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AIM: Hepatocellular adenoma (HCA) has a lower prevalence in Japan than in Western countries and HCA subtypes have been reported for only a few Japanese patients. We analyzed HCA subtype data 38 patients from 23 hospitals in Japan in order to examine character and difference between Western countries. METHODS: To confirm HCA and to analyze subtypes, we performed immunohistochemical examinations. RESULTS: Thirty-eight cases were found to have HCA without cirrhosis. The male/female ratio was 18/20. Ages ranged from 15 to 79 (average, 43.2) years. Male and elder patients are not rare, furthermore, most of elder patients are male. Glycogen storage disease, past history of medicament use, hepatitis B virus surface antigen-positivity, antihepatitis C virus -positivity, diabetes mellitus, obesity, lipid metabolism disorder and alcoholism were present in of 6, 8, 1, 1, 6, 6, 4, and 6 cases, respectively. As to HCA subtypes, HNF1alpha-inactivated HCA, beta-catenin activated HCA (b-HCA), inflammatory HCA (IHCA) and unclassified HCA (U-HCA) accounted for nine (23.7%), four (10.5%), 17 (44.7%) and eight (21.1%) cases, respectively. Two cases showed coexistence of HCA and hepatocellular carcinoma (HCC) at surgery, and another had HCC which had been detected 23 years after HCA diagnosis. The HCA subtype of one of the former cases was U-HCA, while the remaining two had b-HCA and U-HCA. CONCLUSIONS: In Japanese HCA cases, the proportions of U-HCA, male and elder cases were slightly higher than in Western countries, and most of elder patients were male. IHCA was however common regardless of race, and was assumed to be the predominant subtype of HCA.
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Transforming growth factor-ß (TGF-ß) is a key driver for liver fibrogenesis. TGF-ß must be activated in order to function. Plasma kallikrein (PLK) is a TGF-ß activator that cleaves the latency-associated protein (LAP) between arginine58 and lysine59 residues and releases active TGF-ß from the latent TGF-ß-LAP complex. Thus, the generation of two LAP degradation products, ending at arginine58 (R58/LAP-DPs) and beginning from lysine59 (L59/LAP-DPs), reflects PLK-dependent TGF-ß activation. However, the significance and details of TGF-ß activation in patients with chronic liver disease (CLD) remain uncertain. We herein examined the PLK-dependent TGF-ß activation in patients by detecting R58 and L59/LAP-DPs. A total of 234 patients with CLD were included in this study. Liver biopsy specimens were used for immunostaining to detect R58/LAP-DPs, while plasma samples were subjected to an enzyme-linked immunosorbent assay to measure the L59/LAP-DP concentration. R58/LAP-DP was robustly expressed in and around the sinusoidal cells before the development of the fibrous regions. The R58/LAP-DP expression at fibrosis stage 1 was higher than at any other stages, and the relationship between the plasma L59/LAP-DP level and the stage of fibrosis also showed a similar trend. The abundance of plasma L59/LAP-DP showed no correlation with the levels of direct serum biomarkers of liver fibrosis; however, its changes during interferon-based therapy for chronic hepatitis C were significantly associated with virological responses. Our results suggest that PLK-dependent TGF-ß activation occurs in the early stages of fibrosis and that its unique surrogate markers, R58 and L59/LAP-DPs, are useful for monitoring the clinical course of CLD.
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A 32-year-old Japanese woman was admitted to our hospital for the diagnosis and treatment of multiple liver tumors. She had been receiving 125 mg testosterone enanthate every 2 weeks following female-to-male gender identity disorder (GID) diagnosis at 20 years of age. Ultrasonography, computed tomography, and magnetic resonance imaging showed 11 hepatic nodular tumors with a maximum diameter of 28 mm. Liver tumors with hepatocellular adenoma (HCA) were diagnosed with needle biopsy. Segmentectomy of the left lateral lobe including two lesions, subsegmentectomy of S6 including two lesions, enucleation of each tumor in S5 and S7, and open surgical radiofrequency ablation for each tumor in S4 and S7 were performed. Immunohistochemical specimens showed that the tumor cells were diffusely and strongly positive for glutamine synthetase and that the nuclei were ectopically positive for ß-catenin. Thus, the tumors were diagnosed as ß-catenin-activated HCA (b-HCA). Transcatheter arterial chemoembolization plus subsequent radiofrequency ablation was performed for the 3 residual lesions in S4 and S8. Although testosterone enanthate was being continued for GID, no recurrence was observed until at least 22 months after the intensive treatments. HCA development in such patients receiving testosterone should be closely monitored using image inspection.
