RESUMEN

AIMS: This study aimed at exploring HOXB13 expression and function in gastric cancer (GC), and the underlying molecular mechanism. MATERIALS AND METHODS: HOXB13 and fat mass and obesity-associated protein (FTO) expression in GC and non-GC tissues of GC patients were analyzed using Gene Expression Profiling Interactive Analysis (GEPIA) and verified by quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and western blotting. The regulatory relationship between FTO and HOXB13 was verified via RT-qPCR, methylated RNA immunoprecipitation sequencing (MeRIP-seq), and double luciferase reporter gene assay. The effects of HOXB13 and FTO on proliferation, invasion, and migration of GC cells were studied using EdU and Transwell assays. KEY FINDINGS: HOXB13 and FTO expression was abnormally high in GC tissues and cell lines, with no significant correlation between HOXB13 and FTO expression and the prognosis of GC patients. Inhibiting FTO expression in GC cells decreased HOXB13 methylation and upregulated HOXB13 expression. Inhibiting HOXB13 and FTO expression suppressed GC cell proliferation, migration, and invasion. Decreased HOXB13 expression suppressed PI3K/AKT/mTOR signaling pathway activity, while atypical HOXB13 expression promoted it. A probable downstream target of HOXB13 was insulin-like growth factor 1 receptor (IGF-1R); a decrease in IGF-1R relieved GC cell migration, invasion, and proliferation and inhibited PI3K/AKT/mTOR signaling pathway activity promoted by atypical HOXB13 expression. SIGNIFICANCE: HOXB13 and FTO expression is elevated in GC. FTO suppresses HOXB13 methylation; FTO and HOXB13 expression promotes GC cell proliferation, migration, and invasion. HOXB13 expression intensifies GC invasion through PI3K/AKT/mTOR signaling via IGF-1R. HOXB13 and associated signaling pathways can be effective targets for GC therapy.

Asunto(s)

Perfilación de la Expresión Génica , Proteínas de Homeodominio/fisiología , Receptor IGF Tipo 1/metabolismo , Neoplasias Gástricas/metabolismo , Tejido Adiposo/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Movimiento Celular , Proliferación Celular , Progresión de la Enfermedad , Humanos , Inmunoprecipitación , Metiltransferasas/metabolismo , Invasividad Neoplásica , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Regulación hacia Arriba

RESUMEN

BACKGROUND: Previous studies revealed that DEP domain containing 1 (DEPDC1) is involved in the carcinogenesis and progression of several types of human cancer. However the role of DEPDC1 in gastric cancer has not been studied. OBJECTIVE: The objective of this study was to study the expression and pathophysiological function of DEPDC1 in gastric cancer. METHODS: DEPDC1 expression in gastric adenocarcinoma cells was examined with Western blot and qRT-PCR. Clinical pathological features of patients were determined by immunohistochemistry. The effect of DEPDC1 expression on cell proliferation was studied by in vitro cell proliferation assay; and cell cycle influence was assessed by flow cytometry. Survival curves were plotted using Kaplan-Meier. RESULTS: DEPDC1 was overexpressed in gastric adenocarcinoma tissues compared with the paired adjacent normal gastric tissues, in accordance with mRNA level downloaded from GEPIA database. DEPDC1 expression level was significantly associated with cancer metastasis and differentiation. DEPDC1 upregulation caused cell cycle accelerating from G1 to S phase, and it was correlated with poorer overall survival. CONCLUSION: Therefore, DEPDC1 upregulation in gastric adenocarcinoma is associated with tumor development and poor clinical outcomes of the patients, implying DEPDC1 might be a potential therapeutic target against gastric cancer.

