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1.
J Transl Med ; 20(1): 68, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35115027

RESUMO

BACKGROUND: Interferon regulatory factor 2 (IRF-2) acts as an anti-oncogene in gastric cancer (GC); however, the underlying mechanism remains unknown. METHODS: This study determined the expression of IRF-2 in GC tissues and adjacent non-tumor tissues using immunohistochemistry (IHC) and explored the predictive value of IRF-2 for the prognoses of GC patients. Cell function and xenograft tumor growth experiments in nude mice were performed to test tumor proliferation ability, both in vitro and in vivo. Chromatin immunoprecipitation sequencing (ChIP-Seq) assay was used to verify the direct target of IRF-2. RESULTS: We found that IRF-2 expression was downregulated in GC tissues and was negatively correlated with the prognoses of GC patients. IRF-2 negatively affected GC cell proliferation both in vitro and in vivo. ChIP-Seq assay showed that IRF-2 could directly activate AMER-1 transcription and regulate the Wnt/ß-catenin signaling pathway, which was validated using IHC, in both tissue microarray and xenografted tumor tissues, western blot analysis, and cell function experiments. CONCLUSIONS: Increased expression of IRF-2 can inhibit tumor growth and affect the prognoses of patients by directly regulating AMER-1 transcription in GC and inhibiting the Wnt/ß-catenin signaling pathway.


Assuntos
Neoplasias Gástricas , Proteínas Adaptadoras de Transdução de Sinal , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Fator Regulador 2 de Interferon/genética , Fator Regulador 2 de Interferon/metabolismo , Camundongos , Camundongos Nus , Neoplasias Gástricas/patologia , Proteínas Supressoras de Tumor , Via de Sinalização Wnt , beta Catenina/metabolismo
2.
J Transl Med ; 20(1): 579, 2022 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-36494846

RESUMO

Primary liver cancer (PLC) is a common gastrointestinal malignancy worldwide. While hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are two major pathologic types of PLC, combined HCC and ICC (cHCC-ICC) is a relatively rare subtype that shares both hepatocyte and cholangiocyte differentiation. However, the molecular feature of this unique tumor remains elusive because of its low incidence and lack of a suitable animal model. Herein, we generated a novel spontaneous cHCC-ICC model using a Sleeping Beauty-dependent transposon plasmid co-expressing oncogenic Myc and AKT1 and a CRISPR-Cas9 plasmid expressing single-guide RNA targeting p53 into mouse hepatocytes via in situ electroporation. The histological and transcriptional analysis confirmed that this model exhibits cHCC-ICC features and activates pathways committing cHCC-ICC formation, such as TGF-ß, WNT, and NF-κB. Using this model, we further screened and identified LAMB1, a protein involved in cell adhesion and migration, as a potential therapeutic target for cHCC-ICC. In conclusion, our work presents a novel genetic cHCC-ICC model and provides new insights into cHCC-ICC.


Assuntos
Neoplasias dos Ductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Hepáticas , Camundongos , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Modelos Animais de Doenças , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Ductos Biliares Intra-Hepáticos/patologia , Estudos Retrospectivos
3.
FASEB J ; 35(10): e21871, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34473374

RESUMO

Recent investigations of gut microbiota have contributed to understanding of the critical role of microbial community in pathophysiology. Dysbiosis not only causes disturbance directly to the gastrointestinal tract but also affects the liver through gut-liver axis. Various types of dysbiosis have been documented in alcoholic liver disease (ALD), nonalcoholic fatty liver disease, autoimmune hepatitis (AIH), primary sclerosing cholangitis, and may be crucial for the initiation, progression, or deterioration to end-stage liver disease. A few microbial species have been identified as the causal factors leading to these chronic illnesses that either do not have clear etiologies or lack effective treatment. Notably, cytolysin-producing Enterococcus faecalis, Klebsiella pneumoniae and Enterococcus gallinarum were defined for ALD, NASH, and AIH, respectively. These groundbreaking discoveries drive a rapid development in innovative therapeutics, such as fecal microbial transplantation and implementation of specific bacteriophages in addition to prebiotics, probiotics, or synbiotics for intervention of dysbiosis. Although most emerging interventions are in preclinical development or early clinical trials, a better delineation of specific dysbiosis in these disorders at metabolic, immunogenic, or molecular levels in establishing particular causal effects aids in modulating or correcting the microbial community which is the part of daily life for human being.