Assuntos
Androgênios/efeitos adversos , Carcinoma Hepatocelular/induzido quimicamente , Identidade de Gênero , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Primárias Múltiplas/induzido quimicamente , Testosterona/análogos & derivados , Adulto , Carcinoma Hepatocelular/classificação , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/cirurgia , Feminino , Humanos , Neoplasias Hepáticas/classificação , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirurgia , Neoplasias Primárias Múltiplas/classificação , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/cirurgia , Testosterona/efeitos adversosRESUMO
AIM: Serum Mac-2 binding protein (M2BP) and Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) are used to estimate the liver fibrosis stage in chronic liver diseases. However, few head-to-head studies have been carried out to compare the two biomarkers in non-alcoholic fatty liver disease (NAFLD). METHODS: Serum M2BP and WFA+ -M2BP levels were compared against clinical characteristics and liver histological manifestations in the same samples collected from 213 biopsy-proven NAFLD patients. RESULTS: Median levels (range) of M2BP and WFA+ -M2BP were 1.58 (0.70-7.75) pg/mL and 0.85 (0.22-11.32) cut-off index (COI), respectively. Fibrosis stages 1, 2, 3, and 4 were determined in 136, 37, 17, and 23 patients, respectively. Median levels of both biomarkers increased stepwise with fibrosis progression. The M2BP and WFA+ -M2BP levels showed a significant positive correlation (r = 0.643, P = 2.91 × 10-26 ), but a marked discrepancy between both biomarkers was noted in five stage 4 and three stage 1 patients, who had high WFA+ -M2BP but relatively low M2BP levels. Most of these outliers had findings suggestive of more advanced fibrosis. For diagnosing any fibrosis severity, WFA+ -M2BP had greater area under the receiver operating characteristic curve (AUC) and predictive accuracy than M2BP. Among eight fibrosis markers/indices, WFA+ -M2BP yielded the second highest AUC (0.832) and the highest predictive accuracy (82.2%) to diagnose cirrhosis. In addition, WFA+ -M2BP showed the second highest predictive accuracy to diagnose severe fibrosis (78.4%) and significant fibrosis (76.1%). CONCLUSION: This head-to-head comparison suggests that WFA+ -M2BP is superior to M2BP for distinguishing liver fibrosis stages in NAFLD patients. A marked discrepancy between the two biomarkers may be indicative of advanced NAFLD (UMIN000023286).
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The contamination of ground water by fluoride has been reported worldwide. Most fluoride (approximately 70%) is filtered by the kidneys; humans or experimental animals with renal damage therefore may be more affected by fluoride exposure than those with normal kidney function. Tubulointerstitial fibrosis, which involves macrophage-promoted extracellular matrix production and myofibroblast migration, can be induced in rats by unilateral ureteral obstruction (UUO). We examined the effects of fluoride exposure on tubulointerstitial fibrosis in the obstructed kidney of UUO rats. The left ureters of 6-week-old male rats were ligated using silk sutures. Fluoride was then administered for 2 weeks at doses of 0, 75, and 150ppm in the drinking water. Real-time polymerase chain reaction was performed to analyze transforming growth factor beta 1 (TGF-ß1) transcription; histological and immunohistochemical staining were used to identify positive areas within the renal cortex and staining-positive cells by image analysis. Significant increases were observed in the obstructed kidneys of UUO rats exposed to 150ppm fluoride (compared to 0ppm) for areas or number of cells that stained with Masson trichrome or with antibodies against collagen type I, alpha-smooth muscle actin (α-SMA, a myofibroblast marker), ED1, ED2, and ED3 (macrophage markers), and TGF-ß1. Taken together, these observations suggested that fluoride exacerbates tuburointerstitial nephropathy resulting from UUO, and that this effect occurs via activation of the M2 macrophage-TGF-ß1-fibroblast/myofibroblast-collagen synthesis pathway.