Asunto(s)

Proteínas Activadoras de GTPasa/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Gástricas/genética , Proliferación Celular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias Gástricas/fisiopatología , Transfección , Regulación hacia Arriba

RESUMEN

The high mortality of colorectal cancer (CRC) patients and the limitations of conventional tumor-node-metastasis (TNM) stage emphasized the necessity of exploring hub genes closely related to carcinogenesis and prognosis in CRC. The study is aimed at identifying hub genes associated with carcinogenesis and prognosis for CRC. We identified and validated 212 differentially expressed genes (DEGs) from six Gene Expression Omnibus (GEO) datasets and the Cancer Genome Atlas (TCGA) database. We investigated functional enrichment analysis for DEGs. The protein-protein interaction (PPI) network was constructed, and hub modules and genes in CRC carcinogenesis were extracted. A prognostic signature was developed and validated based on Cox proportional hazards regression analysis. The DEGs mainly regulated biological processes covering response to stimulus, metabolic process, and affected molecular functions containing protein binding and catalytic activity. The DEGs played important roles in CRC-related pathways involving in preneoplastic lesions, carcinogenesis, metastasis, and poor prognosis. Hub genes closely related to CRC carcinogenesis were extracted including six genes in model 1 (CXCL1, CXCL3, CXCL8, CXCL11, NMU, and PPBP) and two genes and Metallothioneins (MTs) in model 2 (SLC26A3 and SLC30A10). Among them, CXCL8 was also related to prognosis. An eight-gene signature was proposed comprising AMH, WBSCR28, SFTA2, MYH2, POU4F1, SIX4, PGPEP1L, and PAX5. The study identified hub genes in CRC carcinogenesis and proposed an eight-gene signature with good reproducibility and robustness at the molecular level for CRC, which might provide directive significance for treatment selection and survival prediction.

Asunto(s)

Neoplasias Colorrectales/etiología , Biología Computacional , Carcinogénesis , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Humanos , Pronóstico , Modelos de Riesgos Proporcionales , Mapas de Interacción de Proteínas

RESUMEN

Since the herb pair Huang Lian-Gan Jiang (HL-GJ) was put forward as conventional compatibility for cold-heat regulation in the middle energizer in the theory of Traditional Chinese Medicine (TCM), their therapeutic effects were observed on the prevention and treatment of intestinal inflammation and tumors including colorectal cancer (CRC). However, the active compounds, crucial targets, and related pathways of HL-GJ against CRC remained unclear. The purpose of this research was to establish a comprehensive and systemic approach that could identify the active compounds, excavate crucial targets, and reveal anti-CRC mechanisms of HL-GJ against CRC based on network pharmacology. We used methods including chemical compound screening based on absorption, distribution, metabolism, and excretion (ADME), compound target prediction, CRC target collection, network construction and analysis, Gene Ontology (GO), and pathway analysis. In this study, eight main active compounds of HL-GJ were identified, including Gingerenone C, Isogingerenone B, 5,8-dihydroxy-2-(2-phenylethyl) Chromone, 2,3,4-trihydroxy-benzenepropanoic acid, 3,4-dihydroxyphenylethyl Alcohol Glucoside, 3-carboxy-4-hydroxy-phenoxy Glucoside, Moupinamide, and Obaculactone. HRAS, KRAS, PIK3CA, PDE5A, PPARG, TGFBR1, and TGFBR2 were identified as crucial targets of HL-GJ against CRC. There were mainly 500 biological processes and 70 molecular functions regulated during HL-GJ against CRC (P < 0.001). There were mainly 162 signaling pathways contributing to therapeutic effects (P < 0.001), the top 10 of which included DAP12 signaling, signaling by PDGF, signaling by EGFR, NGF signaling via TRKA from the plasma membrane, signaling by NGF, downstream signal transduction, DAP12 interactions, signaling by VEGF, signaling by FGFR3, and signaling by FGFR4. The study established a comprehensive and systematic paradigm to understand the pharmacological mechanisms of multiherb compatibility such as an herb pair, which might accelerate the development and modernization of TCM.

