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1.
Dis Markers ; 2019: 7512805, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583030

RESUMO

Background: The ratio of early mitral inflow velocity to the global diastolic strain rate (E/E'sr) and global longitudinal systolic strain (GLS) of the left ventricle (LV) are emerging indices of diastolic and systolic functions, respectively, for the LV. Their prognostic significance in the prediction of mortality and cardiovascular (CV) outcomes remains underexplored in hemodialysis (HD) patients. Methods: This prospective study included 190 maintenance HD patients. The E/E'sr ratio and GLS were assessed using two-dimensional speckle tracking echocardiography. The clinical outcomes included overall mortality, CV mortality, and major adverse cardiovascular events (MACE). The associations between the E/E'sr ratio, GLS, and clinical outcomes were evaluated using multivariate Cox regression analysis. The incremental values of the E/E'sr ratio and GLS in outcome prediction were assessed by χ 2 changes in Cox models. Results: Over a median follow-up period of 3.7 years, there were 35 overall deaths, 16 CV deaths, and 45 MACE. Impaired diastolic function with a higher E/E'sr ratio was associated with overall mortality (HR, 1.484; 95% CI, 1.201-1.834; p < 0.001), CV mortality (HR, 1.584; 95% CI, 1.058-2.371; p = 0.025), and MACE (HR, 1.205; 95% CI, 1.040-1.397; p = 0.013) in multivariate adjusted Cox analysis. Worsening GLS was associated with overall mortality (HR, 1.276; 95% CI, 1.101-1.480; p = 0.001), CV mortality (HR, 1.513; 95% CI, 1.088-2.104; p = 0.014), and MACE (HR, 1.214; 95% CI, 1.103-1.337; p < 0.001). The E/E'sr ratio and GLS had better outcome prediction than the E to early diastolic mitral annular velocity (E/E') ratio and left ventricular ejection fraction (LVEF). Moreover, adding the E/E'sr ratio and GLS to Cox models containing relevant clinical and conventional echocardiographic parameters improved the prediction of overall mortality (p < 0.001), CV mortality (p < 0.001), and MACE (p < 0.001). Conclusion: The E/E'sr ratio and GLS, as emerging indices of LV diastolic and systolic functions, significantly predict mortality and CV outcomes and outperform conventional echocardiographic parameters in outcome prediction in HD patients.

2.
Oncogene ; 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31558801

RESUMO

Metastatic tumors have been shown to establish a supportive pre-metastatic niche (PMN) in distant organs, which in turn determines disseminated tumor cells' targeting of such organs. PMN is formed through the recruitment of bone-marrow-derived cells (BMDCs); however, the role of BMDCs in PMN formation is not fully understood. On the basis of RNA-seq data and bioinformatic analysis, secretion of extracellular vesicle (EV) miR-92a by BMDCs of lung cancer-bearing mice contributes to the establishment of liver PMN. Both BMDC-derived EVs and miR-92a mimics potentiate the activation of hepatic stellate cells (HSCs), subsequently increasing extracellular matrix (ECM) deposition in mice. Consequently, remodeling of the liver microenvironment enhanced immunosuppressive cell accumulation and cancer cell attachment. EVs miR-92a directly suppressed its target SMAD7, leading to the enhancement of transforming growth factor-ß signaling in HSC. Elevated levels of circulating miR-92a are found in the sera of lung cancer patients, and EVs isolated from these patients have a similar ability to increase HSCs activation and ECM protein expression. Our study reveals the sequential steps of liver PMN formation in lung cancer, providing critical mediators that prepare PMN in the liver, and identifies new targets that offer valuable options for diagnosis and therapeutic intervention.