Assuntos
Fluoretos/toxicidade , Nefropatias/patologia , Obstrução Ureteral/patologia , Actinas/genética , Actinas/metabolismo , Animais , Relação Dose-Resposta a Droga , Fluoretos/sangue , Rim/efeitos dos fármacos , Rim/fisiopatologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Miofibroblastos/citologia , Miofibroblastos/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND: The receptor for advanced glycation end products (RAGE) is recognized to be responsible for cancer progression in several human cancers. In this study, we investigated the clinical impact of RAGE expression in patients with hepatocellular carcinoma (HCC) after hepatectomy. MATERIALS AND METHODS: Sixty-five consecutive patients who underwent initial hepatectomy for HCC were investigated. The relationships between immunohistochemical expression of RAGE and clinicopathologic features, clinical outcome (overall survival [OS], and disease-free survival [DFS]) were evaluated. RESULTS: The cytoplasmic expression of RAGE in HCC cells was observed in 46 patients (70.8%) and correlated with histologic grade (poorly differentiated versus moderately differentiated HCC, P = 0.021). Five-year OS in RAGE-positive and RAGE-negative groups were 72% and 94%, respectively, whereas 5-y DFS were 29% and 55%, respectively. There were significant differences between OS and DFS (P = 0.018 and 0.031, respectively). Multivariate analysis indicated that RAGE was an independent predictor for both OS and DFS (P = 0.048 and 0.032, respectively). CONCLUSIONS: Our data suggest for the first time a positive correlation between RAGE expression and poor therapeutic outcome. Furthermore, RAGE downregulation may provide a novel therapeutic target for HCC.
Assuntos
Carcinoma Hepatocelular , Hepatectomia/mortalidade , Neoplasias Hepáticas , Receptores Imunológicos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/cirurgia , Regulação para Baixo , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Receptor para Produtos Finais de Glicação AvançadaRESUMO
BACKGROUND: Marked accumulation of alveolar macrophages (AM) conferred by apoptosis resistance has been implicated in pathogenesis of chronic obstructive pulmonary disease (COPD). Apoptosis inhibitor of macrophage (AIM), has been shown to be produced by mature tissue macrophages and AIM demonstrates anti-apoptotic property against multiple apoptosis-inducing stimuli. Accordingly, we attempt to determine if AIM is expressed in AM and whether AIM is involved in the regulation of apoptosis in the setting of cigarette smoke extract (CSE) exposure. METHODS: Immunohistochemical evaluations of AIM were performed. Immunostaining was assessed by counting total and positively staining AM numbers in each case (n = 5 in control, n = 5 in non-COPD smoker, n = 5 in COPD). AM were isolated from bronchoalveolar lavage fluid (BALF). The changes of AIM expression levels in response to CSE exposure in AM were evaluated. Knock-down of anti-apoptotic Bcl-xL was mediated by siRNA transfection. U937 monocyte-macrophage cell line was used to explore the anti-apoptotic properties of AIM. RESULTS: The numbers of AM and AIM-positive AM were significantly increased in COPD lungs. AIM expression was demonstrated at both mRNA and protein levels in isolated AM, which was enhanced in response to CSE exposure. AIM significantly increased Bcl-xL expression levels in AM and Bcl-xL was involved in a part of anti-apoptotic mechanisms of AIM in U937 cells in the setting of CSE exposure. CONCLUSIONS: These results suggest that AIM expression in association with cigarette smoking may be involved in accumulation of AM in COPD.