RESUMEN

BACKGROUND The aim of this study was to elucidate the involvement of cPLA2-AA-COX-2 pathway factors and their potential role in lung cancer early diagnosis and prognosis. MATERIAL AND METHODS We selected 80 lung cancer patients as the cancer group, and 30 normal patients were selected as the normal group. Serum contents of COX-2, cPLA2, COX-1, mPGES, PGE2, and PGI2 were measured, and mRNA levels of COX-2, cPLA2, COX-1, and mPGES in serum were determined. Spearman's P-test was used to analyze the correlation between expression of PGI2 and mPGES in serum and the clinical characteristics of these lung cancer patients. The factors affecting the prognosis lung cancer were analyzed by COX regression model. RESULTS The serum contents of COX-2, cPLA2, COX-1, mPGES, PGE2, and PGI2 in the cancer patient group were significantly higher (p<0.05) than in the normal group; after treatment, the serum contents of these factors were significantly decreased (p<0.05). However, distant metastasis had a significant effect on serum contents of mPGES and PGI2 (p<0.05), but not on the other factors. The mRNA levels of COX-2, cPLA2, COX-1, and mPGES in cancer patients were significantly higher than in normal patients. In addition, the 5-year survival rate of patients with high expression of mPGES and/or PGI2 was lower than that of the low expression group. Cox regression analysis showed that the expression of mPGES and PGI2 had statistical significance in predicting the prognosis of lung cancer. CONCLUSIONS The cPLA2-AA-COX-2 pathway is closely associated with lung cancer. These findings are important for clinical diagnosis of lung cancer.

Asunto(s)

Ácido Araquidónico/metabolismo , Ciclooxigenasa 2/metabolismo , Neoplasias Pulmonares/metabolismo , Fosfolipasas A2 Citosólicas/metabolismo , Adulto , Anciano , Ácido Araquidónico/sangre , Ácido Araquidónico/genética , Ciclooxigenasa 2/sangre , Ciclooxigenasa 2/genética , Citosol/metabolismo , Dinoprostona/metabolismo , Detección Precoz del Cáncer/métodos , Femenino , Humanos , Oxidorreductasas Intramoleculares/metabolismo , Isoenzimas , Pulmón/metabolismo , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Fosfolipasas A2 Citosólicas/sangre , Fosfolipasas A2 Citosólicas/genética , Pronóstico , Prostaglandina-E Sintasas/genética , Prostaglandina-E Sintasas/metabolismo , ARN Mensajero/metabolismo , Transducción de Señal/genética

RESUMEN

DEP domain containing 1 (DEPDC1) is a novel tumor-associated gene, which is aberrantly expressed in multiple types of cancer and involves in tumorigenesis and cancer progression. Here, we examined the functional involvement and underlying mechanism of DEPDC1 in breast cancer. In this study, the immunohistochemistry results demonstrated that DEPDC1 was high-expressed in breast cancer tissues compared with the paired adjacent normal breast tissues, and its tendency at protein level was consistent with mRNA level from TCGA data. Moreover, DEPDC1 mRNA level revealed the strongest association with poor prognosis and development in breast cancer. In vitro assays showed that DEPDC1 overexpression resulted in significant promotion of proliferation by regulating cell cycle in MCF-7 cells, whilst an opposite effect was found in the MDA-MB-231 cells with DEPDC1 deletion. Notably, further investigation indicated DEPDC1's ability of promoting breast cancer cells migration and invasion. In addition, we discovered that DEPDC1 caused hyper-activation of PI3K/AKT/mTOR signaling in breast cancer cells. Therefore, the increased DEPDC1 expression in breast cancer is correlated with disease progression and poor survival, which suggested that DEPDC1 might be a potential therapeutic target against this disease.

RESUMEN

OBJECTIVE@#This study aimed to investigate the expression and clinical significance of proline-rich tyrosine kinase 2 (Pyk2) and phospho-protein kinase B (p-AKT) in tongue squamous cell carcinoma (TSCC) and adjacent nontumor tissues.@*METHODS@#The Pyk2 and p-AKT protein levels were detected via immunohistochemistry in 45 cases of TSCC tissues and 30 cases of adjacent nontumor tissues. The relationships of the two protein levels and clinicopathological characteristics were also analyzed.@*RESULTS@#Pyk2 and p-AKT levels were significantly higher in the TSCC tissues than in the adjacent nontumor tissues (P<0.05). Nontumor tissues showed poor or no expression. The expression levels of the two proteins were positively correlated (γs=0.412). The expression of Pyk2 was associated with histopathological differentiation type, regional lymph node metastasis, and TNM staging (P<0.05), but not with age and gender. The expression of p-AKT was only related to histopathological differentiation types (P<0.05).@*CONCLUSIONS@#The abnormal expression of Pyk2 and p-AKT proteins might be closely related to the development and progression of TSCC. Joint detection can be used as an indicator to estimate the degree of TSCC.

