RESUMEN
BACKGROUND: Annexin A10 expression influences the prognosis of several gastrointestinal cancers. We explored the association of annexin A10 expression with the overall survival (OS) of patients who underwent curative surgery for cholangiocarcinoma. METHODS: Patients who underwent curative surgery for cholangiocarcinoma (except gallbladder cancer) and had pathological stage T1-3N0M0 disease were enrolled. Annexin A10 expression was examined by performing immunohistochemical staining. Patient demographics and survival outcome data were retrieved from medical records. RESULTS: In total, 185 patients were enrolled. The primary tumor location was intrahepatic and extrahepatic (including the perihilar region) for 89% and 11% of patients, respectively. Positive annexin A10 staining was detected for 61 (33%) patients and associated with extrahepatic or perihilar cholangiocarcinoma (p = 0.001) and lower histological grade (p < 0.001). Patients with positive annexin A10 staining exhibited significantly poorer survival relative to patients with negative staining results (median OS, 2.5 vs. 4.9 years, p = 0.025). In the multivariate analysis adjusting for age, sex, tumor location, tumor grade, hepatitis infection, and disease stage, positive annexin A10 remained an independent predictor of poor OS (hazard ratio 1.572, p = 0.034). In the subgroup analysis, the association between annexin A10 and prognosis was restricted to intrahepatic cholangiocarcinoma. Among patients with intrahepatic cholangiocarcinoma, patients with positive annexin A10 staining exhibited significantly poorer survival compared with patients with negative annexin A10 staining (median OS, 2.3 vs. 4.9 years, p = 0.008). CONCLUSION: Positive annexin A10 expression was associated with poor prognosis of intrahepatic cholangiocarcinoma.
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Anexinas/metabolismo , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/mortalidad , Colangiocarcinoma/genética , Colangiocarcinoma/mortalidad , Anciano , Neoplasias de los Conductos Biliares/patología , Biomarcadores de Tumor/genética , Colangiocarcinoma/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Tasa de SupervivenciaRESUMEN
BACKGROUND: The kinesin Eg5, a mitosis-associated protein, is overexpressed in many cancers. Here we explored the clinical significance of Eg5 in hepatocellular carcinoma (HCC). METHODS: HCC tissues from surgical resection were collected. Total RNA was prepared from tumorous and nontumorous parts. Eg5 expression levels were correlated with overall survival (OS) and disease-free survival (DFS). In vitro efficacy of LGI-147, a specific Eg5 inhibitor, was tested in HCC cell lines. In vivo efficacy of Eg5 inhibition was investigated in a xenograft model. RESULTS: A total of 108 HCC samples were included. The patients were divided into three tertile groups with high, medium, and low Eg5 expression levels. OS of patients with low Eg5 expression was better than that of patients with medium and high Eg5 expression (median, 155.6 vs. 75.3 vs. 57.7 months, p = 0.002). DFS of patients with low Eg5 expression was also better than that of patients with medium and high Eg5 expression (median, 126.3 vs. 46.2 vs. 39.4 months, p = 0.001). In multivariate analyses, the associations between Eg5 expression and OS (p < 0.001) or DFS remained (p < 0.001). LGI-147 reduced cell growth via cell cycle arrest and apoptosis and induced accumulation of abnormal mitotic cells. In the xenograft model, the tumor growth rate under LGI-147 treatment was significantly slower than under the control. CONCLUSION: High Eg5 expression was associated with poor HCC prognosis. In vitro and in vivo evidence suggests that Eg5 may be a reasonable therapeutic target for HCC.
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Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/metabolismo , Cinesinas/metabolismo , Neoplasias Hepáticas/metabolismo , Apoptosis , Carcinoma Hepatocelular/patología , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , ADN de Neoplasias/metabolismo , Femenino , Humanos , Cinesinas/antagonistas & inhibidores , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Pronóstico , Huso Acromático/metabolismo , Análisis de SupervivenciaRESUMEN
BACKGROUND AND AIMS: Fibroblast growth factor 19 (FGF19) and fibroblast growth factor receptor 4 (FGFR4) signalling play critical roles in hepatocarcinogenesis. This study explored the potential of FGF19- and FGFR4-related biomarkers in predicting early tumour recurrence (ETR) and survival in patients with resectable hepatocellular carcinoma (HCC). METHODS: We examined the mRNA expressions of FGF19, FGFR4, klotho-beta (KLB), cyclin D1 (CCND1) and FGF4 in 151 surgically resected, primary unifocal HCCs through quantitative real-time polymerase chain reaction. Generalized additive models were fitted to detect nonlinear effects of continuous covariates and define thresholds of biomarker expressions. Univariate and multivariate analyses were performed to evaluate prognostic values of these biomarkers for tumour recurrence and patient survival. RESULTS: Overexpression of FGF19, FGFR4, KLB, CCND1 and FGF4 mRNA was detected in 40%, 32%, 26%, 15% and 35% of 151 tumours respectively. ETR was the strongest prognostic factor predicting worse overall survival (hazard ratio [HR], 5.678; 95% confidence interval, 3.7-8.713; P < 0.001). Furthermore, we revealed that mRNA expression levels of KLB (HR, 3.857; P = 0.021) and FGF19 (HR, 3.248; P = 0.017) were significantly associated with the occurrence of ETR. CONCLUSIONS: Frequent overexpression of FGF19/FGFR4-related biomarkers was detected in resectable HCC. Expression levels of KLB and FGF19 may determine patient survival outcomes through their effects on ETR.