Assuntos
Doença Hepática Terminal/tratamento farmacológico , Microbioma Gastrointestinal , Probióticos/uso terapêutico , Animais , Doença Hepática Terminal/microbiologia , Humanos
4.
J Transl Med ; 19(1): 379, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488791

RESUMO

BACKGROUND: Since interferon regulatory factor (IRF) family functions in immune response to viral infection, its role in colorectal cancer (CRC) has not been inspected before. This study tries to investigate members of IRF family using bioinformatics approaches in aspect of differential expressions, biological function, tumor immune infiltration and clinical prognostic value for patients with CRC. METHODS: Transcriptome profiles data, somatic mutations and clinical information of CRC were obtained from COAD/READ dataset of The Cancer Genome Atlas (TCGA) as a training set. Gene expression data (GSE17536 and GSE39582) were downloaded from the Gene Expression Omnibus as a validating set. A random forest algorithm was used to score the risk for every case. Analyzing gene and function enrichment, constructing protein-protein interaction and noncoding RNA network, identifying hub-gene, characterizing tumor immune infiltration, evaluating differences in tumor mutational burden (TMB) and sensitivity to chemotherapeutics or immunotherapy were performed by a series of online tools and R packages. Immunohistochemical (IHC) examinations were carried out validation in tissue samples. RESULTS: Principal-component analysis (PCA) suggested that the transcript expression levels of nine members of IRF family differed between normal colorectum and CRC. The risk score constructed by IRF family not only acted as an independent factor for predicting survival in CRC patients with different biological processes, signaling pathways and TMB, but also indicated different immunotherapy response with diverse immune and stromal cells infiltration. IRF3 and IRF7 were upregulated in CRC and suggested a shorter survival time in patients with CRC. Differentially expressed members of IRF family exhibited varying degrees of immune cell infiltration. IHC analysis showed a positive association between IRF3 and IRF7 expression and tumor-infiltrating immune cells, including CD4+ T cell and CD68+ macrophages. CONCLUSIONS: On account of differential expression, IRF family members can help to predict both response to immunotherapy and clinical prognosis of patients with CRC. Our bioinformatic investigation not only gives a preliminary picture of the genetic features as well as tumor microenvironment, but it may provide a clue for further experimental exploration and verification on IRF family members in CRC.


Assuntos
Neoplasias Colorretais , Fatores Reguladores de Interferon , Biomarcadores Tumorais , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores Reguladores de Interferon/genética , Prognóstico , Microambiente Tumoral
5.
J Transl Med ; 19(1): 347, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389031

RESUMO

BACKGROUND: Tumor-associated macrophages (TAM) are immunosuppressive cells that contribute to impaired anti-cancer immunity. Iron plays a critical role in regulating macrophage function. However, it is still elusive whether it can drive the functional polarization of macrophages in the context of cancer and how tumor cells affect the iron-handing properties of TAM. In this study, using hepatocellular carcinoma (HCC) as a study model, we aimed to explore the effect and mechanism of reduced ferrous iron in TAM. METHODS: TAM from HCC patients and mouse HCC tissues were collected to analyze the level of ferrous iron. Quantitative real-time PCR was used to assess M1 or M2 signature genes of macrophages treated with iron chelators. A co-culture system was established to explore the iron competition between macrophages and HCC cells. Flow cytometry analysis was performed to determine the holo-transferrin uptake of macrophages. HCC samples from The Cancer Genome Atlas (TCGA) were enrolled to evaluate the prognostic value of transferrin receptor (TFRC) and its relevance to tumor-infiltrating M2 macrophages. RESULTS: We revealed that ferrous iron in M2-like TAM is lower than that in M1-like TAM. In vitro analysis showed that loss of iron-induced immunosuppressive M2 polarization of mouse macrophages. Further experiments showed that TFRC, the primary receptor for transferrin-mediated iron uptake, was overexpressed on HCC cells but not TAM. Mechanistically, HCC cells competed with macrophages for iron to upregulate the expression of M2-related genes via induction of HIF-1α, thus contributing to M2-like TAM polarization. We further clarified the oncogenic role of TFRC in HCC patients by TCGA. TFRC is significantly increased in varieties of malignancies, including HCC, and HCC patients with high TFRC levels have considerably shortened overall survival. Also, TFRC is shown to be positively related to tumor-infiltrating M2 macrophages. CONCLUSIONS: Collectively, we identified iron starvation through TFRC-mediated iron competition drives functional immunosuppressive polarization of TAM, providing new insight into the interconnection between iron metabolism and tumor immunity.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Linhagem Celular Tumoral , Humanos , Ferro , Camundongos , Macrófagos Associados a Tumor
6.
J Cell Biochem ; 121(4): 2938-2949, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31692072

