histologic features) and the method of resection by unconditional logistic regression. Patient conditions (smoking, alcohol, hypertension, diabetes mellitus, hyperlipidemia) were compared between case-control pairs matched on polyp-related characteristics by conditional logistic regression. RESULTS: Hemorrhage occurred in 38 lesions (0.57%) of 37 patients (1.2%): 22 required endoscopic hemostasis and 1 required blood transfusion. Although polyp size was associated with the occurrence of delayed hemorrhage (10.0 +/- 6.9 mm in hemorrhage cases vs 5.6 +/- 3.8 mm in others, P < .0001), other polyp-related factors were not significant. Hypertension was a complication in 25 of 37 (68%) cases and in 21 of 74 (28%) matched controls, showing an adjusted odds ratio of 5.6 (95% CI 1.8-17.2, P = .001). Other patient characteristics were not significant. The interval between polypectomy and hemorrhage was significantly longer in patients with hypertension (median 6 days, range 2-14 days) than in those without hypertension (2.5 days, 1-9 days; P = .019). LIMITATIONS: This study does not provide information regarding prevention of hemorrhage. CONCLUSIONS: Hypertension is a significant risk factor for delayed colorectal postpolypectomy hemorrhage. The interval between polypectomy and hemorrhage can be as long as 14 days in the presence of hypertension.


Subject(s)
Colonic Polyps/surgery , Colonoscopy/adverse effects , Postoperative Hemorrhage/epidemiology , Aged , Case-Control Studies , Diabetes Mellitus/epidemiology , Female , Hemostasis, Endoscopic , Humans , Hyperlipidemias/epidemiology , Incidence , Logistic Models , Male , Middle Aged , Multivariate Analysis , Postoperative Hemorrhage/etiology , Risk Assessment , Time Factors
5.
Int J Hyperthermia ; 22(8): 699-712, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17390999

ABSTRACT

In cancer immunotherapies combined with hyperthermia, one or two cytokines have been tested to augment the anti-tumor effect. However, the therapies have not shown sufficient improvement. The aim of this study is to find a new potent tumor immunotherapy in order to augment antitumor effect of hyperthermia by the cytokine cocktails in vivo. We used a combination therapy of local hyperthermia (LH) and various cytokine cocktails composed of IFNs (IFN-alpha, -beta, and -gamma), Thl cytokines (IL-2, -12, -15, and -18), a Th2 cytokine (IL-4), inflammatory cytokines (IL-lalpha and TNF-alpha), and dendritic cell-inducible cytokines (IL-3 and GM-CSF). These cytokines in a proper combination augmented the anti-tumor effect of LH and prolonged survival time in Lewis lung carcinoma or B16 melanoma significantly. Moreover, the 12-cytokine cocktail suppressed B 16 metastasis to the lung and lymph nodes, and complete regression of the tumors without regrowth occurred in 3 of 5 mice. In the cured three B16 mice, there was hyperplasia of lymphatic organs with many CD3-positive T lymphocytes. The most effective cytokine combination should be able to augment the anti-tumor effect of other therapies besides hyperthermia that induce the necrosis of tumor cells.


Subject(s)
Carcinoma, Lewis Lung/therapy , Cytokines/therapeutic use , Hyperthermia, Induced , Immunotherapy, Active/methods , Melanoma, Experimental/therapy , Animals , Combined Modality Therapy , Disease Models, Animal , Male , Mice , Survival Analysis , Treatment Outcome
6.
Am J Trop Med Hyg ; 73(5): 934-5, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16282306

ABSTRACT

Amebiasis is a common parasitic infectious disease in developing countries. In developed countries, it is occasionally encountered in travelers to the tropics and in homosexual males. During the past eight years, we detected four cases of amebic colitis among 5,193 subjects who underwent colonoscopy because of positive fecal occult blood test results in a mass screening. All four cases did not have any abdominal symptoms. Ulcerative lesions were observed only in the cecum and ascending colon; another portion of the colon and rectum appeared normal. We may encounter amebic colitis during colonoscopic examination even in subjects who are asymptomatic.