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Carcinoma Hepatocelular/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de la Membrana/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Carcinogénesis , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/cirugía , Proliferación Celular/efectos de los fármacos , Femenino , Factores de Crecimiento de Fibroblastos/genética , Humanos , Proteínas Klotho , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/cirugía , Modelos Logísticos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Pronóstico , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia , Taiwán , Adulto JovenRESUMEN
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a major cause of cancer-related death worldwide. Previously, we demonstrated that glypican-3 (GPC3) is highly expressed in HCC, and that GPC3 induces oncogenicity and promotes the growth of cancer cells through IGF-1 receptor (IGF-1R). In the present study, we investigated the mechanisms of GPC3-mediated enhancement of IGF-1R signaling. We demonstrated that GPC3 decreased IGF-1-induced IGF-1R ubiquitination and degradation and increased c-Myc protein levels. GPC3 bound to Grb10, a mediator of ligand-induced receptor ubiquitination, and the overexpression of Grb10 blocked GPC3-enhanced IGF-1-induced ERK phosphorylation. GPC3 promoted the growth of NIH3T3 and PLC-PRF-5 cells in serum-free medium but did not promote the growth of IGF-1R negative R- cells. Grb10 overexpression decreased GPC3-promoted cell growth. Therefore, the present study elucidates the mechanisms of GPC3-induced oncogenicity, which may highlight new strategies for the treatment of HCC.
RESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) frequently exhibits biliary differentiation, which is typically overlooked. Hepatocyte nuclear factor 1ß (HNF1ß), a bile duct-specific transcription factor expressed in bile ducts but not in the normal hepatocytes, is also expressed in HCC. MATERIALS AND METHODS: The expression of HNF1ß and the biliary differentiation marker cytokeratin 19 (CK19) were retrospectively evaluated using immunohistochemistry in 159 surgically resected primary HCCs. RESULTS: A significant correlation was observed between HNF1ß protein expression and younger age (p = 0.0293), high serum α-fetoprotein levels (p = 6 × 10(-4)), and high tumor grade (p = 0.0255). However, HNF1ß expression exhibited no correlation with tumor stage. Patients with HCCs and HNF1ß expression were more likely to exhibit early tumor recurrence (ETR; p = 0.0048) and a lower 5-year survival rate (p = 0.0001). A multivariate analysis indicated HNF1ß expression as an independent prognostic factor in HCC (p = 0.0048). A combinatorial analysis revealed additive adverse effects of HNF1ß when concomitant with CK19 expression and p53 mutation. Furthermore, HNF1ß expression can predict poor prognosis in patients with ETR. CONCLUSION: Our results indicated that HNF1ß expression is a crucial predictor of poor prognosis in HCC and is independent of tumor stage. Moreover, concomitant HNF1ß and CK19 expressions exhibited additive adverse effects in HCC, confirming that HCC with biliary differentiation has a poor prognosis.
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Carcinoma Hepatocelular/metabolismo , Factor Nuclear 1-beta del Hepatocito/biosíntesis , Neoplasias Hepáticas/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Estadificación de Neoplasias/métodos , Adolescente , Adulto , Anciano de 80 o más Años , Biomarcadores de Tumor/biosíntesis , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/cirugía , Femenino , Estudios de Seguimiento , Hepatectomía , Humanos , Inmunohistoquímica , Incidencia , Queratina-19/biosíntesis , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/epidemiología , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Taiwán/epidemiología , Factores de Tiempo , Adulto JovenRESUMEN
INTRODUCTION: Mutation in the core promoter of the telomerase reverse transcriptase (TERT) gene was determined to be a frequent event in malignant melanoma and other cancers. However, the role of TERT promoter mutation in hepatocellular carcinomas (HCCs) remains largely unknown. METHODS: Genomic DNA samples from the tumor tissue of 195 HCCs were analyzed for TERT promoter mutation at 2 hotspots (-124 and -146 bp from the ATG start site, g.1,295,228 and g.1,295,250, respectively) through direct sequencing. RESULTS: The TERT promoter mutation was identified in 57 of the 195 HCCs (29.2%) and was associated with old age (P = 0.0122), presence of anti-hepatitis C (HCV; P = 0.0048), and absence of hepatitis B surface antigen (HBsAg; P = 0.0007). However, the TERT promoter mutation did not correlate with serum α-fetoprotein levels, liver cirrhosis, tumor size, tumor grade, tumor stage, early tumor recurrence, ß-catenin mutation or p53 mutation. A multivariate analysis confirmed that the absence of hepatitis B infection is an independent factor associated with TERT promoter mutation. Furthermore, among HCC patients infected with hepatitis C, those with concomitant hepatitis B infection exhibited infrequent TERT promoter mutation (P = 0.0435). Remarkably, patients presenting with TERT promoter mutation-positive and -negative HCCs exhibited similar disease-free and overall survival rates. CONCLUSIONS: Our study indicated that the TERT promoter mutation frequently occurred in HCV-associated HCCs. The absence of Hepatitis B infection was significantly associated with the TERT promoter mutation. These findings suggest that various etiological factors may be involved in differing mechanisms to preserve telomeres during the carcinogenesis of HCCs.