Assuntos
Proteínas Reguladoras de Apoptose/biossíntese , Regulação da Expressão Gênica , Macrófagos Alveolares/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Idoso , Antígenos CD/biossíntese , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/biossíntese , Antígenos de Diferenciação de Linfócitos T/genética , Proteínas Reguladoras de Apoptose/genética , Líquido da Lavagem Broncoalveolar , Células Cultivadas , Feminino , Células HEK293 , Humanos , Lectinas Tipo C/biossíntese , Lectinas Tipo C/genética , Macrófagos Alveolares/patologia , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/patologia , Células U937RESUMO
Autophagy, a process that helps maintain homeostatic balance between the synthesis, degradation, and recycling of organelles and proteins to meet metabolic demands, plays an important regulatory role in cellular senescence and differentiation. Here we examine the regulatory role of autophagy in idiopathic pulmonary fibrosis (IPF) pathogenesis. We test the hypothesis that epithelial cell senescence and myofibroblast differentiation are consequences of insufficient autophagy. Using biochemical evaluation of in vitro models, we find that autophagy inhibition is sufficient to induce acceleration of epithelial cell senescence and myofibroblast differentiation in lung fibroblasts. Immunohistochemical evaluation of human IPF biospecimens reveals that epithelial cells show increased cellular senescence, and both overlaying epithelial cells and fibroblasts in fibroblastic foci (FF) express both ubiquitinated proteins and p62. These findings suggest that insufficient autophagy is an underlying mechanism of both accelerated cellular senescence and myofibroblast differentiation in a cell-type-specific manner and is a promising clue for understanding the pathogenesis of IPF.
Assuntos
Autofagia , Fibrose Pulmonar Idiopática/fisiopatologia , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Diferenciação Celular/fisiologia , Senescência Celular/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Células Epiteliais/patologia , Células Epiteliais/fisiologia , Humanos , Miofibroblastos/citologia , Proteína Sequestossoma-1 , Tunicamicina/farmacologia , Ubiquitina/biossínteseRESUMO
We present a case of organizing pneumonia complicated by pneumothorax in association with cyst formation that developed during corticosteroid treatment. Although it has been reported that the check-valve mechanism is a plausible cause of cyst and pneumothorax formation in patients with organizing pneumonia, the details of the corresponding pathological changes that occur in air-trapping have not been elucidated. A pathological examination of lung specimens obtained with video-assisted thoracoscopic surgery suggested that granulation tissues plugging the bronchiole lumens might be a potential cause of the check-valve mechanism in this case. In this report, we also reviewed eight other cases of organizing pneumonia with pneumothorax or cyst formation.
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Cistos/etiologia , Pneumopatias/etiologia , Pneumonia/complicações , Pneumotórax/etiologia , Corticosteroides/efeitos adversos , Adulto , Cistos/diagnóstico , Humanos , Pneumopatias/diagnóstico , Masculino , Pneumonia/diagnóstico , Pneumonia/tratamento farmacológico , Pneumotórax/diagnóstico , Pneumotórax/cirurgia , Cirurgia Torácica Vídeoassistida , Tomografia Computadorizada por Raios XRESUMO
Autoimmune pancreatitis (AIP) can be difficult to distinguish from pancreatic cancer. We report a case of histopathologically proven AIP mimicking neuroendocrine tumor (NET) or pancreatic cancer in a 53-year-old man. He was referred to our hospital for further evaluation of a pancreatic mass detected on ultrasonography at a medical check-up. Abdominal ultrasonography showed a 15-mm hypoechoic mass located in the pancreatic body. Computed tomography revealed a tumor without any contrast enhancement, and magnetic resonance imaging demonstrated the mass to be hyperintense on diffusion-weighted image. Endoscopic retrograde cholangiopancreatography revealed slight dilatation of a branch of the pancreatic duct without stricture of the main pancreatic duct. The common bile duct seemed intact. Under suspicion of a non-functioning NET or malignant neoplasm, laparotomy was performed. At laparotomy, an elastic firm and well-circumscribed mass was found suggestive of a non-functioning NET, thus enucleation was performed. Histopathologically, the lesion corresponded to AIP.