3.
Kaohsiung J Med Sci ; 35(9): 559-565, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31339657

RESUMO

CSN6 is a subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN). CSN is involved in cellular and developmental processes such as signal transduction, transcriptional activation, cell cycle control, and tumorigenesis. CSN6 is highly expressed in several human cancers, including colorectal cancer, and breast cancer. However, no previous research has elaborated on the relationship between CSN6 expression and survival in patients with upper tract urothelial carcinoma (UTUC). Therefore, the purpose of this study is to evaluate the clinical significance of CSN6 in UTUC. CSN6 expression in 89 patients with UTUC enrolled in this study was examined using immunohistochemistry. The associations between CSN6 expression and clinicopathological variables were analyzed. CSN6 expression was significantly correlated with patients with high pathological stage (P = .006), male gender (P = .025), and high serum creatinine levels (P = .014). In univariate and multivariable analysis, high CSN6 expression was associated with a higher bladder recurrence (P = .005) and poor cancer-specific survival (P = .001) for UTUC. In conclusion, CSN6 expression is a potential biomarker for predicting cancer recurrence and clinical survival in UTUC. Further research is necessary to investigate its role in the progression of UTUC.

4.
Int J Med Sci ; 16(3): 366-375, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911270

RESUMO

Long-chain fatty acids are the most abundant fatty acids and are essential for various physiological processes. Translocation of long-chain fatty acids across cell membrane is dependent on transport proteins. Solute carrier family 27 member 6 (SLC27A6) is a transport protein which mediates long-chain fatty acid uptake. The bioinformatic analysis revealed that the expression of SLC27A6 in non-tumoral breast tissue was higher than that in tumoral breast cancer in clinic samples. When SLC27A6 expression in non-tumorigenic cell H184B5F5/M10 was repressed, the fatty acids uptake capacity and cell proliferation was inhibited, and cell cycle was delayed. The protein expression of cell cycle regulators including cell division protein kinase 4 (CDK4), CDK6, and cyclin D1 was significantly decreased in SLC27A6-silenced H184B5F5/M10. By contrast, relatively low SLC27A6 expression in tumorigenic breast cancer cell Hs578T when compared to H184B5F5/M10. Repressing SLC27A6 expression did not affect these phenotypes in Hs578T. The interaction network of SLC27A6 was further investigated via STRING database. The function of these SLC27A6-associated proteins mainly involved in lipid biosynthesis, fatty acid metabolic process, and fatty acid transport. In conclusion, this study reveals inverse correlation between SLC27A6 expression and tumoral tissues and provides a new insight into SLC27A6-mediated cell growth and cell cycle regulation in non-tumorigenic breast cells.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Transporte de Ácido Graxo/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas de Transporte de Ácido Graxo/genética , Ácidos Graxos/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Glândulas Mamárias Humanas/citologia , Mapas de Interação de Proteínas
5.
Breast Cancer Res ; 21(1): 23, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755260

RESUMO

BACKGROUND: Metastasis is the major cause of death from breast cancer. Colonization and adaption of metastatic cells in distant organs is a rate-limiting step of the cancer spreading. The underlying mechanisms responsible for the colonization of breast cancer to lung metastatic niches are not fully understood. METHODS: Specific gene contributions to lung metastasis were identified by comparing gene profiles of 4T1 tumors metastasizing to various organs via microarray. The oncogenic properties CXCL17 were examined by in vivo spontaneous metastasis mouse model. The chemotactic activity of CXCL17 on CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) was examined by both in vitro and in vivo models. The therapeutic effects of MDSC depletion and platelet-derived growth factor-BB (PDGF-BB) inhibition were examined by orthotic models. RESULTS: Here, we demonstrate that breast cancer cells secrete CXCL17, which increases the accumulation of CD11b+Gr-1+ MDSCs in the lungs. Metastatic lung-infiltrating CD11b+Gr-1+ MDSCs induce angiogenesis in the lungs and facilitate cancer extravasation and survival that ultimately promote lung metastases. CXCL17 increases CD11b+Gr-1+ MDSCs to express PDGF-BB, which not only contributes to CD11b+Gr-1+ MDSC-mediated angiogenesis in the lung metastatic niche, but is also involved in the colonization of breast cancer. Consequently, both CD11b+Gr-1+ MDSC depletion and PDGF receptor inhibitor effectively prevents CXCL17-driven lung metastasis in breast cancer. More importantly, patients with high levels of CXCL17 have shorter distant metastasis-free and overall survival rates, indicators of poor prognosis. CONCLUSION: Our study reveals that MDSCs derived by CXCL17 contribute to the establishment of a lung metastatic niche by PDGF-BB secretion and provide a rationale for development of CXCL17 or PDGF-BB antagonists to inhibit or prevent lung metastasis in cases of breast cancer.