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Carcinoma Hepatocelular/genética , Hepatitis C/complicaciones , Neoplasias Hepáticas/genética , Regiones Promotoras Genéticas , Telomerasa/genética , Carcinoma Hepatocelular/virología , Estudios de Cohortes , Femenino , Hepatitis B/complicaciones , Humanos , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Mutación , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
Endocan (or called Esm-1) has been shown to have tumorigenic activities and its expression is associated with poor prognosis in various cancers. Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV)-encoded oncoprotein and has been shown to play an important role in the pathogenesis of EBV-associated nasopharyngeal carcinoma (NPC). To further understand the role of LMP1 in the pathogenesis of NPC, microarray analysis of LMP1-regulated genes in epithelial cells was performed. We found that endocan was one of the major cellular genes upregulated by LMP1. This induction of endocan by LMP1 was confirmed in several epithelial cell lines including an NPC cell line. Upregulation of endocan by LMP1 was found to be mediated through the CTAR1 and CTAR2 domains of LMP1 and through the LMP1-activated NF-κB, MEK-ERK and JNK signaling pathways. To study whether endocan was expressed in NPC and whether endocan expression was associated with LMP1 expression in NPC, the expression of endocan and LMP1 in tumor tissues from 42 NPC patients was evaluated by immunohistochemistry. Expression of endocan was found in 52% of NPC specimens. Significant correlation between LMP1 and endocan expression was observed (p<0.0001). Moreover, NPC patients with endocan expression were found to have a shorter survival than NPC patients without endocan expression (p=0.0104, log-rank test). Univariate and Multivariate analyses revealed that endocan was a potential prognostic factor for NPC. Finally, we demonstrated that endocan could stimulate the migration and invasion ability of endothelial cells and this activity of endocan was dependent on the glycan moiety and the phenylalanine-rich region of endocan. Together, these studies not only identify a new molecular marker that may predict the survival of NPC patients but also provide a new insight to the pathogenesis of NPC.
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Infecciones por Virus de Epstein-Barr , Regulación Neoplásica de la Expresión Génica , Regulación Viral de la Expresión Génica , Herpesvirus Humano 4 , Neoplasias Nasofaríngeas , Proteínas de Neoplasias/biosíntesis , Proteoglicanos/biosíntesis , Regulación hacia Arriba , Proteínas de la Matriz Viral/biosíntesis , Adolescente , Adulto , Anciano , Carcinoma , Supervivencia sin Enfermedad , Infecciones por Virus de Epstein-Barr/metabolismo , Infecciones por Virus de Epstein-Barr/mortalidad , Infecciones por Virus de Epstein-Barr/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/virología , Tasa de SupervivenciaRESUMEN
AIMS: Annexin A10 (ANXA10) is a calcium- and phospholipid-binding protein expressed normally in the gastric mucosa. In this study, we evaluated the potential use of ANXA10 as a diagnostic marker. METHODS AND RESULTS: We observed ANXA10 expression in the gastric mucosa, the Brunner gland of the duodenum and the urothelium, but absence of expression in other normal organs. Following the screening of 1327 primary carcinomas of major organs, we identified ANXA10 expression in 46% of gastric, 72% of ampullary, 78% of pancreatic and 33% of biliary adenocarcinomas. ANXA10 was expressed in 83% of non-invasive urothelial carcinomas, but was expressed in only 9% of invasive urothelial carcinomas. ANAX10 was rarely expressed in carcinomas of other organs. Of 227 metastatic adenocarcinomas, ANXA10 was expressed in 83% of metastatic pancreatic and 47% of metastatic gastric adenocarcinomas, but was expressed in only 2% of metastatic adenocarcinomas from other organs. In the liver, the sensitivity and specificity for identifying the pancreas as the primary site of metastatic adenocarcinoma were 83 and 95%, respectively. CONCLUSION: Our study results indicate that the inclusion of ANXA10 in an immunohistochemical panel will be helpful in the differential diagnosis of adenocarcinoma of an unknown primary site.