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Cigarette smoke induces damage to proteins and organelles by oxidative stress, resulting in accelerated epithelial cell senescence in the lung, which is implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. Although the detailed molecular mechanisms are not fully understood, cellular energy status is one of the most crucial determinants for cell senescence. Creatine kinase (CK) is a constitutive enzyme, playing regulatory roles in energy homeostasis of cells. Among two isozymes, brain-type CK (CKB) is the predominant CK in lung tissue. In this study, we investigated the role of CKB in cigarette smoke extract (CSE)-induced cellular senescence in human bronchial epithelial cells (HBECs). Primary HBECs and Beas2B cells were used. Protein carbonylation was evaluated as a marker of oxidative protein damage. Cellular senescence was evaluated by senescence-associated ß-galactosidase staining. CKB inhibition was examined by small interfering RNA and cyclocreatine. Secretion of IL-8, a hallmark of senescence-associated secretary phenotype, was measured by ELISA. CKB expression levels were reduced in HBECs from patients with COPD compared with that of HBECs from nonsmokers. CSE induced carbonylation of CKB and subsequently decreased CKB protein levels, which was reversed by a proteasome inhibitor. CKB inhibition alone induced cell senescence, and further enhanced CSE-induced cell senescence and IL-8 secretion. CSE-induced oxidation of CKB is a trigger for proteasomal degradation. Concomitant loss of enzymatic activity regulating energy homeostasis may lead to the acceleration of bronchial epithelial cell senescence, which is implicated in the pathogenesis of COPD.
Assuntos
Brônquios/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Creatina Quinase Forma BB/metabolismo , Células Epiteliais/efeitos dos fármacos , Fumaça/efeitos adversos , Fumar/efeitos adversos , Brônquios/enzimologia , Brônquios/imunologia , Brônquios/patologia , Células Cultivadas , Creatina Quinase Forma BB/antagonistas & inibidores , Creatina Quinase Forma BB/genética , Ciclina B1/metabolismo , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/enzimologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Humanos , Imuno-Histoquímica , Interleucina-8/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma , Carbonilação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Ubiquitinação , beta-Galactosidase/metabolismoRESUMO
Breast carcinomas sometimes metastasize to the stomach, and the histopathologic distinction of such metastases from primary gastric adenocarcinomas is often difficult. We characterized the clinicopathologic features of 21 breast carcinomas that had metastasized to the stomach and examined the use of a panel of antibodies, including hepatocyte nuclear factor 4A, for distinguishing the metastases from primary gastric diffuse-type adenocarcinomas. Histologically, all the metastatic breast carcinomas showed a poorly differentiated and/or signet ring cell morphology. Although most metastatic breast and primary gastric carcinomas contained signet ring cell components, the cases that were predominantly or exclusively composed of univacuolated-type signet ring cells were limited to metastatic breast carcinomas. Immunohistochemically, hepatocyte nuclear factor 4A was expressed in all 33 primary gastric carcinomas that were examined but was never expressed in metastatic breast carcinomas. Previously reported markers for breast and gastric carcinomas also showed a high specificity, but their sensitivities were quite variable. Estrogen receptor α, progesterone receptor, mammaglobin, and gross cystic disease fluid protein 15 were expressed in 76%, 33%, 52%, and 62%, respectively, of the metastatic breast carcinomas, whereas none of the primary gastric carcinomas expressed these antigens. CDX2, MUC5AC, MUC6, and CK20 were expressed in 36%, 85%, 27%, and 55%, respectively, of the primary gastric carcinomas. All the metastatic breast carcinomas were negative for these antibodies except for 1 case that expressed MUC5AC. Overall, the use of immunohistochemistry efficiently discriminated metastatic breast carcinomas from primary gastric carcinomas. In particular, the present study identified hepatocyte nuclear factor 4A as an excellent marker for differentiating the 2 lesions.
Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Fator 4 Nuclear de Hepatócito/biossíntese , Neoplasias Gástricas/secundário , Adenocarcinoma/secundário , Adulto , Idoso , Carcinoma Lobular/metabolismo , Carcinoma Lobular/secundário , Carcinoma de Células em Anel de Sinete/secundário , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e Especificidade , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologiaRESUMO
Hyperproliferative cell growth due to cyclin D1/cdk4, marker of cellular proliferation, is considered to be regulated by the expression of estrogen receptors (ERs). We investigated the immunohistochemical expression of cyclin D1/cdk4 and ERs in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced rat gastric carcinogenesis. The gastric cancer incidence and expression of cyclin D1/ckd4 in gastric carcinogenesis were significantly higher in males than females. Although the ERα expression index was similar in both sexes, the ERß expression in preneoplastic hyperplastic lesions as well as gastric cancers was significantly higher in females than in males. The present study revealed a gender difference in MNNG-induced rat gastric carcinogenesis that seemed to involve the sex difference in cyclin D1/cdk4 expression, and ERß expression became evident at the preneoplastic promotion stage in gastric carcinogenesis.
Assuntos
Adenocarcinoma/patologia , Carcinógenos/toxicidade , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Metilnitronitrosoguanidina/toxicidade , Neoplasias Gástricas/patologia , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Feminino , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Imuno-Histoquímica/métodos , Masculino , Ratos , Ratos Wistar , Fatores Sexuais , Neoplasias Gástricas/induzido quimicamente , Neoplasias Gástricas/metabolismoRESUMO
Chromosomal rearrangements that result in high expression levels of the ETS-related gene (ERG) present in approximately 50% of prostate cancer (PCa) patients, making this one of the most common oncogenic alterations in PCa. However, ERG overexpression at the protein level has not been rigorously evaluated in Japanese PCa patients. In this study, we evaluated ERG expression using antibody-based detection in 230 prostate specimens in a Japanese PCa cohort. Overall, we identified 20.1% ERG-positive PCa cases. ERG was not detected in benign glands. The specificity of ERG staining for detecting PCa was almost 100%; all of the ERG-positive samples were also diagnosed as PCa. The expression level of the ERG protein correlated with clinicopathological variables, including grade (P= 0.038), stage (P= 0.005), and metastatic status (P= 0.014). No correlation was observed with age (P= 0.196) or with preoperative prostate-specific antigen level (P= 0.322). Although the frequency of ERG-positive cases in Japanese PCa patients (20.1%) was lower than that reported in a PCa cohort in Western countries (approximately 50%), our study demonstrates that the clinical utility of ERG detection at the protein level can serve as an ancillary tool for diagnosing PCa in the Japanese population.
Assuntos
Adenocarcinoma/secundário , Neoplasias da Próstata/patologia , Transativadores/metabolismo , Adenocarcinoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Estudos de Coortes , Humanos , Técnicas Imunoenzimáticas , Japão , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Neoplasias da Próstata/metabolismo , Regulador Transcricional ERGRESUMO
Epidemiologic studies indicate that the incidence of gastric cancer is higher in males than in females. Although the mechanisms mediating this difference are unclear, a role for estrogens has been proposed. We used Western blotting to evaluate the role of estrogen receptor (ER) subtypes ERα and ERß and proliferating cell nuclear antigen (PCNA) in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis in Wistar rats; ERα and ERß mRNA levels also were analyzed by quantitative real-time RT-PCR analysis. The incidence of gastric cancer was significantly higher in male than female rats. In both sexes, ERα expression was similar in MNNG-treated cancerous and noncancerous tissues and normal gastric tissue. However, ERß expression in MNNG-treated cancerous and noncancerous tissues was significantly lower in male rats and higher in female rats than that in normal gastric tissue; MNNG-induced cancerous tissue showed the highest ERß expression. PCNA expression in MNNG-treated cancerous tissues was higher than that in noncancerous tissues, and was higher in male rats than female rats. Western blotting results were consistent with the mRNA changes determined by quantitative real-time RT-PCR. The present study provides evidence of a sex-associated difference in ERß and PCNA expression in MNNG-induced gastric cancers in Wistar rats.