RESUMO

BACKGROUND: Calcium-binding tyrosine phosphorylation-regulated protein (CABYR) is a group of isoforms produced by alternative splicing and is overexpressed in human malignancies including hepatocellular carcinoma (HCC). However, the prognostic value and biological functions of its major protein isoforms, named CABYR-a/b (combined CABYR-a and CABYR-b), in HCC remain to be established. METHODS: CABYR-a/b expression was detected in HCC tissues and cell lines by quantitative real-time polymerase chain reaction and Western blot analysis. The correlation of CABYR-a/b expression with clinical characteristics and its prognosis impact were determined by statistical analysis. Finally, the biological functions and molecular mechanism of CABYR-a/b were also investigated using molecular biology approaches. RESULTS: The present research found that CABYR-a/b was markedly elevated in HCC specimens and cell lines. Upregulated CABYR-a/b level had positive association with tumor size and differentiation in patients. Moreover, cases with elevated CABYR-a/b level had poorer overall survival (OS) and disease-free survival (DFS) than those with reduced CABYR-a/b level. Multivariate analysis and prognostic nomograms demonstrated that CABYR-a/b overexpression was an independent predictive indicator for OS and DFS. The calibration curve for the odds of OS and DFS demonstrated that the prediction by nomograms was in excellent accordance with actual situation. CABYR-a/b downregulation suppressed cell proliferation and induced G1-phase arrest via decreasing cyclin D1 and cyclin dependent kinase 4, while promoted apoptosis by reducing B-cell lymphoma 2 (Bcl-2) and increasing Bcl-2-associated death promoter. CONCLUSION: Our research indicates that CABYR-a/b exerts an oncogenic effect on HCC development and may become a new prognostic indicator for patients with HCC.


Assuntos
Apoptose , Proteínas de Ligação ao Cálcio , Cálcio/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Tirosina/química , Idoso , Processamento Alternativo , Biomarcadores Tumorais/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Carcinoma Hepatocelular/diagnóstico , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Fosforilação , Prognóstico , Ligação Proteica , Isoformas de Proteínas , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/metabolismo , Resultado do Tratamento
7.
Ann Surg Oncol ; 27(5): 1546-1557, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32157528

RESUMO

BACKGROUND: The mechanistic target of rapamycin (mTOR) pathway, containing mTOR complex 1 (mTORC1) and mTORC2, is dysregulated in multiple cancers, including hepatocellular carcinoma (HCC). Mammalian lethal with sec-13 protein 8 (mLST8) is a shared constituent of both mTORC1 and mTORC2, yet little is known regarding its role in HCC development. METHODS: mLST8 expression was detected in a total of 186 pairs of HCC and adjacent non-tumor specimens. The correlation between mLST8 level and clinicopathological features or prognostic significance were analyzed. The role of mLST8 on biological functions was also preliminarily studied. RESULTS: The study revealed that the mLST8 level was dramatically higher in HCC specimens than in adjacent non-tumor specimens. mLST8 overexpression positively correlated with tumor size, differentiation, and vessel invasion. Cases with elevated mLST8 level had more unfavorable overall survival (OS) and disease-free survival (DFS) than those with downregulated mLST8 level. Multivariate analysis demonstrated that mLST8 upregulation was an independent predictive marker for OS and DFS. Calibration curves from nomogram models indicated an excellent coherence between nomogram prediction and actual situation. Decision curve analysis proved that mLST8-based nomograms presented much higher predictive accuracy when compared with conventional clinical staging systems. Mechanistically, mLST8 enhanced cell proliferation and invasion through the AKT (protein kinase B) pathway. CONCLUSIONS: Our study demonstrates that mLST8 exerts an oncogenic role in HCC and may become a promising prognostic biomarker and therapeutic target for HCC patients.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Homólogo LST8 da Proteína Associada a mTOR/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Nomogramas , Prognóstico , Regulação para Cima , Adulto Jovem
8.
Dig Dis Sci ; 65(1): 168-177, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31350707