Assuntos
Becaplermina/metabolismo , Neoplasias da Mama/patologia , Quimiocinas/metabolismo , Neoplasias Pulmonares/patologia , Células Supressoras Mieloides/patologia , Animais , Neoplasias da Mama/sangue , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Antígeno CD11b/metabolismo , Linhagem Celular Tumoral , Quimiocinas/sangue , Quimiocinas CXC/metabolismo , Quimiotaxia , Conjuntos de Dados como Assunto , Feminino , Humanos , Estimativa de Kaplan-Meier , Pulmão/patologia , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Células Supressoras Mieloides/imunologia , Prognóstico , Receptores de Quimiocinas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Int J Mol Sci ; 20(3)2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30696075

RESUMO

Asthma and chronic obstructive pulmonary disease (COPD) are chronic airway inflammatory diseases that share some common features, although these diseases are somewhat different in etiologies, clinical features, and treatment policies. The aim of this study is to investigate the common microRNA-mediated changes in bronchial epithelial cells of asthma and COPD. The microRNA profiles in primary bronchial epithelial cells from asthma (AHBE) and COPD (CHBE) patients and healthy subjects (NHBE) were analyzed with next-generation sequencing (NGS) and the significant microRNA changes common in AHBE and CHBE were extracted. The upregulation of hsa-miR-10a-5p and hsa-miR-146a-5p in both AHBE and CHBE was confirmed with quantitative polymerase chain reaction (qPCR). Using bioinformatic methods, we further identified putative targets of these microRNAs, which were downregulated in both AHBE and CHBE: miR-10a-5p might suppress BCL2, FGFR3, FOXO3, PDE4A, PDE4C, and PDE7A; miR-146a-5p might suppress BCL2, INSR, PDE4D, PDE7A, PDE7B, and PDE11A. We further validated significantly decreased expression levels of FOXO3 and PDE7A in AHBE and CHBE than in NHBE with qPCR. Increased serum miR-146a-5p level was also noted in patients with asthma and COPD as compared with normal control subjects. In summary, our study revealed possible mechanisms mediated by miR-10a-5p and miR-146a-5p in the pathogenesis of both asthma and COPD. The findings might provide a scientific basis for developing novel diagnostic and therapeutic strategies.


Assuntos
Asma/genética , Brônquios/patologia , Biologia Computacional/métodos , Células Epiteliais/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , MicroRNAs/genética , Doença Pulmonar Obstrutiva Crônica/genética , Idoso , Asma/sangue , Asma/patologia , Feminino , Ontologia Genética , Humanos , Masculino , MicroRNAs/sangue , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/patologia , Regulação para Cima/genética
8.
Int J Med Sci ; 16(1): 93-105, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30662333

RESUMO

Upper tract urothelial carcinoma (UTUC) is a relatively uncommon cancer worldwide, however it accounts for approximately 30% of urothelial cancer in the Taiwanese population. The aim of the current study is to identify differential molecular signatures and novel miRNA regulations in UTUC, using next-generation sequencing and bioinformatics approaches. Two pairs of UTUC tumor and non-tumor tissues were collected during surgical resection, and RNAs extracted for deep sequencing. There were 317 differentially expressed genes identified in UTUC tissues, and the systematic bioinformatics analyses indicated dysregulated genes were enriched in biological processes related to aberration in cell cycle and matrisome-related genes. Additionally, 15 candidate genes with potential miRNA-mRNA interactions were identified. Using the clinical outcome prediction database, low expression of SLIT3 was found to be a prognostic predictor of poor survival in urothelial cancer, and a novel miRNA, miR-34a-5p, was a potential regulator of SLIT3, which may infer the potential role of miR-34a-5p-SLIT3 regulation in the altered tumor microenvironment in UTUC. Our findings suggested novel miRNA target with SLIT3 regulation exerts potential prognostic value in UTUC, and future investigation is necessary to explore the role of SLIT3 in the tumor development and progression of UTUC.