Assuntos
Receptor beta de Estrogênio/metabolismo , Metilnitronitrosoguanidina/toxicidade , Neoplasias Gástricas/induzido quimicamente , Neoplasias Gástricas/metabolismo , Animais , Western Blotting , Feminino , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores SexuaisRESUMO
To identify key genes involved in the complex multistep process of hepatotumorigenesis, we reduced multivariate clinicopathological variables by using the Long-Evans Cinnamon rat, a model with naturally occurring and oxidative stress-induced hepatotumorigenesis. Gene expression patterns were analyzed serially by profiling liver tissues from rats of a naive status (4 weeks old), through to those with chronic hepatitis (26 and 39 weeks old) to tumor development (67 weeks old). Of 31 099 probe sets used for microarray analysis, 87 were identified as being upregulated in a stepwise manner during disease progression and tumor development. Quantitative real-time reverse transcription-polymerase chain reaction and statistical analyses verified that IQGAP1 and vimentin mRNA expression levels increased significantly throughout hepatotumorigenesis. A hierarchical clustering algorithm showed both genes clustered together and in the same cluster group. Immunohistochemical and western blot analyses showed similar increases in protein levels of IAGAP1 and vimentin. Finally, pathway analyses using text-mining technology with more comprehensive and recent gene-gene interaction data identified IQGAP1 and vimentin as important nodes in underlying gene regulatory networks. These findings enhance our understanding of the multistep hepatotumorigenesis and identification of target molecules for novel treatments.
Assuntos
Redes Reguladoras de Genes/genética , Neoplasias Hepáticas Experimentais/genética , Estresse Oxidativo , Vimentina/fisiologia , Proteínas Ativadoras de ras GTPase/fisiologia , Animais , Cobre/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Perfilação da Expressão Gênica , Estudos de Associação Genética , Degeneração Hepatolenticular , Humanos , Fígado/metabolismo , Neoplasias Hepáticas Experimentais/etiologia , Neoplasias Hepáticas Experimentais/metabolismo , Masculino , Dados de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Endogâmicos LEC , Ratos Long-Evans , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vimentina/biossíntese , Vimentina/genética , Proteínas Ativadoras de ras GTPase/biossíntese , Proteínas Ativadoras de ras GTPase/genéticaRESUMO
A rare intratubular gonadal stromal tumor was present in the testis of a 7-wk-old male Sprague-Dawley rat. The tumor comprised an intratubular mixture of 2 types of tumor cells with intercellular junctions: the predominant tumor cells were consistent with a Sertoli cell origin, and cells comprising the minor population were situated on basolateral side of the tubuli, consistent with a Leydig cell origin. The neoplastic Sertoli cells had large pleomorphic nuclei and clear cytoplasm with many tubulovesicular cristae and free ribosomes, whereas the neoplastic Leydig cells showed relatively small pleomorphic nuclei, dark cytoplasm with rich smooth endoplasmic reticulum, numerous mitochondria, and lipid droplets. Occasionally, a few transitional type neoplastic cells were observed. The presence of a thick or multilayered basement membrane was confirmed except in tumor-infiltrative lesions. The present case was considered to be a testicular mixed tubular Sertoli-Leydig cell tumor in a Sprague-Dawley rat.
Assuntos
Doenças dos Roedores/patologia , Tumor de Células de Sertoli-Leydig/veterinária , Neoplasias Testiculares/veterinária , Animais , Núcleo Celular/ultraestrutura , Citoplasma/ultraestrutura , Masculino , Microscopia Eletrônica/veterinária , Ratos , Ratos Sprague-Dawley , Tumor de Células de Sertoli-Leydig/patologia , Neoplasias Testiculares/patologiaRESUMO
The criterion tumor volume (TV) for clinically insignificant prostate cancer has been reported, but it differs from study to study: some have reported TV < 200 mm(3); others, < 500 mm(3). The aim of the present study was to distinguish clinically insignificant cancers from significant ones using molecular biological methods. A total of 184 microscopic cancers (MC) defined as limited within a 3 mm circle and 82 main tumor (MT) nodules were selected. Thirteen microsatellite loci at 6q22, 8p23.2-23, 13q14 and 13q33 were evaluated for loss of heterozygosity (LOH). MT were subgrouped as TV > or = 500 mm(3) or < 500 mm(3); TV > or = 200 mm(3) or < 200 mm(3); and TV < 200 mm(3), 200 mm(3) < or = TV < 500 mm(3) or TV > or = 500 mm(3); and frequencies of LOH were compared between these three groups. Frequencies of LOH at 6q16-21, 6q22, 8p23.1, 8p23.2, 13q14 were significantly lower in MC (1.0%, 2.7%, 1.9%, 1.1% and 5.4%) than in MT (30.9%, 40.4%, 12%, 8.7% and 20.6%), but no significant differences in LOH frequency were found within each of the three TV groups, between each cut-off. When insignificant tumor is defined as TV < 200 mm(3) or < 500 mm(3), it should include tumors with malignant potential equivalent to larger tumors. It is suggested that in order to identify insignificant tumor within a strict safety range, TV should be set lower.
