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1.
Neoplasma ; 68(6): 1272-1282, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34459208

RESUMO

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females, whose survival ratio and indicating biomarkers are limited. The rapid development of multiple immunofluorescences gives rise to widespread applications of this new advanced technology called multiplex immunohistochemistry (mIHC), which makes it possible to detect several fluorescent proteins on the same tumor tissue microarray (TMA) within the same time and spatial organization. By taking advantage of this mIHC technology, we detected three tumor-associated antigens (TAA) including the human epidermal growth factor receptor 2 (HER2), the cluster of differentiation 133 (CD133), the programmed death ligand-1 (PD-L1), and one immune-associated macrophage marker, the cluster of differentiation 68 (CD68) in cancer tissues versus para-carcinomatous normal tissues derived from a cohort of 84 CRC patients. All four markers were upregulated in cancer tissue compared with normal tissues. And the expressions of CD133, HER2, PD-L1, and CD68 were correlated with pathological grade, T stage, tumor size, metastasis, respectively. Accordingly, CD133 and PD-L1 could be applied as potential diagnostic biomarkers for CRC at an early stage, while the enrichment of HER2 might act as an advanced indicator in aggressive cancer status of CRC; whereas, CD68 could be potentially considered as an advanced diagnostic indicator in CRC patients, as well as a metastatic promoter in CRC-related TME. The differential expression of these four proteins, as well as their clinicopathological correlation, indicates that these four proteins could be utilized as specific diagnostic and prognostic biomarkers in CRC patients.


Assuntos
Neoplasias Colorretais , Antígenos de Neoplasias , Biomarcadores Tumorais , Neoplasias Colorretais/diagnóstico , Feminino , Humanos , Imuno-Histoquímica , Masculino , Prognóstico
2.
Cell Mol Biol Lett ; 23: 35, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30123297

RESUMO

BACKGROUND: We investigated the activity of loureirin B against liver fibrosis and the underlying molecular mechanisms. METHODS: Hepatic stellate cells (HSCs) from Sprague-Dawley rats were treated with different concentrations of loureirin B. We used the MTT assay to determine HSC proliferation, flow cytometry to analyze apoptosis, and western blot to determine the expressions of Bax, Bcl-2, Wnt1 and ß-catenin. Real-time PCR was used to determine the expressions of Wnt1 and miR-148-3p. RESULTS: The MTT assay showed that loureirin B treatment significantly inhibited the proliferation of HSCs in time- and dose-dependent manners. Loureirin B significantly promoted the apoptosis of HSCs, increased the expression of Bax and decreased the Bcl-2 level. Western blot analysis showed that the expressions of Wnt1 and ß-catenin were obviously lower in the loureirin B treatment group than in the control group. We also found that loureirin B could decrease the Wnt1 mRNA level and increase miR-148-3p expression. Knockdown of miR-148-3p using inhibitor could reverse the effects of loureirin B on the proliferation and apoptosis of HSCs and the expressions of Bax, Bcl-2, Wnt1 and ß-catenin. CONCLUSION: Our results suggest that loureirin B inhibited the proliferation and promoted the apoptosis of HSCs, and suppressed the Wnt/ß-catenin signaling pathway via regulation of miR-148-3p.


Assuntos
Proliferação de Células/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , MicroRNAs/genética , Resinas Vegetais/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/metabolismo , Masculino , Ratos Sprague-Dawley
3.
Exp Ther Med ; 14(5): 4887-4895, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29201193