Assuntos
Carcinoma/genética , Genes Neoplásicos , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Urológicas/genética , Idoso , Biomarcadores Tumorais , Carcinoma/diagnóstico , Biologia Computacional , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Prognóstico , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Neoplasias Urológicas/diagnóstico , Urotélio/patologia
9.
N Engl J Med ; 379(22): 2179-80, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30499642
10.
Int J Mol Sci ; 19(11)2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388870

RESUMO

Fatty acid metabolism is important in the regulation of breast cancer progression. Some of the proteins involved in fatty acid transport have been demonstrated to promote the proliferation, migration, and invasion in breast cancer cells. Solute carrier family 27 member 4 (SLC27A4) is a fatty acid transporter protein and is related to very long chain acyl-CoA synthetase activity. In the present study, bioinformatic analysis revealed that relatively high SLC27A4 expression was observed in all subtypes of breast tumor tissues when compared to normal breast tissues. Silencing SLC27A4 expression significantly reduced uptake of free fatty acids in two breast cancer cell lines, Hs578T and MDA-MB-231. Cell growth inhibition was observed in SLC27A4-silenced Hs578T and cell cycle was arrested at G2/M. In addition, the capacity of migration and invasion decreased in both cell lines after knockdown of SLC27A4. The epithelial⁻mesenchymal transition signaling pathway was inhibited because protein expression of Slug, vimentin, α-smooth muscle actin, and other regulators was lower than that in control cells. Taken together, our results confirm that high SLC27A4 is associated with tumor progression in breast cancer cells. It is worth investigating whether SLC27A4 serves a diagnostic marker and therapeutic target in further studies.

11.
Mol Ther Nucleic Acids ; 13: 543-555, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30414568

RESUMO

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Mesangial cell (MC) loss is correlated with worsening renal function in DN. Disturbance of angiopoietin (Angpt)/Tie ligand-receptor system causes inflammation and abnormal angiogenesis. This association between elevated circulating Angpt2 and poor renal outcome has been in DN patients. However, the pathogenic role of Angpt2 in the MCs remains unknown. We found serum Angpt2 levels were elevated in type 2 diabetes mellitus (DM) patients and db/db mice, which correlated with albuminuria. Angpt2 synergistically induced MC apoptosis under high glucose (HG), and miR-33-5p regulated Angpt2-inducing MC apoptosis treated with HG. Loss of miR-33-5p increased suppressor of cytokine signaling 5 (SOCS5), leading to the inhibition of Janus kinase 1 and signal transducer and activator of transcription 3 signaling transduction. Elevated expression of SOCS5 was found in the MCs in kidney sections of both db/db mice and type 2 DM patients. Decreased miR-33-5p levels were found in the urine of db/db mice and type 2 DM patients, and miR-33-55p levels negatively correlated with albuminuria. Angpt2 leads to MC apoptosis via the miR-33-5p-SOCS5 loop in DN. miR-33-5p is predictive of kidney injury in DN. These findings may provide future applications in predicting renal dysfunction and the therapeutic potential of DN.

12.
J Clin Med ; 7(12)2018 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-30469549

RESUMO

Diabetic nephropathy (DN) is the major cause of end stage renal disease. Proximal tubular epithelial cell (PTEC) injury occurs early in diabetic kidney, and it is correlated with consequent renal failure. Cellular senescence participates in the pathophysiology of DN, but its role remains unclear. We conducted a cross-disciplinary study, including human, in vivo, and in vitro studies, to explore the novel molecular mechanisms of PTEC senescence in DN. We found that HG induced cell senescence in PTECs, supported by enhanced ß-galactosidase staining, p53 and p27 expression, and reduced cyclin E levels. Transcriptome analysis of PTECs from a type 2 diabetic patient and a normal individual using next generation sequencing (NGS) and systematic bioinformatics analyses indicated that miR-378i and its downstream target S-phase kinase protein 2 (Skp2) contribute to HG-induced senescence in PTECs. High glucose (HG) elevated miR-378i expression in PTECs, and miR-378i transfection reduced Skp2 expression. Urinary miR-378i levels were elevated in both db/db mice and type 2 diabetic patients, whereas decreased Skp2 levels were shown in proximal tubule of db/db mice and human DN. Moreover, urinary miR-378i levels were positively correlated with urinary senescence-associated secretory phenotype cytokines and renal function in in vivo and human study. This study demonstrates that the interaction between miR-378i and Skp2 regulates PTEC senescence of DN. miR-378i has the potential to predict renal injury in DN. These findings suggest future applications in both therapy and in predicting renal dysfunction of DN.