Subject(s)
Cecum/pathology , Dysentery, Amebic/physiopathology , Entamoeba histolytica/pathogenicity , Occult Blood , Animals , Cecum/parasitology , Colonoscopy , Dysentery, Amebic/diagnosis , Dysentery, Amebic/parasitology , Entamoeba histolytica/isolation & purification , Humans , Male , Middle Aged
7.
Cancer Res ; 65(11): 4562-7, 2005 Jun 01.
Article in English | MEDLINE | ID: mdl-15930273

ABSTRACT

Mutations in the PIK3CA gene, which encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K), have been reported in human cancers, including colorectal cancer. Most of the mutations cluster at hotspots within the helical and kinase domains. Whereas H1047R, one of the hotspot mutants, is reported to have elevated lipid kinase activity, the functional consequences of other mutations have not been examined. In this study, we examined the effects of colon cancer-associated PIK3CA mutations on the lipid kinase activity in vitro, activation of the downstream targets Akt and p70S6K in vivo and NIH 3T3-transforming ability. Of eight mutations examined, all showed increased lipid kinase activity compared with wild-type p110alpha. All the mutants strongly activated Akt and p70S6K compared with wild-type p110alpha as determined by immunoblotting using phospho-specific antibodies. These mutants also induced morphologic changes, loss of contact inhibition, and anchorage-independent growth of NIH 3T3 cells. The hotspot mutations examined in this study, E542K, E545K, and H1047R, all had high enzymatic and transforming activities. These results show that almost all the colon cancer-associated PIK3CA mutations are functionally active so that they are likely to be involved in carcinogenesis.


Subject(s)
Colorectal Neoplasms/enzymology , Phosphatidylinositol 3-Kinases/genetics , Animals , Biomarkers, Tumor/genetics , Cell Adhesion/physiology , Cell Growth Processes/physiology , Class I Phosphatidylinositol 3-Kinases , Colorectal Neoplasms/genetics , Enzyme Activation , Humans , Mice , NIH 3T3 Cells , Phosphatidylinositol 3-Kinases/metabolism , Protein Conformation , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Tertiary , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , Ribosomal Protein S6 Kinases, 70-kDa/metabolism
8.
Clin Gastroenterol Hepatol ; 3(4): 376-83, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15822043

ABSTRACT

BACKGROUND & AIMS: Pancreatitis remains the major complication of endoscopic retrograde cholangiopancreatography (ERCP), and hyperenzymemia after ERCP is common. Because ulinastatin, a protease inhibitor, has proved effective in the treatment of acute pancreatitis, the aim of this study was to assess the efficacy of ulinastatin for the prevention of post-ERCP pancreatitis and hyperenzymemia. METHODS: In a multicenter, randomized, double-blind, placebo-controlled trial, patients undergoing a first ERCP were randomized to receive ulinastatin (150,000 U) or placebo by intravenous infusion for 10 minutes starting immediately before ERCP. All patients were hospitalized at least 24 hours after ERCP for evaluation of clinical symptoms. Serum pancreatic enzyme levels were measured before and at 4 and 18 hours after ERCP. The primary end point was the incidence of post-ERCP pancreatitis and the secondary objective was the occurrence of hyperenzymemia. RESULTS: A total of 406 patients were enrolled (204 in the ulinastatin group and 202 in the placebo group). There were no differences between the 2 groups regarding baseline characteristics, details of fluoroscopic findings, or endoscopic procedure. The incidence of hyperenzymemia was significantly lower in the ulinastatin group than in the placebo group (amylase, P = .011; lipase, P = .008). Six patients in the ulinastatin group and 15 patients in the placebo group developed pancreatitis (2.9% vs. 7.4%, P = .041). There was no case of severe pancreatitis in either group. Patients who received ulinastatin did not present any side effects related to the medication. CONCLUSIONS: Prophylactic short-term administration of ulinastatin decreases the incidence of pancreatitis and hyperenzymemia after ERCP.


Subject(s)
Cholangiopancreatography, Endoscopic Retrograde/adverse effects , Glycoproteins/administration & dosage , Pancreatitis/prevention & control , Acute Disease , Cholangiopancreatography, Endoscopic Retrograde/methods , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Infusions, Intravenous , Male , Pancreatitis/etiology , Probability , Reference Values , Treatment Outcome
9.
Mol Carcinog ; 43(1): 59-63, 2005 May.
Article in English | MEDLINE | ID: mdl-15791648