RESUMO

Minimal hepatic encephalopathy (MHE) is caused by dysbiosis of gut microbiota, particularly the ammonia-producing bacteria. Given the efficacy of certain treatments on MHE and the connection between alcoholism and MHE, a thorough understanding of how these strategies affect the gut microbiota in patients (alcoholic or non-alcoholic) will facilitate the assessment of their efficacy in the reshaping of gut microbiota. In the present study, a metagenomics approach was adopted to reveal alterations in gut microbiota of 14 MHE patients following treatment with rifaximin alone or rifaximin plus probiotics. Patients were grouped into the alcoholic and non-alcoholic groups to examine differences in terms of their response to treatment. Treatment reduced the overall microbiota diversity and decreased the abundance of certain ammonia-producing bacteria, such as Clostridium, with the treatment of rifaximin plus probiotics presenting a more apparent effect. Non-alcoholic MHE patients responded better to the treatment, as they presented greater reduction in microbiota diversity and a more consistent decline in certain ammonia-producing bacteria genera (such as Clostridium and Streptococcus) belonging to the Firmicutes phylum. In conclusion, treatment with rifaximin alone and rifaximin plus probiotics exhibited a different effect in different MHE patients, decreasing the overall gut microbiota diversity to various extents and reshaping microbiota in different ways. Furthermore, non-alcoholic MHE patients responded better to treatment in microbiota alterations.

4.
Cell Death Dis ; 8(12): 3205, 2017 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-29235470

RESUMO

Recent reports show that B7-H4 is highly expressed in a variety of tumor cells, functions as a negative regulator of T cells and then promotes tumor progression. However, its expression and role in intrahepatic cholangiocarcinoma (ICC) remain unclear. In present study, B7-H4 expression in ICC and peritumoral tissues was determined at the level of mRNA and protein, and its bioactivity in ICC cells was studied after modification of B7-H4 expression. Then, the mechanism related to tumor progression induced by B7-H4 expression in ICC cells was explored. Finally, clinical significance of B7-H4 expression in ICC patients was further analyzed. The results showed that B7-H4 expression in ICC was much higher than that in peritumoral tissues at the level of both mRNA and protein. The high level of B7-H4 in ICC cells induced epithelial-to-mesenchymal transitions and promoted invasion and metastasis of tumor cells through activation of ERK1/2 signaling. The elevated B7-H4 expression was associated with the downregulated Bax, upregulated Bcl-2 expression, and activation of caspase-3. Clinically, high B7-H4 expression in tumor samples was significantly related to malignant phenotype, such as lymph node metastasis, high tumor stage, and poor differentiation. ICC patients with high expression of B7-H4 had shorter overall survival (OS) and disease-free survival. Moreover, the B7-H4 expression was an independent prognostic factor for predicting OS and tumor recurrence of ICC patients after operation. In conclusion, high expression of B7-H4 promotes tumor progression of ICC and may be a novel therapeutic target for ICC patients.


Assuntos
Biomarcadores Tumorais/genética , Colangiocarcinoma/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-bcl-2/genética , Inibidor 1 da Ativação de Células T com Domínio V-Set/genética , Proteína X Associada a bcl-2/genética , Adulto , Idoso , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Análise de Sobrevida , Inibidor 1 da Ativação de Células T com Domínio V-Set/metabolismo , Proteína X Associada a bcl-2/metabolismo
5.
J Clin Pathol ; 70(8): 677-683, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28096273

RESUMO

AIMS: The prognosis of patients with intrahepatic cholangiocarcinoma (ICC) remains poor in terms of overall survival (OS) and recurrence rate. Mortalin, a stress chaperone, has been reported to be involved in carcinogenesis and metastasis. However, its role in ICC has not been defined. METHODS: Mortalin expression in tumour samples from patients with ICC was examined by Western blot and immunohistochemistry, and correlation between its expression and clinicopathological features was assessed. In addition, invasion, migration proliferation and apoptosis, and the expression of epithelial-mesenchymal transition (EMT)-related markers in ICC cells were assessed after mortalin depletion. Finally, the prognostic significance of mortalin in patients with ICC was further evaluated by Kaplan-Meier and Cox regression analysis. RESULTS: We provide evidence that expression of mortalin in human ICC tissues is higher than that in matched peritumoural tissues. The interference of mortalin expression inhibited the proliferation and invasion of ICC cells in vitro. Mechanistically, inhibition of mortalin expression in ICC cells upregulated E-cadherin expression and decreased vimentin and snail expression. Clinically, a high level of mortalin in ICC samples was associated with loss of E-cadherin, and increased expression of vimentin and snail. Patients with ICC and high mortalin expression had a shorter OS and a higher recurrence rate. Multivariate analysis revealed that mortalin overexpression was an independent prognostic indicator for patients with ICC. CONCLUSIONS: Mortalin may promote cell proliferation and invasion via induction of EMT of ICC cells. A high level of mortalin may be used as a prognostic biomarker and therapeutic target for patients with ICC.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Transição Epitelial-Mesenquimal/fisiologia , Proteínas de Choque Térmico HSP70/fisiologia , Apoptose/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Transformação Celular Neoplásica/patologia , Regulação para Baixo/fisiologia , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Recidiva Local de Neoplasia/patologia , Prognóstico , RNA Interferente Pequeno/farmacologia , Regulação para Cima/fisiologia
6.
Oncotarget ; 7(22): 32946-55, 2016 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-27121050