RESUMO

PURPOSE: The interferon regulatory factor 2 (IRF-2) acted as a tumor suppressor. We inspected IRF-2 as a predictor of prognosis in gastric cancer (GC) patients and tried to find out the potential molecular mechanism. METHODS: In this study, the association between IRF-2 expression and clinical or prognosis significance was investigated in 86 pairs of tumor and the adjacent normal gastric tissues from GC patients. After establishing the stable cell lines, the Transwell assays were deduced to evaluate the malignancy of tumor. Then, microarray assay was carried out and the GO/KEGG pathway analyses were conducted to identify IRF-2's target gene. The relationship between IRF-2 and matrix metalloproteinases 1 (MMP-1) was also investigated by the immunohistochemistry in 15 pairs of tumor and adjacent normal gastric tissues. RESULTS: We found that IRF-2 expression level in GC was significantly correlated with the prognosis of the patients. Transwell assays suggested an impaired ability of invasion and migration in IRF-2-overexpressed GC cells and a progressive malignant phenotype in IRF-2-knockdown GC cells. Ninety differentially expressed genes were found between IRF-2-overexpressed GC cells and its normal control sets by microarray. We demonstrated that MMP-1 was canonical in the network of differentially expressed genes by GO and KEGG pathway analysis and its expression level was markedly decreased in IRF-2-overexpressed cells of MKN-45 and increased in IRF-2-knockdown cells of SGC-7901. The expression of MMP-1 was inversely correlated with IRF-2 in GAC TMA specimens. CONCLUSION: IRF-2 may inhibit GC progression by down-regulating MMP-1 level.


Assuntos
Movimento Celular , Fator Regulador 2 de Interferon/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Neoplasias Gástricas/enzimologia , Idoso , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Fator Regulador 2 de Interferon/genética , Masculino , Metaloproteinase 1 da Matriz/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
9.
Lab Invest ; 99(6): 749-763, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30700851

RESUMO

Activation of inflammation is an important mechanism in the development of nonalcoholic steatohepatitis (NASH). This study aims to delineate how mitophagy affects NLRP3 inflammasome activation in hepatic lipotoxicity. Mice were fed a high fat/calorie diet (HFCD) for 24 weeks. Primary rat hepatocytes were treated with palmitic acid (PA) for various periods of time. Mitophagy was measured by protein levels of LC3II and P62. NLRP3, caspase-1, interleukin (IL)-18, and IL-1ß at mRNA and protein levels were used as indicators of inflammasome activation. Along with steatotic progression in HFCD-fed mice, ratio of LC3II/ß-actin was decreased concurrently with increased levels of liver P62, NLRP3, caspase-1, IL-1ß, IL-18, and serum IL-1ß levels in late-stage NASH. PA treatment resulted in mitochondrial oxidative stress and initiated mitophagy in primary hepatocytes. The addition of cyclosporine A did not change LC3II/Τοmm20 ratios; but P62 levels were increased after an extended duration of PA exposure, indicating a defect in autophagic activity. Along with impaired mitophagy, mRNA and protein levels of NLRP3, caspase-1, IL-18 and IL-1ß were upregulated by PA treatment. Pretreatment with MCC950, N-acetyl cysteine or acetyl-L-carnitine reversed inflammasome activation and a pyroptotic cascade. Additionally, mitophagic flux was partially recovered as indicated by increases in LC3II/Tomm20 ratio, parkin, and PINK1 expression, and decreased P62 expression. The findings suggest that impaired mitophagy triggers hepatic NLRP3 inflammasome activation in a murine NASH model and primary hepatocytes. The new insights into inflammasome activation through mitophagy advance our understanding of how fatty acids elicit lipotoxicity through oxidant stress and autophagy in mitochondria.