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Adenocarcinoma/diagnóstico , Anexinas/metabolismo , Neoplasias del Sistema Biliar/diagnóstico , Biomarcadores de Tumor/metabolismo , Mucosa Gástrica/metabolismo , Neoplasias Pancreáticas/diagnóstico , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/metabolismo , Neoplasias del Sistema Biliar/metabolismo , Diagnóstico Diferencial , Humanos , Inmunohistoquímica , Neoplasias Pancreáticas/metabolismo , Neoplasias Gástricas/metabolismoRESUMEN
Collagen triple helix repeat containing-1 (CTHRC1) is a secreted glycoprotein that activates the planar cell polarity pathway of Wnt signaling. Using microarray analysis, we found that the CTHRC1 gene is overexpressed in hepatocellular carcinoma (HCC). The level of CTHRC1 mRNA was measured in 201 surgically resected HCCs using real time reverse transcription-polymerase chain reaction. Overexpression of CTHRC1 in HCC was associated with large tumor size and advanced tumor stage. Furthermore, expression of CTHRC1 as was identified as an independent prognostic factors in the multivariate analysis. Suppression of CTHRC1 expression inhibited tumor migration and invasion whereas overexpression of CTHRC1 promoted tumor invasion. Activation of RhoA, but not Rac1 or Cdc42, was found to play a crucial role in CTHRC1-induced cell migration. CTHRC1 promoted adhesion of cancer cells to extracellular matrix through induction of integrin ß1 expression and activation of focal adhesion kinase. These results suggest CTHRC1 promotes tumor invasion and metastasis by enhancing the adhesion and migratory abilities of tumor cells. It is also a promising biomarker for predicting the prognosis of patients with HCC.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Proteínas de la Matriz Extracelular/genética , Expresión Génica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Adulto , Anciano , Carcinoma Hepatocelular/mortalidad , Adhesión Celular/genética , Movimiento Celular/genética , Matriz Extracelular/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Integrina beta1/genética , Integrina beta1/metabolismo , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , Oportunidad Relativa , Pronóstico , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
The calcium-binding protein S100P is expressed in a variety of human cancer cells and is important in cancer cell growth and invasion. Using differential display, we found S100P is overexpressed in human hepatocellular carcinoma (HCC). We examined the expression of 305 unifocal, primary HCC tumors using immunohistochemistry. The S100P protein was expressed in 173 of the 305 (56.7%) HCC tumors. The expression of S100P correlated with female sex (Pâ=â0.0162), high serum α-fetoprotein level (Pâ=â0.0001), high tumor grade (Pâ=â0.0029), high tumor stage (Pâ=â0.0319), the presence of the p53 mutation (Pâ=â0.0032), and the absence of the ß-catenin mutation (Pâ=â0.0489). Patients with HCC tumors that expressed S100P were more likely to have early tumor recurrence (ETR) (Pâ=â0.0189) and lower 5-year survival (Pâ=â0.0023). The multivariate analysis confirmed that S100P expression was an independent prognostic factor in HCC. The combinatorial analysis showed an additive unfavorable prognostic interaction between S100P expression and the p53 mutation. In contrast, the ß-catenin mutation was associated with better prognosis in both S100P-positive and -negative HCCs. Furthermore, S100P expression was a predictor of survival in HCC patients with high tumor stage or ETR (Pâ=â0.0026 and Pâ=â0.0002, respectively). Our study indicates the expression of the S100P protein is a novel independent predictor for poor prognosis in HCC, and it is also an unfavorable prognostic predictor in HCC patients with high tumor stage or ETR.
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Proteínas de Unión al Calcio/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidad , Expresión Génica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidad , Proteínas de Neoplasias/genética , Adulto , Anciano , Proteínas de Unión al Calcio/metabolismo , Carcinoma Hepatocelular/patología , Femenino , Humanos , Hígado/metabolismo , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/metabolismo , Estadificación de Neoplasias , Pronóstico , Recurrencia , Carga Tumoral , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Lin-41 is a stem cell-specific E3 ligase and a known target of the tumour suppressor microRNA (miRNA) let-7. Lin-41 was recently reported to mediate ubiquitylation and degradation of the miRNA pathway protein Ago2. We demonstrate that Lin-41 is over-expressed in hepatocellular carcinoma (HCC). Lin-41 over-expression correlates with high α-fetoprotein level, high tumour grade and high tumour stage and predicts early tumour recurrence. Lin-41 is a strong predictor of poor long-term survival for patients with HCC. Lin-41 knock-down by RNA interference in HCC cell lines Huh7 and Hep3B suppressed proliferation in vitro and reduced in vivo tumour growth in NOD/SCID mice. On the other hand, over-expression of Lin-41 in the HCC cell line SK-Hep1 enhanced tumourigenicity. Over-expression and knock-down of Lin-41 led to inverse changes in the levels of Ago1 and Ago2 proteins. Over-expression of Ago1 and Ago2 reduced in vivo tumour growth. Lin-41 over-expression suppressed let-7 activity in HCC cell lines and expression of Lin-41 enhanced the expression of let-7-regulated oncogenes c-Myc, Lin-28B, HMGA2 and type 1 insulin-like growth factor receptor (IGF1R). Expression of Lin-28B and c-Myc enhanced the expression of Lin-41. Chromatin immunoprecipitation and reporter assays revealed direct association of c-Myc with the Lin-41 promoter, resulting in transcriptional transactivation. Our results indicate that Lin-41 plays an important role in the growth of HCC by regulating RISC complex proteins Ago1 and Ago2 to inhibit miRNA-mediated gene silencing and promote the expression of oncogenic proteins. Lin-41 is also a strong prognostic factor for patients with HCC.