ABSTRACT

Mutations in the B-raf gene have been reported in a number of human cancers, including melanoma and lung cancer. More than 80% of the reported B-raf mutations were V599E; however, non-V599E mutations have been frequently found in non-small cell lung cancers as compared with melanoma. Some non-V599E mutations have been found surrounding Thr439, which is thought likely to be one of the three Akt phosphorylation sites in the B-raf protein. However, as a previous report indicated that Thr439 was not phosphorylated by Akt, the functional consequences of these mutations have been unclear. Here, we examined the effects of cancer-related B-raf mutations surrounding Thr439 on the activation of the mitogen-activated protein/ extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (Erk) pathway and the transformation of NIH 3T3 fibroblasts. Among the three reported mutations (K438Q, K438T, and T439P) found in non-small cell lung carcinoma and melanoma, none elevated the activity of the MEK/Erk cascade as determined by in vitro kinase assays, immunoblots using antibody specific for phosphorylated Erk, or Elk1-dependent reporter assays. The inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt signaling by LY294002 increased the Erk activation induced by the mutant B-raf proteins, as well as by wild-type B-raf. Furthermore, the B-raf mutants did not have increased NIH 3T3-transforming activities, as determined by colony-formation assays. These results suggest that the B-raf mutations surrounding Thr439 found in human cancers are unlikely to contribute to increased oncogenic properties of B-raf.


Subject(s)
Mutation , Neoplasms/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins B-raf/metabolism , Proto-Oncogene Proteins/metabolism , Amino Acid Motifs , Animals , Cell Line , Humans , Neoplasms/pathology , Phosphorylation , Proto-Oncogene Proteins B-raf/chemistry , Proto-Oncogene Proteins c-akt
11.
Cancer Res ; 64(10): 3428-35, 2004 May 15.
Article in English | MEDLINE | ID: mdl-15150094

ABSTRACT

Recently, mutations in the B-Raf gene have been identified in a variety of human cancers, such as melanoma and colorectal carcinoma, and more than 80% of the B-Raf mutations have been V599E. Although other mutations have been reported, their functional consequences are poorly understood. In our earlier study, we demonstrated that colon tumor-associated B-Raf mutations within the kinase activation segment are not necessarily associated with an increase in mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase (MEK/Erk) or nuclear factor kappaB (NFkappaB) signaling activity or in NIH3T3-transforming ability. In this study, we examined the effect of colon tumor-associated mutations within the B-Raf glycine-rich loop (G loop) on MEK/Erk and NFkappaB signaling and on the transformation of NIH3T3 fibroblasts or IEC-6 intestinal epithelial cells. Of the six G loop mutations examined, only the B-Raf G468A significantly increased MEK/Erk and NFkappaB signaling and NIH3T3 transformation. Only this mutation induced transformed phenotypes of IEC-6 cells. In contrast, the B-Raf G468E mutation significantly decreased MEK/Erk signaling and NIH3T3 transformation and had no effect on NFkappaB signaling. The B-Raf F467C mutation moderately elevated MEK/Erk signaling and NIH3T3 transformation. The other three B-Raf mutations, R461I, I462S, and G463E, did not increase MEK/Erk or NFkappaB signaling or NIH3T3 transformation. Except for F467C, none of the tumors with B-Raf mutations examined in this study had K-Ras mutations. These results suggest that some of the B-Raf G loop mutations reported in colorectal tumors do not increase kinase or transforming activities but might contribute to carcinogenesis via other mechanisms or be irrelevant to carcinogenesis.


Subject(s)
Cell Transformation, Neoplastic/genetics , Colorectal Neoplasms/genetics , MAP Kinase Signaling System/genetics , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Point Mutation , Proto-Oncogene Proteins c-raf/genetics , Amino Acid Sequence , Animals , COS Cells , Cell Adhesion/genetics , Cell Division/genetics , Cell Transformation, Neoplastic/metabolism , Chlorocebus aethiops , Colorectal Neoplasms/enzymology , Enzyme Activation , Humans , I-kappa B Kinase , Mice , Mitogen-Activated Protein Kinases/genetics , Molecular Sequence Data , NIH 3T3 Cells , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins B-raf , Proto-Oncogene Proteins c-raf/metabolism , Sequence Alignment , Signal Transduction , Transcription, Genetic
12.
Cancer Genet Cytogenet ; 149(1): 68-71, 2004 Feb.
Article in English | MEDLINE | ID: mdl-15104286

ABSTRACT

The BRAF gene is mutated in 66% of melanomas and less frequently in various human cancers. More than 80% of these mutations are T to A transversions at nucleotide 1796 (T1796A), leading to a substitution of glutamic acid for valine at amino acid 599 (V599E). We established a new method for rapidly detecting V599E mutations using real-time polymerase chain reaction and melting curve analysis. Furthermore, we examined mutations in gastrointestinal cancer cell lines using this method. We found a mutation in 1 of 12 (8%) colorectal cancer cell lines, but no mutation was detected in 9 gastric cancer cell lines. These results suggest that the BRAF mutation is unlikely to be involved in gastric carcinogenesis.