13.
Int J Med Sci ; 15(11): 1129-1142, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30123050

RESUMO

Cartilage destruction in rheumatoid arthritis (RA) occurs primarily in the pannus-cartilage interface. The close contact of the synovium-cartilage interface implicates crosstalk between synovial fibroblasts and chondrocytes. The aim of this study is to explore the differentially expressed genes and novel microRNA regulations potentially implicated in the dysregulated cartilage homeostasis in joint destruction of RA. Total RNAs were extracted from human primary cultured normal and RA chondrocytes for RNA and small RNA expression profiling using next-generation sequencing. Using systematic bioinformatics analyses, we identified 463 differentially expressed genes in RA chondrocytes were enriched in biological functions related to altered cell cycle process, inflammatory response and hypoxic stimulation. Moreover, fibroblast growth factor 9 (FGF9), kynureninase (KYNU), and regulator of cell cycle (RGCC) were among the top dysregulated genes identified to be potentially affected in the RA joint microenvironment, having similar expression patterns observed in arrays of clinical RA synovial tissues from the Gene Expression Omnibus database. Additionally, among the 31 differentially expressed microRNAs and 10 candidate genes with potential microRNA-mRNA interactions in RA chondrocytes, the novel miR-140-3p-FGF9 interaction was validated in different microRNA prediction databases, and proposed to participate in the pathogenesis of joint destruction through dysregulated cell growth in RA. The findings provide new perspectives for target genes in the management of cartilage destruction in RA.

14.
Int J Mol Sci ; 19(8)2018 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-30115896

RESUMO

Crosstalk of a tumor with its microenvironment is a critical factor contributing to cancer development. This study investigates the soluble factors released by tumor-associated dendritic cells (TADCs) responsible for increasing cancer stem cell (CSC) properties, cell mobility, and epithelial-to-mesenchymal transition (EMT). Dendritic cells (DCs) of colon cancer patients were collected for phenotype and CXCL1 expression by flow cytometry and Luminex assays. The transcriptome of CXCL1-treated cancer cells was established by next generation sequencing. Inflammatory chemokine CXCL1, present in large amounts in DCs isolated from colon cancer patients, and SW620-conditioned TADCs, enhance CSC characteristics in cancer, supported by enhanced anchorage-independent growth, CD133 expression and aldehyde dehydrogenase activity. Additionally, CXCL1 increases the metastatic ability of a cancer by enhancing cell migration, matrix metalloproteinase-7 expression and EMT. The enhanced CXCL1 expression in DCs is also noted in mice transplanted with colon cancer cells. Transcriptome analysis of CXCL1-treated SW620 cells indicates that CXCL1 increases potential oncogene expression in colon cancer, including PTHLH, TYRP1, FOXO1, TCF4 and ZNF880. Concurrently, CXCL1 displays a specific microRNA (miR) upregulated by the prototypical colon cancer onco-miR miR-105. Analysis of publicly available data reveals CXCL1-driven oncogenes and miR-105 have a negative prognostic impact on the outcome of colon cancer. This study indicates a new mechanism by which the colon cancer milieu exploits DC plasticity to support cancer progression.


Assuntos
Quimiocina CXCL1/metabolismo , Neoplasias do Colo/patologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Progressão da Doença , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Quimiocina CXCL1/genética , Neoplasias do Colo/genética , Transição Epitelial-Mesenquimal/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos BALB C , Modelos Biológicos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fenótipo , Transcriptoma/genética , Resultado do Tratamento , Regulação para Cima/genética
16.
Kidney Blood Press Res ; 43(4): 1322-1332, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30099445