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Proteínas Adaptadoras Transductoras de Señales/genética , Carcinoma Hepatocelular/diagnóstico , Silenciador del Gen/fisiología , Neoplasias Hepáticas/diagnóstico , Proteínas de la Membrana/genética , MicroARNs/genética , Células Madre Neoplásicas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Proteínas Argonautas/metabolismo , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Factores Eucarióticos de Iniciación/metabolismo , Femenino , Humanos , Neoplasias Hepáticas/genética , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Células Madre Neoplásicas/metabolismo , Adulto JovenRESUMEN
INTRODUCTION: Insulin-like growth factor-II mRNA-binding protein 3 (IMP3), a newly identified oncofetal RNA-binding protein, plays a pivotal role in the regulation of cell growth and migration during early stages of embryogenesis, and is found to be expressed in various human cancers. In this study, we elucidated the clinicopathological significance of IMP3 expression in intrahepatic cholangiocarcinoma (ICC). METHODS: From March 1995 to December 2003, 61 surgically resected, unifocal primary ICCs were studied. IMP3 protein expression was detected by immunohistochemical staining. RESULTS: IMP3 protein was expressed in 25 of 61 ICCs (41.0%). In addition to correlating with tumor grade (p = 0.0276), tumor stage (p = 0.0059), lymphovascular invasion (p = 0.0198), serum carbohydrate antigen 19-9 level (p = 0.0146), IMP3 expression predicted early tumor recurrence (ETR) (p = 0.0059) and was a strong indicator of worse disease-free survival (p = 0.0001) and overall survival (p = 0.0007). Even though we did not find that IMP3 expression exerted prognostic impact independent of tumor stage, multivariate analysis confirmed that IMP3 expression was an independent risk factor of high-stage tumor and ETR (p = 0.0170, and p = 0.0052, respectively), and thus it contributed to poor prognosis in ICC patients. CONCLUSIONS: IMP3 expression can serve as a novel maker for ETR and prognostic prediction, and may be a target for adjuvant therapy of patients with ICC after tumor resection.
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Biomarcadores de Tumor/biosíntesis , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/metabolismo , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/metabolismo , Proteínas de Unión al ARN/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Neoplasias de los Conductos Biliares , Conductos Biliares Intrahepáticos , Colangiocarcinoma/patología , Femenino , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Pronóstico , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
BACKGROUND: SIRT1 is a NAD+-dependent deacetylase that plays crucial roles in many biological processes, including stress response, apoptosis, cellular metabolism, adaptation to calorie restriction, aging, and tumorigenesis. The purpose of this study is to elucidate the clinicopathological and functional significance of SIRT1 expression in hepatocellular carcinoma (HCC). METHODS: SIRT1 expression in HCC was determined by immunohistochemical staining. The results were correlated with clinicopathological parameters. SIRT1 was overexpressed in HCC cell line SK-Hep1 to study its role in tumorigenesis and resistance to chemotherapy. RESULTS: SIRT1 was overexpressed in 95 of 172 HCCs (55%). SIRT1 overexpression was associated with higher α-fetoprotein level, higher tumor grade, and absence of ß-catenin mutation. SIRT1 expression predicted poor long-term survival for patients with resected HCC. The elevated SIRT1 protein level in HCC was not attributable to the elevation of mRNA level. The half-life of SIRT1 protein was longer in cell lines with higher expression of SIRT1. We further demonstrated that SIRT1 was degraded by the 26S proteasome in an ubiquitin-dependent manner. Overexpression of SIRT1 promoted tumorigenesis and resistance to chemotherapeutical agent and sorafenib. CONCLUSIONS: SIRT1 is an oncogenic protein for HCC and is a predictor of worse outcome after surgical resection of HCC.