Asunto(s)

Humanos , Carcinoma de Células Escamosas , Metabolismo , Quinasa 2 de Adhesión Focal , Metabolismo , Pronóstico , Proteínas Proto-Oncogénicas c-akt , Metabolismo , Neoplasias de la Lengua , Metabolismo

RESUMEN

AIM: To investigate the expression of cyclophilin A (CypA) in human hepatocellular carcinoma (HCC) and explore the effects of CypA on the cell cycle in HCC. MATERIALS AND METHODS: CypA expression was assessed by immunohistochemistry in 48 cases of HCC tissues and paired adjacent tissues. CypA plasmid was transfected into HCC cells and the cell cycle was analyzed. RESULTS: Positivity for CypA was higher in HCC tissues than in adjacent tissues (79.1% vs. 12.5%, p<0.05). Positivity for CypA was significantly higher in stage III and IV HCC than in stage I and II (p<0.05). Elevated CypA induced an increase of the percentage of S-phase cells (from 34.79% to 42.14%) and a decrease of G0-G1 phase cells (from 58.10% to 50.64%). CONCLUSION: CypA is overexpressed in HCC and is associated with TNM stage. CypA also appears to promote the transition of the cell cycle from G1 to S phase.

Asunto(s)

Carcinoma Hepatocelular/patología , Ciclofilina A/metabolismo , Neoplasias Hepáticas/patología , Regulación hacia Arriba , Carcinoma Hepatocelular/metabolismo , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Estadificación de Neoplasias

RESUMEN

BACKGROUND/AIM: Biomarkers are essential in early diagnosis and understanding of the molecular mechanism of human cancer. The expression of cyclophilin J, a novel member of the cyclophilin family, was investigated in primary gastric adenocarcinoma. MATERIALS AND METHODS: Western blot analysis was carried out on 36 paired tumor and normal tissue samples; immunohistochemical analysis was carried out on 120 gastric carcinoma tissues and normal adjacent tissue. RESULTS: Cyclophilin J protein was overexpressed in 72.2% of gastric carcinoma tissues compared to adjacent normal tissues. Immunohistochemical analysis revealed that cyclophilin J was overexpressed in 49.2% (59/120) and 23.3% (28/120) of gastric carcinoma tissues and adjacent tissues, respectively (p<0.05). Expression of cyclophilin J was associated with the degree of differentiation, but not with lymph node metastasis, gender or depth of tumor infiltration. The overall survival of patients showed no association with the overexpression of cyclophilin J protein. CONCLUSION: Cyclophilin J expression was up-regulated in gastric carcinoma compared to normal gastric tissues. However, in order to confirm its association with the survival of patients with gastric cancer, more cases need to be studied.

Asunto(s)

Adenocarcinoma/metabolismo , Ciclofilinas/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Biomarcadores de Tumor , Western Blotting , Ciclofilinas/genética , Femenino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Expresión Génica , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Pronóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología

RESUMEN

BACKGROUND/AIM: Bevacizumab combined with standard chemotherapeutics has become a choice of treatment for several kinds of cancers. Hypertension, third-degree albuminuria, thrombosis and cardiotoxicity are the reported side-effects of bevacizumab. Among them, cardiotoxicity is a most severe, but rare outcome. We report a case of a 62-year-old female with colorectal carcinoma who was given bevacizumab-containing chemotherapy for more than 20 months and achieved a stable disease during the entire course of treatment. Thereafter, she developed cardiotoxicity including grade 3 hypertension, tricuspid regurgitation, pulmonary hypertension, left ventricular diastolic dysfunction and pericardial effusion, and was discontinued from the regimen with bevacizumab. CONCLUSION: Although clinically-effective, the severe cardiotoxicity of bevacizumab developed after over 20 courses of treatment prompted us to look for optimal chemotherapy prescription in order to achieve a better clinical outcome.