Assuntos
Inflamassomos/metabolismo , Mitofagia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Progressão da Doença , Hepatócitos/fisiologia , Metabolismo dos Lipídeos , Masculino , Camundongos Endogâmicos C57BL , Necroptose , Hepatopatia Gordurosa não Alcoólica/etiologia , Estresse Oxidativo , Ratos
10.
Cancer Sci ; 109(4): 1185-1194, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29363233

RESUMO

Recently, many new diagnostic biomarkers have been developed for colorectal cancer. We chose 2 methods with high diagnostic efficiency, the detection of serum microRNA and metabolomics based on gas chromatography/mass spectrometry (GC/MS), and aimed to establish appropriate models. We reviewed the diagnostic value of all microRNA identified by previous diagnostic tests. We selected appropriate microRNA to validate their diagnostic efficiency, and determined the optimal combination. We included 85 patients with colorectal cancer (CRC) and 78 healthy controls (HC) and detected the expression of the microRNA. GC/MS analysis was conducted, and we used 3 multivariate statistical methods to establish diagnostic models. The concentrations of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were detected for comparison with the novel models. Ultimately, 62 published studies and 63 microRNA were included in this review. MiR-21, miR-29a, miR-92a, miR-125b and miR-223 were selected to further validate their diagnostic value. The serum levels of the 5 microRNA in CRC patients were significantly higher than those in the HC. The combination of miR-21, miR-29a, miR-92a and miR-125b had the highest area under the curve (AUC) at 0.952, with a sensitivity of 84.7% and a specificity of 98.7%. The GC/MS analysis exhibited an excellent diagnostic value and the AUC reached 1.0. With regard to traditional biomarkers, the AUC of CEA and CA19-9 were 0.808 and 0.705, respectively. The application prospects are good for microRNA and metabolomics as new diagnostic methods because of their high diagnostic value compared with traditional biomarkers.


Assuntos
Neoplasias Colorretais/sangue , Neoplasias Colorretais/diagnóstico , Metaboloma/fisiologia , MicroRNAs/sangue , Adulto , Área Sob a Curva , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Antígeno CA-19-9/metabolismo , Estudos de Casos e Controles , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Sensibilidade e Especificidade
11.
BMC Cancer ; 18(1): 415, 2018 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-29653559

RESUMO

BACKGROUND: Many novel diagnostic biomarkers have been developed for gastric cancer (GC) recently. We chose two methods with high diagnostic value, the detection of serum microRNAs and metabolomics based on gas chromatography/mass spectrometry (GC/MS), and aimed to establish appropriate models. METHODS: We reviewed the diagnostic accuracies of all microRNAs identified by previous diagnostic tests. Then appropriate microRNAs and their combinations were validated the diagnostic value. We included 80 patients with GC and 82 healthy controls (HCs) and detected the expression of the microRNAs. GC/MS analysis was conducted, and we used three multivariate statistical analyses to establish diagnostic models. The concentrations of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were detected for comparison with the novel models. RESULTS: Sixty-seven published studies and 70 microRNAs were finally included in the systematic review. MiR-18a, miR-19a, miR-21, miR-92a, miR-199a and miR-421 were chosen to further validate their diagnostic efficiencies. Five of those microRNAs in GC patients had significantly different expression. The combination of miR-19a and miR-92a had the highest area under the curve (AUC) at 0.850 with a sensitivity of 91.3% and a specificity of 61.0%. The GC/MS analysis performed an excellent diagnostic value and the AUC reached 1.0. CONCLUSION: There is a good potential for microRNAs and GC/MS analysis as new diagnostic methods in view of their high diagnostic value compared with traditional biomarkers.


Assuntos
Biomarcadores Tumorais , MicroRNA Circulante , Metabolômica , MicroRNAs/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Estudos de Casos e Controles , MicroRNA Circulante/sangue , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Expressão Gênica , Humanos , Masculino , Metabolômica/métodos , MicroRNAs/sangue , Gradação de Tumores , Estadiamento de Neoplasias , Viés de Publicação , Sensibilidade e Especificidade , Neoplasias Gástricas/sangue
12.
J Gastroenterol Hepatol ; 33(11): 1844-1852, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29744928