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Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Resistencia a Antineoplásicos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Sirtuina 1/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibióticos Antineoplásicos/farmacología , Bencenosulfonatos/farmacología , Biomarcadores de Tumor/análisis , Western Blotting , Carcinoma Hepatocelular/metabolismo , Proliferación Celular , Células Cultivadas , Doxorrubicina/farmacología , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Semivida , Humanos , Técnicas para Inmunoenzimas , Inmunoprecipitación , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Mutación/genética , Clasificación del Tumor , Estadificación de Neoplasias , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Pronóstico , Proteolisis , Piridinas/farmacología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sirtuina 1/genética , Sorafenib , Tasa de Supervivencia , Adulto Joven , alfa-Fetoproteínas/genética , alfa-Fetoproteínas/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Male gender is a risk factor for the development of hepatocellular carcinoma (HCC) but the mechanisms are not fully understood. The RNA binding motif gene on the Y chromosome (RBMY), encoding a male germ cell-specific RNA splicing regulator during spermatogenesis, is aberrantly activated in human male liver cancers. This study investigated the in vitro oncogenic effect and the possible mechanism of RBMY in human hepatoma cell line HepG2 and its in vivo effect with regards to the livers of human and transgenic mice. RBMY expression in HepG2 cells was knocked down by RNA interference and the cancer cell phenotype was characterized by soft-agar colony formation and sensitivity to hydrogen-peroxide-induced apoptosis. The results revealed that RBMY knockdown reduced the transformation and anti-apoptotic efficiency of HepG2 cells. The expression of RBMY, androgen receptor (AR) and its inhibitory variant AR45, AR-targeted genes insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) was analyzed by quantitative RT-PCR. Up-regulation of AR45 variant and reduction of IGF-1 and IGFBP-3 expression was only detected in RBMY knockdown cells. Moreover, RBMY positive human male HCC expressed lower level of AR45 as compared to RBMY negative HCC tissues. The oncogenic properties of RBMY were further assessed in a transgenic mouse model. Liver-specific RBMY transgenic mice developed hepatic pre-cancerous lesions, adenoma, and HCC. RBMY also accelerated chemical carcinogen-induced hepatocarcinogenesis in transgenic mice. Collectively, these findings suggest that Y chromosome-specific RBMY is likely involved in the regulation of androgen receptor activity and contributes to male predominance of HCC.
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Neoplasias Hepáticas/genética , Proteínas Nucleares/genética , Oncogenes , Proteínas de Unión al ARN/genética , Animales , Línea Celular Tumoral , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Transgénicos , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Viral hepatitis-associated intrahepatic cholangiocarcinoma is thought to have common disease processes with hepatocellular carcinoma, but until now the histomorphological and genetic features of viral hepatitis-associated intrahepatic cholangiocarcinoma is still unknown. From 2000 to 2010, 170 patients with intrahepatic cholangiocarcinoma who received detailed pathological assessment and regular follow-up at the National Taiwan University Hospital were selected for this study. Of 170 patients, 69 (41%) were positive for hepatitis B and/or C virus. These patients were younger, were more frequently male, and had elevated serum α-fetoprotein levels as compared with seronegative intrahepatic cholangiocarcinoma patients. Grossly these tumors were mostly of the mass-forming type, and histologically, cholangiolar differentiation was more frequently seen. We identified N-cadherin as an immunohistochemical marker strongly associated with hepatitis virus infection. The prevalence of viral hepatitis in patients with N-cadherin-positive intrahepatic cholangiocarcinoma was 75%, and that in N-cadherin-negative patients was only 37%. N-cadherin-positive patients were younger, had elevated α-fetoprotein, and had no hepatolithiasis. All N-cadherin-positive intrahepatic cholangiocarcinomas were of the mass-forming type. N-cadherin positivity was strongly associated with cholangiolar morphology and lack of carcinoembryonic antigen and MUC2 expression, whereas K-RAS mutations were less frequent. Our results indicate that a subgroup of intrahepatic cholangiocarcinoma characterized by cholangiolar differentiation and N-cadherin expression is strongly associated with viral hepatitis.