Asunto(s)

Inhibidores de la Angiogénesis/efectos adversos , Antineoplásicos/efectos adversos , Bevacizumab/efectos adversos , Neoplasias Colorrectales/complicaciones , Cardiopatías/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Biopsia , Cardiotoxicidad , Colonoscopía , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/tratamiento farmacológico , Femenino , Cardiopatías/diagnóstico , Humanos , Persona de Mediana Edad , Tomografía Computarizada por Rayos X

RESUMEN

BACKGROUND/AIM: To evaluate the clinical efficiency of tumor-infiltrating lymphocytes (TILs) compared to cisplatin for malignant pleural effusion and ascites through intrapleural and intraperitoneal infusion. PATIENTS AND METHODS: Thirteen patients with malignant pleural effusion and ascites were divided into a TIL-treated group and a cisplatin-treated group. Patients were given TILs or cisplatin, through intrapleural and intraperitoneal infusion respectively, after drainage of the malignant serous effusion by thoracentesis or abdominocentesis. RESULTS: The overall response rate and disease control rate of the TIL-treated group (33.33% and 83.33%) were higher than that of the cisplatin-treated group (28.57% and 71.43%). The progression-free survival for the TIL-treated group was significantly longer (p=0.002) and better than that of the cisplatin-treated group (66.67% vs. 28.57%). Quality of life apparently improved in the TIL-treated group and was clearly higher than that in the cisplatin-treated group. CONCLUSION: The use of TILs has a better clinical efficiency for malignant pleural effusion and ascites than cisplatin through intrapleural and intraperitoneal infusion without severe adverse effects.

Asunto(s)

Antineoplásicos/administración & dosificación , Ascitis/terapia , Cisplatino/administración & dosificación , Inmunoterapia Adoptiva , Linfocitos Infiltrantes de Tumor/trasplante , Derrame Pleural Maligno/terapia , Adulto , Anciano , Antineoplásicos/efectos adversos , Ascitis/diagnóstico , Ascitis/mortalidad , Biomarcadores de Tumor , Cisplatino/efectos adversos , Femenino , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Infusiones Parenterales , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Persona de Mediana Edad , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/mortalidad , Calidad de Vida , Análisis de Supervivencia , Resultado del Tratamiento

RESUMEN

CASE REPORT: This case study reports on a patient who relapsed with thymoma (mixed type) nine years after tumor resection. After four courses of rescue chemotherapy (docetaxel and cisplatinum), the patient was further diagnosed with pure red cell aplasia. It was noticed that cyclosporin A (CsA), which was administered to treat aplasia, could reverse chemoresistance. Its mechanism is not completely clear, but the hypothesis of CsA inhibiting P-glycoprotein mediated drug efflux is the most acceptable.

Asunto(s)

Ciclosporina/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Inmunosupresores/uso terapéutico , Aplasia Pura de Células Rojas/tratamiento farmacológico , Aplasia Pura de Células Rojas/etiología , Timoma/complicaciones , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclosporina/farmacología , Resultado Fatal , Humanos , Inmunosupresores/farmacología , Masculino , Persona de Mediana Edad , Aplasia Pura de Células Rojas/diagnóstico , Timoma/diagnóstico , Timoma/tratamiento farmacológico , Tomografía Computarizada por Rayos X