RESUMO

BACKGROUND/AIMS: Fluid overload is common and associated with morbidity and mortality in patients with end-stage renal disease. The relationship between fluid overload and cardiac function is complex, and whether fluid overload is associated with adverse outcomes in patients undergoing hemodialysis (HD) independently of systolic and diastolic function of the left ventricle (LV) remains unclear. METHODS: The present study aimed to investigate the relationship between overhydration and all-cause and cardiovascular (CV) mortality after adjusting for LV function in 178 maintenance HD patients. The relative hydration status (overhydration/ extracellular water, ∆HS) was measured using a body composition monitor, and then used to assess the fluid status. A ∆HS ≥7% was defined as fluid overload. Global left ventricular longitudinal systolic strain (GLS), and the early filling and early diastolic mitral annular velocity (E/E') ratio were assessed using speckle-tracking and tissue Doppler echocardiography. RESULTS: During a mean follow-up period of 2.7 years, 24 patients died, including 11 CV deaths. An increased ∆HS was significantly associated with all-cause and CV mortality in the univariate analysis. This prognostic significance remains after multivariate adjusting for GLS and E/E' ratio for all-cause (HR, 1.123; 95% CI, 1.063-1.186; p-value < 0.001) and CV (HR, 1.088; 95% CI, 1.005-1.178; p-value =0.037) mortality. Moreover, ∆HS significantly improved the prognostic value beyond conventional clinical and echocardiographic parameters. CONCLUSION: A higher ∆HS was independently associated with increased all-cause and CV mortality after adjusting for systolic and diastolic function of the LV. This suggests that ∆HS may be a relevant target for improving outcomes in maintenance HD patients.


Assuntos
Doenças Cardiovasculares/mortalidade , Falência Renal Crônica/terapia , Estado de Hidratação do Organismo/fisiologia , Idoso , Ecocardiografia Doppler , Feminino , Seguimentos , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Diálise Renal , Resultado do Tratamento , Disfunção Ventricular Esquerda
17.
Int J Oncol ; 53(2): 886-894, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29845229

RESUMO

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer. In the present study, bioinformatics tools were systematically used to investigate the potential upstream effector involved in the progression of ccRCC. Using the Gene Expression Omnibus database and Library of Integrated Network-based Cellular Signatures L1000 platform, it was identified that GA-binding protein subunit ß1 (GABPB1) was a potential effector gene. GABPB1 is a transcription factor subunit and its function in ccRCC is unclear. Elevated expression of GABPB1 mRNA in ccRCC was also observed in other clinical datasets from the Oncomine database. Following reverse transcription-quantitative polymerase chain reaction and western blot analysis, the ccRCC 786-O and A498 cell lines showed higher expression levels of GABPB1 than HK-2, a normal kidney cell line. Knockdown of GABPB1 in the 786-O and A498 cells significantly decreased the ability to form colonies by inducing the expression of p21Waf/Cip1. SurvExpress database analysis indicated that a higher expression of GABPB1 was associated with poor survival outcome in patients with renal cancer. These findings imply that GABPB1 serves an important role in the progression of ccRCC.


Assuntos
Carcinoma de Células Renais/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Fator de Transcrição de Proteínas de Ligação GA/genética , Neoplasias Renais/genética , Regulação para Cima , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Progressão da Doença , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Renais/metabolismo , Prognóstico , Análise de Sobrevida
18.
Kidney Blood Press Res ; 43(2): 545-554, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29642068

RESUMO

BACKGROUND/AIMS: Diabetic nephropathy is the leading cause of end-stage renal disease and accounts for 30∼40% of patients requiring maintenance dialysis, thereby increasing the burden on health insurance programs. Diabetic nephropathy is also the strongest predictor of cardiovascular morbidity and mortality. The aim of this study was to examine whether angiopoietin-2 (Angpt2), a modulator of endothelial function, affects the clinical outcomes of diabetic patients. METHODS: This study enrolled 236 patients with diabetes mellitus with estimated glomerular filtration rate (eGFR) < 60ml/min/1.73m2 from January 2006 to December 2011, who were followed until June 2017. Clinical outcomes included renal outcomes (commencing dialysis and rapid decline in renal function (eGFR decline > 3 ml/min per 1.73 m2/year)), major adverse cardiovascular events (MACEs), and all-cause mortality. RESULTS: Over a mean follow-up period of 3.9±2.7 years, 135 (57.2%) patients commenced dialysis, 106 (44.9%) had rapid decline in renal function, and 50 (21.2%) had MACEs or died from all-causes. Log-formed Angpt2 was significantly associated with increased risks of commencing dialysis (HR: 3.91, 95% CI: 1.56-9.76), rapid renal function decline (OR: 6.81, 95% CI: 1.06-43.88), and MACEs or all-cause mortality (HR: 6.34, 95% CI: 1.18-33.97) in the adjusted analysis. Patients in the highest quartile had hazard ratios of 2.90 and 3.11 for commencing dialysis and rapid renal function decline, respectively, compared to those in the lowest quartile after adjustments. Similar significant dose-response results were found in composite outcomes of either MACEs or all-cause mortality. CONCLUSION: Angpt2 is an independent predictor of adverse clinical outcomes in diabetic patients. Further studies are needed to identify the pathogenic role of Angpt2 in renal deterioration and cardiovascular complications of diabetes mellitus.