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Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Cadherinas/metabolismo , Colangiocarcinoma/patología , Hepatitis Viral Humana/patología , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/virología , Conductos Biliares Intrahepáticos/metabolismo , Biomarcadores de Tumor/metabolismo , Transdiferenciación Celular , Transformación Celular Neoplásica , Transformación Celular Viral , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/virología , Femenino , Genes ras , Hepatitis B/complicaciones , Hepatitis B/patología , Hepatitis C/complicaciones , Hepatitis C/patología , Hepatitis Viral Humana/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Mutación , alfa-Fetoproteínas/análisisRESUMEN
BACKGROUND: Cytokeratin 19 (CK19), a molecular marker of hepatic progenitor cells and cholangiocytes, is expressed in hepatocellular carcinomas (HCC), but not in normal hepatocytes. However, role of CK19 in HCC progression, especially when interacted with p53 and ß-catenin mutations, remained largely unknown. MATERIALS AND METHODS: From January 1983 to December 1997, 210 surgically resected, unifocal, primary HCCs were studied retrospectively. CK19 protein expression was detected by immunohistochemistry while mutations of p53 and ß-catenin genes were detected by direct DNA sequencing. RESULTS: CK19 protein expression was detected in 35.7% (75/210), p53 mutation in 47.2% (83/176) and ß-catenin mutation in 14.5% (27/186). The tumor size (p=0.0023), grade (p = 0.00093), tumor stage (p = 4 x 10-7), high α-fetoprotein (p=0.0004), p53 mutation (p = 0.024), absence of ß-catenin mutation (p = 0.0013), and CK19 expression (p = 3 x 10-5) were markers predictive of early tumor recurrence (ETR). CK19 expression, stage, and ETR were strong indicators of poor prognosis (all p < 0.0001). Importantly, combination analysis showed an additive unfavorable prognostic interaction of CK19 expression and p53 mutation. On the contrary, concurrent CK19 expression and ß-catenin mutation was rare and CK19 expression abolished the suppression effect of ß-catenin mutation on HCC progression. CONCLUSIONS: CK19 expression is associated with more aggressive HCC. CK19 cooperates with p53 mutation towards advanced disease. In contrast, CK19 expression and ß-catenin mutation play dramatic opposite roles in vascular invasion, ETR and the prognosis of HCC.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidad , Genes p53 , Queratina-19/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidad , Mutación , Recurrencia Local de Neoplasia/genética , beta Catenina/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Análisis de Secuencia de ADN , Tasa de Supervivencia , Factores de Tiempo , Adulto Joven , alfa-Fetoproteínas/metabolismo , beta Catenina/metabolismoRESUMEN
BACKGROUND AND AIMS: Annexin A10 (ANXA10) and its liver-specific short isoform (ANXA10S) had tissue-restricted expression. The downregulation of ANXA10S is correlated with tumor progression and poor prognosis in hepatocellular carcinoma. The aim of the present study was to validate the tissue distribution and explore the role of the ANXA10 protein expression in gastric carcinoma. METHODS: We examined the ANXA10 protein expression in human and animal tissues and 356 resected primary gastric carcinomas, using specific mouse and rabbit polyclonal antibodies, by immunohistochemical staining. RESULTS: The ANXA10 protein is a nuclear protein specifically expressed in fetal and adult gastric mucosa and Brunner's gland across species, including humans, minipigs, woodchucks, and mice, and is commonly lost in gastric mucosa with intestinal metaplasia. The ANXA10 protein was expressed in 43.5% (155 cases) of gastric carcinomas; 74.2% (98/132) in the diffuse-type gastric carcinoma (DGC), 73.7% (28/38) in the mixed-type gastric carcinoma, and significantly lower in the intestinal-type gastric carcinoma (IGC) and indeterminate groups, 16.8% (28/167) and 5.3% (1/19), respectively (P<1×10(-8)). IGC with ANXA10 expression was correlated with a higher stage (P=0.049), particularly higher in stage IIIA/IIIB/IV IGC than lower-stage (IA/IB/II) tumors (P=0.005), but was not correlated with age, sex, and nodal status. In contrast, DGC with ANXA10 expression was associated with younger age, female patients, and importantly, lower tumor stage and lymph node metastasis (P=0.007, P=0.065, P=0.024, and P=0.0014, respectively). Moreover, DGC with ANXA10 expression had a better 5-year patient survival (P=0.0048), whereas IGC with ANXA10 expression had a lower 5-year survival (P=0.034). CONCLUSIONS: The ANXA10 protein expression is a novel marker of gastric differentiation, and is differentially expressed in IGC and DGC, with opposite prognostic significance.