Assuntos
Perda de Heterozigosidade , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Idoso , Desequilíbrio Alélico , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-IdadeRESUMO
Ovarian mucinous borderline tumor of müllerian type (MMBT) and mixed epithelial borderline tumor of müllerian type (MEBT) are uncommon subtypes of ovarian surface epithelial tumors. Both are often associated with endometriosis, but their histogenesis is still debated. We have noticed occasional foci of subepithelial cuboidal cells resembling uterine cervical reserve cells (RCs) in MMBTs/MEBTs, which have not been documented in the literature to the best of our knowledge. This study was carried out to identify the presence of RC-like cells (RCLCs) in MMBTs/MEBTs and their immunohistochemical features in comparison to those of cervical RCs. We analyzed 10 consecutive cases of RC-like MMBTs/MEBTs, 6 of which were associated with endometriosis. Immunohistochemistry was performed for p63, cytokeratin 34BE12, cytokeratin 17 (CK17), and low-molecular cytokeratin CAM5.2. In 9 of 10 cases, RCLCs were appreciated in hematoxylin-eosin stain, although their amount in the tumor varied from case to case. Immunohistochemically, RCLCs were positive for p63 in 9 cases. They were positive for both 34BE12 and CK17 and were very weakly positive or negative for CAM5.2 in 8 cases. This immunohistochemical profile is similar to that seen in the cervical RCs. Reserve cell-like cells were also found in the foci of endometriosis coexisting with MMBTs/MEBTs in 1 of 5 cases examined. We draw attention to the existence of the RCLCs in MMBTs/MEBTs and in endometriosis. Their similarity to the cervical RCs may indicate their potential role as precursor cell that may subsequently differentiate into different müllerian cell types, thus merit further study.
Assuntos
Tumor Mulleriano Misto/metabolismo , Tumor Mulleriano Misto/patologia , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Adulto , Idoso , Biomarcadores/metabolismo , Diferenciação Celular , Colo do Útero/metabolismo , Colo do Útero/patologia , Endometriose/metabolismo , Endometriose/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Imuno-Histoquímica , Queratina-17/metabolismo , Queratinas/metabolismo , Proteínas de Membrana/metabolismo , Pessoa de Meia-IdadeRESUMO
AIMS/BACKGROUND: Loss of heterozygosity (LOH) at 8p is the most frequent chromosomal alteration in tumorigenesis of human cancers. However, the genetic change in metastasis of hepatocellular carcinoma (HCC) still has to be investigated. METHODS: We used 16 microsatellite markers informative in Japanese patients, selected from among 61 published microsatellite markers at 8p23.2-21 to compare the frequency of LOH in primary tumours (Tps) and metastatic tumours (Tms) in a PCR-based analysis. Sixty-three informative cancerous lesions (26 were Tps, 37 were Tms) from 23 cases of HCC were used. RESULTS: The frequency of LOH at 8p23.2-21 with at least one marker was 19% in Tps and 68% in Tms. Allelic loss at 8p23.2-21 was significantly more frequent in Tms than in Tps (P=0.0003). More specifically, the frequency of LOH at D8S262, D8S1819, D8S503, D8S1130, D8S552, D8S1109, and D8S261 in Tms was 36-60% respectively. CONCLUSIONS: In contrast, allelic loss at the same markers in Tp was only detected in 0-17% of the tumour respectively. The significant difference in the frequency of LOH at 8p between primary cancer and metastatic cancer in individual cases of HCC suggests LOH at 8p to be involved in the enhancement of tumour aggressiveness, especially during metastasis.