RESUMO

BACKGROUND AND AIM: Irritable bowel syndrome (IBS) is a highly prevalent chronic functional gastrointestinal disorder. Recent studies have showed increasing important role of gut microbiota in the pathophysiological changes of IBS. Our study aims to elaborate the association between intestinal flora with the genesis and the development of IBS. METHODS: Illumina high-throughput sequencing technology was applied to investigate microbial communities of IBS patients and healthy donors. Stool specimens from the IBS-D patients were equally premixed and implanted into germ free C57B/6 mice to construct IBS animal model, and the normal group was also transplanted with normal premixed feces. The post-transplant defecation and intra-epithelial lymphocyte counts were evaluated. Microbial communities were also checked by the illumina high-throughput sequencing technology. RESULTS: Fifteen genuses significantly different were found expressed in the gut flora of IBS patients, and six genuses showed significantly different abundances between the stool specimens of mice of IBS group and normal group. Among these differences, Parasutterella expression was remarkably different in both screening and validation experiments and also related to chronic intestinal inflammation; therefore, Parasutterella expression is considered in association with the development and progression of IBS. CONCLUSION: Parasutterella may be related with the genesis and development of IBS and also associated with chronic intestinal inflammation in IBS patients.


Assuntos
Betaproteobacteria/patogenicidade , Microbioma Gastrointestinal , Síndrome do Intestino Irritável/etiologia , Síndrome do Intestino Irritável/microbiologia , Adolescente , Adulto , Idoso , Animais , Betaproteobacteria/genética , Betaproteobacteria/isolamento & purificação , DNA Bacteriano/isolamento & purificação , Modelos Animais de Doenças , Progressão da Doença , Transplante de Microbiota Fecal , Fezes/microbiologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Adulto Jovem
13.
Tohoku J Exp Med ; 245(2): 89-98, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29899182

RESUMO

Hepatocellular carcinoma (HCC) remains a major health problem for delayed diagnosis, inefficient surveillance and poor prognosis. Recent studies have indicated that non-coding RNAs contribute to the development of new strategies for diagnosis and treatment of HCC. In the present study, we employed 18 pairs of HCC and matched non-tumor tissues for the identification of differentially expressed microRNAs (miRNAs) in HCC, among which 7 paired specimens were selected randomly for microarray detection. Totally, twenty-three miRNAs were screened out to have statistically significant differences with the threshold of P < 0.01 and fold-change ≥ 2.0 or ≤ 0.5 using miRNA microarray. In the validation stage, two miRNAs exhibited higher expression levels in the HCC tissues compared with those in the matched non-tumor tissues, whereas the expression levels of ten miRNAs were lower in the HCC tissues than those in the matched non-tumor tissues. In further analysis, eight miRNAs, including miR-4270, miR-125b-5p, miR-199a-3p, miR-10a-5p, miR-424-5p, miR-195-5p, miR-106b-5p and miR-3651, were retained, when another constraint about the signal intensity of microarray probes was established. Among these miRNAs, our study was the first to show the higher expression level of miR-3651 and the lower expression level of miR-4270 in HCC. The areas under the receiver-operating-characteristic curve values of miR-3651 and miR-4270 were 0.730 and 0.967, respectively, indicating their potential diagnostic values. Our results may help provide the context for expanded interpretations of miRNA studies involved in the progression of liver disease, potentially serving as a diagnostic tool of HCC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , MicroRNAs/genética , Adulto , Idoso , Área Sob a Curva , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
14.
Int J Mol Sci ; 18(4)2017 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-28387715

RESUMO

Pre-mRNA processing factor 19 (Prp19) is involved in many cellular events including pre-mRNA processing and DNA damage response. Recently, it has been identified as a candidate oncogene in hepatocellular carcinoma (HCC). However, the role of Prp19 in tumor biology is still elusive. Here, we reported that Prp19 arrested cell cycle in HCC cells via regulating G2/M transition. Mechanistic insights revealed that silencing Prp19 inhibited the expression of cell division cycle 5-like (Cdc5L) via repressing the translation of Cdc5L mRNA and facilitating lysosome-mediated degradation of Cdc5L in HCC cells. Furthermore, we found that silencing Prp19 induced cell cycle arrest could be partially resumed by overexpressing Cdc5L. This work implied that Prp19 participated in mitotic progression and thus could be a promising therapeutic target of HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proteínas de Ciclo Celular/genética , Enzimas Reparadoras do DNA/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Processamento de RNA/metabolismo , Proteínas de Ligação a RNA/genética , Carcinoma Hepatocelular/genética , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Enzimas Reparadoras do DNA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Lisossomos/genética , Proteínas Nucleares/genética , Fatores de Processamento de RNA/genética , Proteínas de Ligação a RNA/metabolismo
15.
J Biomed Sci ; 23(1): 71, 2016 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-27733149