Subject(s)
Colorectal Neoplasms/genetics , DNA, Neoplasm/isolation & purification , Gastrointestinal Neoplasms/genetics , Mutation/genetics , Proto-Oncogene Proteins c-raf/genetics , Amino Acid Substitution , DNA Primers/chemistry , DNA, Neoplasm/genetics , Humans , Nucleic Acid Denaturation , Proto-Oncogene Proteins B-raf , Reverse Transcriptase Polymerase Chain Reaction/methods , Tumor Cells, Cultured
13.
Cancer Res ; 63(23): 8132-7, 2003 Dec 01.
Article in English | MEDLINE | ID: mdl-14678966

ABSTRACT

Mutations in the B-Raf gene have been reported in a number of human cancers, including colorectal carcinoma. More than 80% of the B-Raf mutations were V599E. Although other mutations have been reported, their functional consequences were unclear. Here, we examined the effect of colon tumor-associated B-Raf mutations within the kinase activation segment, including V599E, on extracellular signal-regulated kinase (Erk) and nuclear factor kappaB (NFkappaB) signaling, and on the transformation of NIH3T3 fibroblasts. Among the six mutations examined, only the B-Raf V599E and K600E mutations greatly increased Erk and NFkappaB signaling, and the transformation of NIH3T3 cells. The B-Raf F594L mutation moderately elevated Erk signaling and NIH3T3 transformation, but did not significantly increase NFkappaB signaling. Although the basal kinase activity of the B-Raf T598I mutant was comparable with that of wild-type, its oncogenic Ras-induced kinase activity was decreased to 60% of wild-type activity. The B-Raf D593V and G595R mutants showed severely reduced kinase activity and affected neither NFkappaB signaling nor NIH3T3 transforming activity. These results suggest that the B-Raf activation segment mutations other than V599E reported in colorectal tumors do not necessarily contribute to carcinogenesis by increasing kinase and transforming activities.


Subject(s)
Colorectal Neoplasms/enzymology , Colorectal Neoplasms/genetics , MAP Kinase Kinase Kinase 1 , Mutation , Proto-Oncogene Proteins c-raf/genetics , 14-3-3 Proteins , Amino Acid Sequence , Animals , Cell Transformation, Neoplastic/genetics , Enzyme Activation , HSP90 Heat-Shock Proteins/metabolism , Humans , MAP Kinase Kinase Kinases/metabolism , Mice , Mitogen-Activated Protein Kinase Kinases/metabolism , Molecular Sequence Data , NF-kappa B/physiology , NIH 3T3 Cells , Proto-Oncogene Proteins B-raf , Proto-Oncogene Proteins c-raf/metabolism , Signal Transduction/physiology , Transcription, Genetic , Tyrosine 3-Monooxygenase/metabolism
14.
J Infect Dis ; 187(5): 820-8, 2003 Mar 01.
Article in English | MEDLINE | ID: mdl-12599056

ABSTRACT

Hepatitis delta virus (HDV) is a naturally occurring satellite of hepatitis B virus (HBV). There are few studies of the effects of the combination of HBV and HDV proteins (HDV antigens [HDAgs]) on intracellular signaling pathways. To understand the influence of HBV and HDV coinfection on hepatocytes, we investigated the effect of HBV proteins and HDAgs on the serum response element (SRE)-dependent pathway. Reporter assays revealed that only HBV X protein (HBx), alone or with the large isoform of HDAg (LHDAg), synergistically activated the SRE-dependent pathway. The effect of HBx and LHDAg on Elk1 or serum response factor (SRF) was examined, because both proteins bind to the SRE. HBx activated the transcriptional ability of Elk1, whereas LHDAg activated the transcriptional ability of SRF. Thus, HBx and LHDAg synergistically activated the SRE-dependent pathway. These results may help us understand clinical phenomena in patients coinfected with HBV and HDV.