RESUMEN

OBJECTIVE: To investigate the efficacy of cytokine-induced killer cell-based immunotherapies in patients with advanced malignant solid tumors and the difference in clinical efficiency among 3 kinds of cytokine-induced killer cell-based immunotherapies. METHODS: One hundred forty-six cases with advanced solid tumor, 230 cycles of cytokine-induced killer cell-based immunotherapies, were involved in this study. T-lymphocyte subsets, carcinoembryonic antigen, and adverse reactions were recorded. RESULTS: CD3+ T lymphocyte, Th, NKT, and Th/Tc were increased after cytokine-induced killer cell-based treatment, from 55.67 ± 3.64 to 84.12 ± 5.15, 26.56 ± 4.47 to 42.76 ± 3.68, 1.82 ± 0.58 to 7.08 ± 0.92, 0.79 ± 3.64 to 1.35 ± 0.20, respectively ( P < .001). Carcinoembryonic antigen was decreased from 398.39 ± 219.16 to 127.26 ± 153.41 ( P < .001). Difference values were greater than 0 ( P < .001). Difference value of carcinoembryonic antigen was obviously less than 0 ( P < .001). There was no obvious difference in all variations between cytokine-induced killer cell and DC+CIK groups ( P > .05). The highest amount of CD3+ T lymphocyte and Th was recorded after at least 4 cycles of immunotherapy. And CD8+ T/CD4+ T also began to decrease after 4 cycles of immunotherapy. Difference value of T lymphocyte and Tc of patients with surgery is higher than that of patients without surgery. CONCLUSION: Cytokine-induced killer cell-based immunotherapy is capable of increasing T-lymphocyte subsets, recovering cellular immunity without severe side effects, and is suitable for different kinds of solid cancer. Clinical efficiency of cytokine-induced killer cell-based immunotherapy is influenced by many factors such as surgery, stage.

Asunto(s)

Células Asesinas Inducidas por Citocinas/inmunología , Inmunoterapia , Neoplasias/inmunología , Neoplasias/terapia , Adulto , Anciano , Antígenos de Neoplasias/inmunología , Células Asesinas Inducidas por Citocinas/patología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Humanos , Inmunofenotipificación , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/diagnóstico , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Resultado del Tratamiento

RESUMEN

Borrmann type IV gastric cancer is a particular histological type of carcinoma, which has the characteristic of diffused infiltration that invades the entire stomach, resulting in the thickening and stiffness of the stomach wall. Borrmann type IV gastric cancer is known for the difficulty of detecting tumor cells in endoscopic biopsy specimens. This is crucial in obtaining the pathological results to make a therapeutic decision. The case reported in the present study was highly suspected to be Borrmann type IV gastric cancer according to the clinical manifestations and gastrointestinal barium meal examinations, but demonstrated negative results in multiple endoscopic biopsies and positron emission tomography-computed tomography (PET-CT) examination. The patient was discharged as no affirmative diagnosis was specified. Two weeks after discharge, the patient was administered to another hospital under emergency treatment due to frequent urination. Cystoscopy examination revealed marked thickening of the right bladder wall over a large area. Biopsy specimens were sampled. Pathological consultation suggested a gastrointestinal original of the lesion, which was most likely poorly differentiated gastric adenocarcinoma with neuroendocrine metastasis to the bladder.

RESUMEN

AIM: To characterize the biochemical features of the newest member of cyclophilin family of peptidyl-prolyl cis/trans-isomerases (PPIases), cyclophilin J (CYPJ). MATERIALS AND METHODS: PPIase assays were performed on purified hCYPJ and its mutated variants. The substrate specificity, half-maximal inhibitory concentration (IC50) of cyclosporin A (CsA) inhibition and circular dichroism (CD) spectrum of CYPJ were measured. Mercury pathway profiling luciferase assays were also performed. RESULTS: The catalytic number/Michaelis constant (kcat/KM) value of CYPJ was 9.5×10(4) s(-1)M(-1). CYPJ additionally catalyzed norleucine-proline, isoleucine-proline and glutamine-proline peptides compared to CYPA and Escherichia coli PPIases. CYPJ was inhibited by CsA in a dose-dependent manner with IC50 of 12.1±0.9 µM. The CD spectrum of CYPJ was similar to CYPA. CYPJ significantly up-regulated the transcription of E-box, E2F, retinoblastoma (Rb), p53, activator protein 1 (AP1), NF-κB and phospho-cAMP response element (CRE) cis-response element in 293T cells. CONCLUSION: CYPJ structurally resembles CYPA. It is sensitive to inhibition by CsA and plays a role in regulating cell growth, proliferation, and apoptosis.