RESUMO

BACKGROUND: The mechanism of Nova1's role in hepatocellular carcinoma has not been delineated. Also its interaction with GABAA receptor γ2 in HCC is unveiled. This study is aimed to make it clear the distribution, prognostic value of GABAARγ2 in human hepatocellular carcinoma. And its role in HCC tumorigenesis under the regulation of its alternative splicing factor Nova1. METHODS: Immunohistochemistry staining was used to investigate the distribution and clinical significance of GABAARγ2 protein expression in hepatocellular carcinoma. In vivo tumorigenticity test was conducted in nude mice by regulation the expression of Nova1. Later, western blot and co-immunoprecipitation were carried out to verify the interaction between Nova1 and GABAARγ2 in HCC tissue. RESULTS: Immunohistochemical staining showed GABAARγ2 expression in HCC. Survival analysis showed intratumoral GABAARγ2 was an independent prognostic factor for overall survival (OS) and disease free survival (DFS). Up-regulation of Nova1 expression promotes subcutaneous HCC growth in nude mice and western blot showed the ectopic expression of Nova-1 restro-regulates the expression of GABAARγ2 and GABA. Protein level interaction of GABAARγ2 and Nova-1 was evidenced by co-immunoprecipitation. CONCLUSIONS: Nova1 interacts with GABAARγ2 not only in CNS but also in HCC. Nova1's potential mechanism as an oncogene may due to its interaction with GABAA Rγ2. A better understanding of the mechanism of Nova1 for HCC progression provides a novel target for an optimal immunotherapy against this fatal malignancy.


Assuntos
Carcinogênese , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Oncogenes , Proteínas de Ligação a RNA/genética , Receptores de GABA-A/genética , Animais , Carcinoma Hepatocelular/diagnóstico , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/diagnóstico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Antígeno Neuro-Oncológico Ventral , Especificidade de Órgãos , Prognóstico , Proteínas de Ligação a RNA/metabolismo , Receptores de GABA-A/metabolismo
16.
J Gastroenterol Hepatol ; 31(1): 155-63, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26173586

RESUMO

BACKGROUND AND AIM: MicroRNA-18a (miR-18a) has been reported to be upregulated in gastric cancer (GC) tissues compared with normal gastric tissues. However, little is known about its prognostic value and biological roles. METHODS: In this study, miR-18a expression in gastric adenocarcinoma (GAC) tissues and adjacent non-tumor tissues was validated by in situ hybridization, and the predictive values of miR-18a were explored. The biological roles of miR-18a and the underlying signal pathway were investigated in GC cell lines. RESULTS: Overexpressed intra-tumoral miR-18a was associated with poor survival rate and was an independent prognostic factor for overall survival rate (P < 0.001) in GC patients. Forced expression of miR-18a remarkably enhanced cell proliferation, migration, and invasion in GC cells, while inhibition of miR-18a caused the opposite effects. Further study showed that miR-18a suppressed the expression of interferon regulatory factor 2 (IRF2) by directly binding to its 3'-untranslated region. Moreover, miR-18a expression levels are inversely correlated with IRF2 in human GC tissues. Western blot showed that forced expression of miR-18a could not only downregulate the expression of IRF2, but also inhibit the expression of P53, suggesting that IRF2 might play as a tumor suppressor by regulating P53 signaling in GC. CONCLUSION: miR-18a modulated P53 expression by directly targeting IRF2 and had a high predictive value for prognosis of GAC patients. These results may lead to identification of therapeutic candidates of GC.