Subject(s)
DNA-Binding Proteins , Hepatitis delta Antigens/metabolism , Serum Response Element/genetics , Signal Transduction , Trans-Activators/metabolism , Transcription Factors , Transcriptional Activation , Animals , COS Cells , HeLa Cells , Hepatitis delta Antigens/genetics , Humans , Protein Isoforms , Proto-Oncogene Proteins/metabolism , Serum Response Factor/metabolism , Trans-Activators/genetics , Transcription, Genetic , Transfection , Tumor Cells, Cultured , Viral Regulatory and Accessory Proteins , ets-Domain Protein Elk-1
15.
Jpn J Cancer Res ; 93(11): 1213-20, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12460462

ABSTRACT

We investigated the frequency and mechanism of beta-catenin/T cell factor (Tcf) signaling activation in a panel of 36 human gastrointestinal and liver cancer cell lines. Reporter assay and electrophoretic mobility shift assay revealed that the beta-catenin/Tcf signaling was upregulated in 12 of 12 (100%) colorectal, 5 of 8 (68%) gastric, 2 of 7 (29%) hepatic, and none of 9 pancreatic cancer cell lines. The activation of the pathway was mainly due to the mutation of adenomatous polyposis coli (APC) or beta-catenin, and Tcf-4 was highly expressed in these cell lines with upregulated signaling. Nuclear beta-catenin was observed not only in the signaling-activated cell lines, but also in 14 of 25 (56%) primary gastric cancers, 15 of 20 (75%) colon cancers, 5 of 19 (26%) hepatocellular carcinomas, and none of 13 pancreatic cancers. The presence of signaling-upregulated gastric cancer cell lines with intact APC and beta-catenin suggests the involvement of other mechanisms than mutations of APC or beta-catenin.


Subject(s)
Carcinoma, Hepatocellular/etiology , Colorectal Neoplasms/etiology , Cytoskeletal Proteins/physiology , DNA-Binding Proteins/physiology , Liver Neoplasms/etiology , Stomach Neoplasms/etiology , Trans-Activators/physiology , Transcription Factors/physiology , Cytoskeletal Proteins/analysis , Cytoskeletal Proteins/genetics , DNA-Binding Proteins/analysis , Genes, APC , Humans , Immunohistochemistry , Lymphoid Enhancer-Binding Factor 1 , Trans-Activators/analysis , Trans-Activators/genetics , Transcription Factors/analysis , Tumor Cells, Cultured , Up-Regulation , beta Catenin
16.
Hepatology ; 35(4): 853-60, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11915031

ABSTRACT

alpha-fetoprotein (AFP) messenger RNA (mRNA) has been proposed as a marker of hepatocellular carcinoma (HCC) cells disseminated into the circulation, but its clinical significance remains controversial. We prospectively assessed the prognostic value of AFP mRNA in patients undergoing curative hepatic resection for HCC. Peripheral blood samples were taken from 87 patients before and after surgery to determine the presence of AFP mRNA by use of a reverse-transcription polymerase chain reaction. A primary endpoint was recurrence-free interval. AFP mRNA was detectable preoperatively in 31 patients (36%) and postoperatively in 30 patients (34%). With a median follow-up period of 28 months (range, 3-41 months), HCC recurred in 46 patients (53%). Among 4 groups separated according to preoperative and postoperative AFP mRNA status, patients with consistent positivity of AFP mRNA showed the highest recurrence rate (85%) and trend to distant or multiple recurrence. The recurrence-free interval was significantly shorter in patients with postoperative positivity of AFP mRNA than in those without (53% [95% CI, 36-71] vs. 88% [95% CI, 79-96] at 1 year, 37% [95% CI, 17-57] vs. 60% [95% CI, 46-75] at 2 years; P =.014), whereas the preoperative positivity of AFP mRNA provided no significance (P =.100). Cox's proportional-hazards model identified the postoperative positivity of AFP mRNA as an independent prognostic factor for HCC recurrence (relative risk, 2.33; 95% CI, 1.26-4.34; P =.007). In conclusion, postsurgical recurrence of HCC can be predicted by detecting AFP mRNA-expressing cells in peripheral blood.


Subject(s)
Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/surgery , Liver Neoplasms/metabolism , Liver Neoplasms/surgery , Neoplasm Recurrence, Local , RNA, Messenger/blood , alpha-Fetoproteins/genetics , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Forecasting , Humans , Male , Middle Aged , Predictive Value of Tests , Proportional Hazards Models , Prospective Studies
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