RESUMO

The ubiquitin-dependent proteasomal degradation of proteins controls signaling and cellular survival. In this study, we found that ubiquitin associated protein 2 (UBAP2) was significantly downregulated in hepatocellular carcinoma (HCC) tissues compared with adjacent normal tissues. Furthermore, higher expression of UBAP2 in cancer tissues was correlated with good prognosis in HCC patients. Knockdown of UBAP2 significantly enhanced the invasion and proliferation of HCC cells in vitro and promoted tumor growth in vivo, while enforced expression of UBAP2 impaired the aggressive ability and tumor growth of HCC cells. Mechanistically, UBAP2 formed a complex with Annexin A2 and promoted the degradation of Annexin A2 protein by ubiquitination, and then inhibited HCC progression. Collectively, UBAP2 appears as a novel marker for predicting prognosis and a therapeutic target for HCC.


Assuntos
Anexina A2/metabolismo , Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte/metabolismo , Neoplasias Hepáticas/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Ubiquitinação
7.
Biochem Pharmacol ; 80(1): 136-43, 2010 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-20303335

RESUMO

Activated hepatic stellate cells (HSCs) play a crucial role in the development of liver fibrosis. Noninvasive monitoring of the activation of HSCs has been challenging due to the lack of specific receptors or motifs on the cells. The present study provides the evidence that integrin alpha v beta 3 expressed on HSCs is a biomarker reflecting the activation of HSCs. Solid-phase synthesis of cRGDyK (Arg-Gly-Asp-(D)Tyr-Lys) peptide and FAM-conjugated peptide were employed for binding to integrin alpha v beta 3. The increased expression of integrin alpha v and beta 3 at mRNA and protein levels was detected during HSC activation. The affinity of cRGDyK to integrin alpha v beta 3 was examined by both radioligand binding assay and FAM-conjugated peptide binding measurements. Quantitative RT-PCR and Western blotting showed a less dramatic, but significant increase in alpha v and beta 3 integrin mRNA and protein expression following activation of rat HSCs. Radioiodinated cRGDyK binds to both purified and membrane-bound integrin alpha v beta 3 with high affinity in a dissociable manner. FAM-conjugated cRGDyK was coupled to activated HSCs in a time- and dose-dependent, receptor-mediated manner. Activated HSCs express sufficient number of integrin alpha v beta 3 receptor. cRGDyK peptide binds to both purified and membrane-bound integrin alpha v beta 3 with high affinity in a reversible fashion. Thus, the cRGDyK peptide represented a new agent potentially useful for the diagnosis of liver fibrosis.


Assuntos
Células Estreladas do Fígado/metabolismo , Oligopeptídeos/metabolismo , Sequência de Aminoácidos , Animais , Western Blotting , Células Cultivadas , Fluoresceína-5-Isotiocianato/metabolismo , Fluoresceínas/metabolismo , Técnica Indireta de Fluorescência para Anticorpo , Corantes Fluorescentes/metabolismo , Indóis/metabolismo , Integrina alfaVbeta3/metabolismo , Radioisótopos do Iodo , Cirrose Hepática/metabolismo , Masculino , Peptídeos/metabolismo , Ligação Proteica , RNA Mensageiro/metabolismo , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
Zhonghua Zhong Liu Za Zhi ; 31(3): 164-9, 2009 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-19615251