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Adenocarcinoma/química , Anexinas/análisis , Biomarcadores de Tumor/análisis , Neoplasias Gástricas/química , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Anexinas/genética , Biomarcadores de Tumor/genética , Western Blotting , Diferenciación Celular , Núcleo Celular/química , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Marmota , Ratones , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Pronóstico , ARN Mensajero/análisis , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Tasa de Supervivencia , Porcinos , Porcinos Enanos , Taiwán , Factores de TiempoRESUMEN
BACKGROUND: To investigate the significance of Aurora B expression in hepatocellular carcinoma (HCC). METHODS: The Aurora B and Aurora A mRNA level was measured in 160 HCCs and the paired nontumorous liver tissues by reverse transcription-polymerase chain reaction. Mutations of the p53 and ß-catenin genes were analyzed in 134 and 150 tumors, respectively, by direct sequencing of exon 2 to exon 11 of p53 and exon 3 of ß-catenin. Anticancer effects of AZD1152-HQPA, an Aurora B kinase selective inhibitor, were examined in Huh-7 and Hep3B cell lines. RESULTS: Aurora B was overexpressed in 98 (61%) of 160 HCCs and in all 7 HCC cell lines examined. The overexpression of Aurora B was associated with Aurora A overexpression (P = 0.0003) and p53 mutation (P = 0.002) and was inversely associated with ß-catenin mutation (P = 0.002). Aurora B overexpression correlated with worse clinicopathologic characteristics. Multivariate analysis confirmed that Aurora B overexpression was an independent poor prognostic factor, despite its interaction with Aurora A overexpression and mutations of p53 and ß-catenin. In Huh-7 and Hep3B cells, AZD1152-HQPA induced proliferation blockade, histone H3 (Ser10) dephosphorylation, cell cycle disturbance, and apoptosis. CONCLUSION: Aurora B overexpression is an independent molecular marker predicting tumor invasiveness and poor prognosis of HCC. Aurora B kinase selective inhibitors are potential therapeutic agents for HCC treatment.
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Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Recurrencia Local de Neoplasia/genética , Proteínas Serina-Treonina Quinasas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Aurora Quinasa B , Aurora Quinasas , Biomarcadores de Tumor/metabolismo , Western Blotting , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Femenino , Citometría de Flujo , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Mutación/genética , Invasividad Neoplásica , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Adulto Joven , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
MicroRNAs (miRNAs) play critical roles in embryonic development and are frequently deregulated in human cancers. The let-7 family members are tumor-suppressing miRNAs and are frequently downregulated in cancer cells. Lin-28 and Lin-28B are RNA-binding proteins highly expressed in embryonic tissues. Lin-28 proteins block let-7 precursors from being processed to mature miRNAs by inducing terminal uridylation and degradation of let-7 precursors. Here, we report that Lin-28B, but not Lin-28, is highly expressed in hepatocellular carcinoma (HCC). Lin-28B expression was more frequently noted in high-grade HCCs with high alpha-fetoprotein levels. Knockdown of Lin-28B by RNA interference in the HCC cell line HCC36 suppressed proliferation in vitro and reduced in vivo tumor growth in NOD/SCID mice. In contrast, overexpression of Lin-28B in the HCC cell line HA22T enhanced tumorigenicity. Overexpression of Lin-28B also induced epithelial-mesenchymal transition in HA22T cells and hence, invasion capacity. Large-scale real-time PCR array analysis revealed that, among 380 miRNAs, only let-7/mir-98 family members were regulated by Lin-28B. Lin-28B overexpression enhanced the expression of the known let-7 targets c-myc and HMGA2. It was also found that Lin-28B enhanced the expression of type 1 insulin-like growth factor receptor in a let-7-dependent manner. These results indicate that Lin-28B regulates tumor formation and invasion in HCC through coordinated repression of the let-7/mir-98 family and induction of multiple oncogenic pathways.
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Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Proteínas de Unión al ARN/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Apoptosis , Western Blotting , Carcinoma Hepatocelular/genética , Adhesión Celular , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Humanos , Neoplasias Hepáticas/genética , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , MicroARNs/genética , MicroARNs/metabolismo , Persona de Mediana Edad , Invasividad Neoplásica , ARN Mensajero/genética , Proteínas de Unión al ARN/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto JovenRESUMEN
OBJECT: Stathmin, an important cytosolic phosphoprotein, is involved in cell proliferation and motility. This study was performed to elucidate the role of stathmin in the progression of medulloblastoma. METHODS: The expression of stathmin protein was examined by immunohistochemical staining of tumor sections obtained in 17 consecutive patients with medulloblastoma who underwent resection between 1995 and 2005. Four patients were excluded because they were either lost to follow-up or underwent biopsy sampling only, leaving a total of 13 patients in the study. The stathmin expression was scored according to the immunoreactive fraction of tumor cells, and the level was correlated with various clinicopathological factors. RESULTS: The expression level of stathmin protein was < or = 10% in 9 patients, 11-50% in 1, and > 50% in 3. No staining was seen in the tissues adjacent to the tumors. For comparison, the authors grouped the expression level of stathmin into high (> 50%) and low (< or = 50%). It was found that patients with high expression of stathmin had more frequent tumor dissemination at the time of resection or soon after total excision of the tumor (p = 0.0035), and hence experienced a fulminant course with lower patient survival (p < 0.0001), with an average survival period of 6.7 months (range 2-10 months). The expression level of stathmin did not correlate with patient age, sex, CSF cytological findings, use of adjuvant therapies, Ki 67 index, or risk classification of the tumors according to previously described categories in the literature. CONCLUSIONS: High stathmin expression correlates with tumor dissemination, is an important prognostic factor of medulloblastoma, and may serve as a useful marker for more intensive adjuvant therapies.