Asunto(s)

Ciclofilinas/metabolismo , Catálisis , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Ciclofilinas/antagonistas & inhibidores , Ciclofilinas/genética , Ciclosporina/metabolismo , Ciclosporina/farmacología , Relación Dosis-Respuesta a Droga , Factores de Transcripción E2F/genética , Factores de Transcripción E2F/metabolismo , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica , Células HEK293 , Humanos , Cinética , Mutación , FN-kappa B/genética , FN-kappa B/metabolismo , Unión Proteica , Proteínas Recombinantes/metabolismo , Proteína de Retinoblastoma/genética , Proteína de Retinoblastoma/metabolismo , Especificidad por Sustrato , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/metabolismo , Transcripción Genética , Transfección , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo

RESUMEN

OBJECTIVE: To record the efficacy and toxicity of combining bevacizumab with cisplatin in treating malignant pleural effusion and ascites through intrapleural and intraperitoneal infusion. PATIENTS AND METHODS: Forty-three patients were admitted to the Oncology Department of Yantai Yuhuangding Hospital with confirmed malignant effusion since January, 2011. Twenty of them received intrapleural and intraperitoneal perfusion of 200 mg bevacizumab plus 60 mg cisplatin every three weeks, and 23 patients received 60 mg cisplatin alone after draining effusion as much as possible. Reduction of effusion was determined by type-B ultrasonography. RESULTS: The complete remission rate and effective rate of bevacizumab group was superior to that of the cisplatin group. The quality of life recovery rate of bevacizumab group was superior to that of the cisplatin group. The anhelation and abdominal distention of bevacizumab group was significantly improved. There was no significant difference in level III/IV toxicities and adverse effects between two groups. CONCLUSION: Bevacizumab significantly improved the objective response rate and quality of life of patients with malignant pleural effusion and ascites, while not causing notable adverse events.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ascitis/tratamiento farmacológico , Derrame Pleural Maligno/tratamiento farmacológico , Bevacizumab/administración & dosificación , Cisplatino/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Inducción de Remisión , Resultado del Tratamiento

RESUMEN

Cyclophilin (Cyp) A has been reported to be overexpressed in the majority of cancer cells, including hepatocellular carcinoma (HCC). However, the biological functions of CypA in HCC are far from being understood. To determine the biological functions of CypA in HCC, the present study screened human fetal liver complementary DNA for proteins interacting with CypA using the yeast two-hybrid system. A nuclear protein, serine/arginine-rich (SR)-25, was isolated as a novel CypA-binding protein that is distinct from those previously described in the literature. Binding assays and co-immunoprecipitation confirmed the physical association between CypA and SR-25. The present study demonstrated that CypA may interact with SR-25 through its peptidyl-prolyl isomerase domain. In addition, CypA may induce the expression of SR-25 in Hep3B cells. The messenger RNA levels of CypA and SR-25 in HCC indicated that there was a significant correlation between the expression of CypA and the expression of SR-25 in HCC. It can be speculated that the interaction between CypA and SR-25 proteins may be involved in potential carcinogenic functions of CypA in HCC. Further studies will focus on elucidating in detail the molecular mechanisms of the interaction between CypA and SR-25.

RESUMEN

Cyclophilin J (CYPJ) is a new member of the peptidyl-prolyl cis/trans-isomerase (PPIase) identified with upregulated expression in human glioma. However, the biological function of CYPJ remained unclear. We aimed to study the role of CYPJ in hepatocellular carcinoma (HCC) carcinogenesis and its therapeutic potential. We determined the expression of CYPJ in HCC/adjacent normal tissues using Western blot, Northern blot and semi-quantitative RT-PCR, analyzed the biochemical characteristics of CYPJ, and resolved the 3D-structure of CYPJ/Cyclosporin A (CsA) complex. We also studied the roles of CYPJ in cell cycle, cyclin D1 regulation, in vitro and in vivo tumor growth. We found that CYPJ expression was upregulated in over 60% HCC tissues. The PPIase activity of CYPJ could be inhibited by the widely used immunosuppressive drug CsA. CYPJ was found expressed in the whole cell of HCC with preferential location at the cell nucleus. CYPJ promoted the transition of cells from G1 phase to S phase in a PPIase-dependent manner by activating cyclin D1 promoter. CYPJ overexpression accelerated liver cell growth in vitro (cell growth assay, colony formation) and in vivo (xenograft tumor formation). Inhibition of CYPJ by its inhibitor CsA or CYPJ-specific RNAi diminished the growth of liver cancer cells in vitro and in vivo. In conclusion, CYPJ could facilitate HCC growth by promoting cell cycle transition from G1 to S phase through the upregulation of cyclin D1. Suppression of CYPJ could repress the growth of HCC, which makes CYPJ a potential target for the development of new strategies to treat this malignancy.