Assuntos
Adenocarcinoma/genética , Regulação Neoplásica da Expressão Gênica/genética , Expressão Gênica/genética , Fator Regulador 2 de Interferon/genética , MicroRNAs/fisiologia , Neoplasias Gástricas/genética , Proteína Supressora de Tumor p53/genética , Regiões 3' não Traduzidas , Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Idoso , Linhagem Celular , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Humanos , Fator Regulador 2 de Interferon/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Invasividade Neoplásica/genética , Valor Preditivo dos Testes , Prognóstico , Ligação Proteica , Transdução de Sinais/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Regulação para Cima
17.
Int J Cancer ; 136(2): 249-57, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24420637

RESUMO

Increasing evidence indicates that deregulation of RING-finger ubiquitin-protein ligases (E3s) involves in the development of hepatocellular carcinoma (HCC). These RING-finger E3s serve as oncoproteins or tumor suppressors in HCC under specific conditions. In this review, we summarize current knowledge about abnormal RING-finger E3s and their clinical significance in the development of HCC, and discuss parts of critical substrates for these RING-finger E3s in detail. Furthermore, in light of success of Bortezomib in treating hematological malignancies, we describe the preclinical and clinical studies of therapeutic approaches targeting aberrant RING-finger E3s in HCC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Carcinoma Hepatocelular/enzimologia , Humanos , Neoplasias Hepáticas/enzimologia , Terapia de Alvo Molecular , Domínios RING Finger , Ubiquitina-Proteína Ligases/metabolismo
19.
Tumour Biol ; 35(11): 11427-33, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25123264

RESUMO

Ubiquitin carboxyl-terminal hydrolase 37 (UCH37) is a member of deubiquitinating enzymes. It can suppress protein degradation through disassembling polyubiquitin from the distal subunit of the chain. The aim of this study was to assess the value of UCH37 in predicting tumor recurrence after curative resection in epithelial ovarian cancer (EOC) patients. In this study, the expression level of UCH37 in 5 paired EOC and normal tissue was tested by Western blot. And the association of UCH37 expression and prognostic value was analyzed in 100 tumor specimens from EOC patients, who underwent curative resection between 2003 and 2011. We found that UCH37 was up-regulated in most of the tumor tissue and high expression of UCH37 was an independent significant predictor associated with the poor outcome and recurrence of EOC (p=0.0037 and p=0.0042 in overall and disease-free survival, respectively), especially in the advanced stage of EOC (p=0.0106 and p=0.0115 in overall and disease-free survival, respectively), and may become a novel predictor for prognosis of EOC patients after curative resection. Our data suggest for the first time that UCH37 overexpression is associated with advanced tumor progression and poor clinical outcome of EOC patients and may help physicians make informed decisions regarding adjuvant treatment following curative resection.


Assuntos
Biomarcadores Tumorais/metabolismo , Recidiva Local de Neoplasia/metabolismo , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo , Ovário/metabolismo , Ubiquitina Tiolesterase/metabolismo , Carcinoma Epitelial do Ovário , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Taxa de Sobrevida
20.
Tumour Biol ; 35(5): 4891-6, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24453032

RESUMO

Baculoviral IAP repeat containing 6 (BIRC6), an unusually large member of the IAP family, may play an important role in oncogenesis. The aim of this study was to assess the value of BIRC6 in predicting tumor recurrence after curative resection in epithelial ovarian cancer (EOC) patients. In this study, the differences of BIRC6 expression in four paired EOC and normal tissue were performed by Western blot, and expression of BIRC6 protein was analyzed in 100 clinicopathologically characterized EOC cases from those who underwent curative resection between 2003 and 2011 by immunohistochemistry. Kaplan-Meier survival estimates and log-rank tests were used to assess the prognostic significance. It was found that BIRC6 expression was higher in the carcinoma tissue than in normal control tissue at protein level by Western blot. There was a significant difference of BIRC6 expression in patients categorized according to tumor differentiation (p = 0.016). Univariate analyses and multivariate analyses revealed that BIRC6 was an independent significant predictor for overall survival and disease-free survival. A prognostic significance of BIRC6 was also found by Kaplan-Meier method. The expression of BIRC6 in the cytoplasm is associated with EOC differentiation and may be a novel predictor for poor prognosis of EOC patients after curative resection.


Assuntos
Proteínas Inibidoras de Apoptose/fisiologia , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/mortalidade , Adulto , Idoso , Carcinoma Epitelial do Ovário , Feminino , Humanos , Proteínas Inibidoras de Apoptose/análise , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/química , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/química , Neoplasias Ovarianas/patologia , Prognóstico
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