RESUMO

OBJECTIVE: Hepatic stellate cells (HSC) in hepatocellular carcinoma (HCC) transdifferentiate into extracellular matrix-producing myofibroblasts. Activated HSC can promote invasion and metastasis of HCC. To understand the differences of HSC in normal liver and HCC, we compared the gene expression patterns in HCC cell induction-activated and culture-activated rat HSC. METHODS: HSC were isolated by density centrifugation and exposed to conditioned medium from rat HCC cell line C5F. Expression of 22 012 genes in quiescent HSC, culture-activated HSC and HCC induction-activated HSC was analyzed by cDNA microarray and confirmed by real-time RT-PCR and Western blot. RESULTS: 1672 genes were differentially expressed in culture-activated HSC, including proinflammatory factors, cell adhesion molecules, cell surface receptors, signaling transduction molecules and immune factors. 711 genes were differentially expressed in HCC induction-activated HSC. Some of them were identical to those in culture-activated HSC. HCC Induction-activated HSC showed specific gene expression patterns, including Raf1, Rac2, Adam17, Wnt6, MMP-9 and TNF, suggesting that HCC cells can specifically induce HSC activation. CONCLUSION: The gene expression patterns in HCC induction-activated HSC are different from those in culture-activated HSC. HCC induction-activated HSC may play a major role in the invasion and metastasis of HCC. In vivo activation should be considered as the standard for the study of HSC biology. HCC induction-activated HSC should be considered as the standard for HSC biology studies.


Assuntos
Carcinoma Hepatocelular/metabolismo , Perfilação da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Células Cultivadas , Regulação Neoplásica da Expressão Gênica , Células Estreladas do Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Ratos , Ratos Endogâmicos F344
9.
Hepatology ; 49(2): 491-503, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19065669

RESUMO

UNLABELLED: It has been reported that tetraspanin CD151 acts as a promoter of metastasis in several tumors and plays an important role in c-Met/hepatocyte growth factor signaling. However, the role of CD151 alone and coexpression of CD151/c-Met in hepatocellular carcinoma (HCC) remains unclear. We found that expression of CD151 was positively related to metastatic potential of HCC cell lines, and modified cells with CD151(high) showed higher secretion of matrix metalloproteinase 9 and aggressiveness in vitro and higher metastatic ability in vivo. Furthermore, HCC patients with vascular invasion, large tumors, multiple tumors, high tumor-node-metastasis stage, and undifferentiated tumor were prone to have higher CD151 expression. The postoperative 3-, 5-, and 7-year overall survival (OS) of patients in HCCs with CD151(high) were significantly lower than those in the CD151(low) group, and correspondingly cumulative recurrence rates in HCCs with CD151(high) were significantly higher than those in the CD151(low) group. Both CD151 and c-Met were remarkably overexpressed in HCCs, compared with adjacent nontumorous and normal liver tissues. Pearson correlation analysis showed a slight correlation between CD151 and c-Met in HCCs. Importantly, the 5- and 7-year OS rates in CD151(high)/c-Met(high) patients were 50.5% and 37.8%, respectively, significantly lower than those of CD151(low)/c-Met(low) patients (63.9% and 54.6%, respectively). Five- and 7-year cumulative recurrence rates in CD151(high)/c-Met(high) patients were 53.3% and 71.9%, respectively, markedly higher than those of CD151(low)/c-Met(low) patients (39.0% and 52.5%, respectively). Multivariate analysis revealed that CD151 and combination of CD151/c-Met were independent prognostic indicators for OS and cumulative recurrence. CONCLUSION: CD151 is positively associated with invasiveness of HCC, and CD151 or combination of CD151/c-Met is a novel marker in predicting the prognosis of HCC and a potential therapeutic target.


Assuntos
Antígenos CD/genética , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Proteínas Proto-Oncogênicas c-met/genética , Adulto , Idoso , Antígenos CD/metabolismo , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Linhagem Celular Tumoral , Clonagem Molecular , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica/genética , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas c-met/metabolismo , RNA Mensageiro/genética , Tetraspanina 24 , Transfecção
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