Asunto(s)

Carcinoma Hepatocelular , Ciclofilinas , Ciclosporina , Neoplasias Hepáticas , Proteínas de Neoplasias , Animales , Células COS , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Chlorocebus aethiops , Ciclina D1/biosíntesis , Ciclina D1/genética , Ciclofilinas/antagonistas & inhibidores , Ciclofilinas/química , Ciclofilinas/genética , Ciclofilinas/metabolismo , Ciclosporina/química , Ciclosporina/farmacología , Fase G1/efectos de los fármacos , Fase G1/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Estructura Terciaria de Proteína , Fase S/efectos de los fármacos , Fase S/genética , Regulación hacia Arriba/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Gastric signet ring cell carcinoma (GSRCC) is a unique pathological type of gastric carcinoma that is extremely invasive and has a poor prognosis after diagnosis. The expression of microRNAs has been closely linked to the carcinogenesis of gastric cancer and has been considered as a powerful prognostic marker. Distinctive expression of miRNAs in GSRCC was investigated in the present study. Samples of GSRCC were compared to that of intestinal gastric adenocarcinoma using Agilent microarray technique, and two differentially expressed miRNAs were identified, hsa-miR-665 and hsa-miR­95. qRT-PCR verification showed downregulation of both miRNAs in signet ring cell carcinoma and upregulation in gastric adenocarcinoma, which was not consistent with the results obtained by the microarray. Target gene prediction using online databases conferred two strong candidate genes, GLI2 and PLCG1. GO/KO analysis of these two genes showed close correlations with carcinogenesis and chemoresistance. It was concluded that hsa-miR-665 and hsa-miR-95 were downregulated in GSRCC but upregulated in intestinal gastric adenocarcinoma, and the relatively differential expression of the miRNAs negatively controlling their target genes could be closely related to the high invasive metastasis and chemoresistance of GSRCC.

Asunto(s)

Adenocarcinoma/genética , Carcinoma de Células en Anillo de Sello/genética , Factores de Transcripción de Tipo Kruppel/genética , MicroARNs/biosíntesis , Proteínas Nucleares/genética , Fosfolipasa C gamma/genética , Neoplasias Gástricas/genética , Adenocarcinoma/patología , Carcinoma de Células en Anillo de Sello/patología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Gástricas/patología , Proteína Gli2 con Dedos de Zinc

RESUMEN

Sorcin is a soluble resistance-related calcium-binding protein, which is expressed in normal mammalian tissues, such as the liver, lungs and heart. It has been observed to be elevated in a number of cancer types, including colorectal, gastric and breast cancer. Its upregulation is usually associated with the development of chemotherapeutic drug resistance. The aim of this study was to evaluate the sorcin expression levels in human serum samples of breast cancer subjects at various stages, and subsequently compare the outcome of neoadjuvant chemotherapy when the sorcin levels fluctuated. In total, 50 subjects were recruited from patients who were admitted to Yantai Yuhunagding Hospital (Yantai, China) and diagnosed with breast cancer. Blood samples prior to and following chemotherapy were assessed using two-dimensional gel electrophoresis (2-DE) and western blot analysis. The 2-DE analysis of the serum samples revealed that sorcin was upregulated in six out of 29 neoadjuvant chemotherapy (NAC)-sensitive patients and, in those who developed multidrug resistance, sorcin was upregulated in 15 out of 21 patients (P<0.01). The differential expression levels of sorcin were confirmed by western blot and immunohistochemical analysis. In conclusion, sorcin expression in the human serum of breast cancer patients who are resistant to NAC was elevated when compared with that of NAC-sensitive patients.