Assuntos
Angiopoietina-2/sangue , Doenças Cardiovasculares/etiologia , Nefropatias Diabéticas , Insuficiência Renal Crônica/etiologia , Idoso , Angiopoietina-2/fisiologia , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/mortalidade , Nefropatias Diabéticas/fisiopatologia , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico
19.
Mol Ther ; 26(2): 568-581, 2018 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-29292163

RESUMO

Hypoxia, the most commonly observed characteristic in cancers, is implicated in the establishment of an immunosuppressive niche. Recent studies have indicated that extracellular vesicle (EV)-mediated cancer-stroma interactions are considered to play a critical role in the regulation of various cellular biological functions, with phenotypic consequences in recipient cells. However, the mechanisms underlying the relationship between EVs and hypoxia during cancer progression remain largely unknown. In this study, we found that EVs derived from hypoxic lung cancers increased M2-type polarization by miR-103a transfer. Decreased PTEN levels caused by hypoxic cancer-cell-derived EV miR-103a increased activation of AKT and STAT3 as well as expression of several immunosuppressive and pro-angiogeneic factors. In contrast, inhibition of miR-103a by an miRNA inhibitor effectively decreased hypoxic cancer-mediated M2-type polarization, improving the cytokine prolife of tumor infiltration macrophages. Macrophages received cancer-cell-derived EV miR-103a feedback to further enhance cancer progression and tumor angiogenesis. Finally, circulating EV miR-103a levels were higher in patients with lung cancer and closely associated with the M2 polarization. In conclusion, our results delineate a novel mechanism by which lung cancer cells induce immunosuppressive and pro-tumoral macrophages through EVs and inspire further research into the clinical application of EV inhibition or PTEN restoration for immunotherapy.

20.
Int J Oncol ; 52(2): 433-440, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29345293

RESUMO

In the tumor microenvironment, soluble molecules play important role in the establishment of a pre-metastatic niche. The S100 calcium-binding protein family are inflammatory molecules that contribute to the development of a pro-inflammatory tumor microenvironment. S100B belongs to the S100 family and serum S100B (also known as S100beta) serves as a marker for metastasis in lung cancer, ovarian cancer and melanoma. However, the association between S100B and the metastasis of breast cancer is not yet well understood. In the present study, a relatively low S100B expression was observed in the tumor samples compared to normal breast tissue among online microarray datasets. When the estrogen receptor (ER)-negative breast cancer cell lines, MDA-MB-231 and Hs578T, were treated with recombinant human S100B, cell migration was significantly inhibited and epithelial cadherin expression was increased. Our results revealed that a high S100B expression predicted a good overall survival in patients with ER-negative breast cancer, and good distant metastases-free survival in all patients with breast cancer via the analysis of the KM plotter and SurvExpress databases. Although previous studies have indicated that the interaction of S100B with wild-type p53 inhibits p53 function, a high S100B expression is associated with a good prognosis in patients with p53 mutant and p53 wild-type breast cancers. On the whole, our findings demonstrate that S100B treatment suppresses the migratory capacity of ER-negative breast cancer and that S100B expression may serve a predictive marker for metastasis in breast cancer.


Assuntos
Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Prognóstico , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Subunidade beta da Proteína Ligante de Cálcio S100/farmacologia , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genética
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