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1.
Front Mol Biosci ; 8: 745409, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34760926

RESUMO

Pancreatic adenocarcinoma (PAAD) is characterized by high malignancy, frequent metastasis, and recurrence with an unfavorable prognosis. This study is aimed at constructing a prognostic model for tumor-infiltrating immune cells and a competing endogenous RNA (ceRNA) network in PAAD and analyzing susceptibilities of chemotherapy and immunotherapy of PAAD. Gene expression profiles and clinical information of PAAD were downloaded from The Cancer Genome Atlas (TCGA) database and divided into the tumor group and the normal group. A total of five PAAD survival-related key genes in the ceRNA network and three survival-related immune infiltrating cells were uncovered, and two survival risk models and nomograms were constructed. The efficiency and performance of the two models were verified using multi-index area under the curve analysis at different time points, decision curve analysis, and calibration curves. Co-expression analysis showed that LRRC1, MIR600HG, and RNF166 in the ceRNA network and tumor-infiltrating immune cells including CD8 T cells and M1 macrophages were likely related to the PAAD prognosis, and the expression of key ceRNA-related genes was experimently validated in tissues and cell lines by RT-qPCR. Patients with low risk scores for key genes in the ceRNA network displayed a positive response to anti-programmed death-1 (PD-1) treatment and greater sensitivity to chemotherapeutic drugs such as docetaxel, lapatinib, and paclitaxel. More importantly, our results suggested that the IC50 values of gemcitabine in PAAD were not significantly different between the high and low risk groups. The expression levels of immune checkpoints were significantly different in the high-risk and low-risk groups. The prognostic model, nomogram, and drug analysis may provide an essential reference for PAAD patient management in the clinic.

2.
Sensors (Basel) ; 21(22)2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34833724

RESUMO

This paper proposes a hybrid dual path sub-sampling phase-locked loop (SSPLL), including a proportional path (P-path) and an integral path (I-path), with 0.8 V supply voltage. A differential master-slave sampling filter (MSSF), replacing the sub-sampling charge pump (SSCP), composed the P-path to avoid the degraded feature caused by the decreasing of the supply voltage. The I-path is built by a rail-to-rail SSCP to suppress the phase noise of the voltage-controlled oscillator (VCO) and avoid the trouble of locking at the non-zero phase offset (as in type-I PLL). The proposed design is implemented in a 40-nm CMOS process. The measured output frequency range is from 5.3 to 5.9 GHz with 196.5 fs root mean square (RMS) integrated jitter and -251.6 dB FoM.

3.
World J Gastrointest Surg ; 13(9): 1102-1109, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34621484

RESUMO

BACKGROUND: Although acute graft-vs-host disease (aGvHD) is a rare complication of liver transplantation, it is poorly understood and has an extremely high mortality rate. No standardized diagnostic criteria or treatment regimens currently exist. CASE SUMMARY: The present study investigated the etiology, diagnosis, and treatment of aGvHD following liver transplantation. Presentation, diagnosis, disease course, histology, and treatment of an aGvHD case are reported, and associated literature is reviewed. A 64-year-old female required LTx due to primary biliary cirrhosis. The donor was a 12-year-old male. Three weeks following liver transplantation, the recipient developed pyrexia, diarrhea, rashes, and antibiotic-unresponsive pancytopenia. Clinical symptoms together with laboratory investigations suggested a diagnosis of aGvHD, which was confirmed via peripheral blood fluorescent in situ hybridization. Donor XY chromosome fluorescent in situ hybridization indicating early chimerism achieved 93% sensitivity in the detection of GvHD. Existing immunosuppressants were discontinued, and high-dose intravenous methylprednisolone was initiated along with antibiotics. While diarrhea resolved, the patient's general condition continued to deteriorate until demise due to multi-system organ failure at 37 d post-liver transplantation. This case illustrates the life-threatening nature of aGvHD. CONCLUSION: Herein, we have summarized a post-LTx aGvHD case and reviewed associated literature in order to increase awareness and provide potentially risk-mitigating recommendations.

4.
Front Cell Dev Biol ; 9: 659680, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34368121

RESUMO

NAP1L1 has been reported to be significantly involved in the carcinogenesis of hepatocellular carcinoma (HCC). Yet, its detailed molecular basis is still to be determined. Based on the analysis of The Cancer Genome Atlas (TCGA) database, NAP1L1 mRNA was found to be upregulated and predicted the poor prognosis initially. Subsequently, consistent with the prediction, the upregulated expression of NAP1L1 mRNA and protein levels was confirmed by quantitative polymerase chain reaction (qPCR), Western blot, and immunohistochemistry assays. Upregulated NAP1L1 protein positively promoted the disease progression and poor prognosis of HCC. In addition, NAP1L1 protein expression was considered as an independent prognostic factor in HCC. Inhibition of NAP1L1 expression by siRNA or shRNA pathway significantly reduced the cell proliferation and cell cycle transformation in vitro and in vivo. Mechanism analysis first showed that the function of NAP1L1 was to recruit hepatoma-derived growth factor (HDGF), an oncogene candidate widely documented in tumors. Furthermore, the latter interacted with c-Jun, a key oncogenic transcription factor that can induce the expression of cell cycle factors and thus stimulate the cell growth in HCC. Finally, transfecting HDGF or c-Jun could reverse the suppressive effects on HCC growth in NAP1L1-suppressed HCC cells. Our data indicate that NAP1L1 is a potential oncogene and acts via recruiting HDGF/c-Jun in HCC.

5.
FEBS Open Bio ; 11(10): 2705-2714, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34448542

RESUMO

Cell senescence is closely related to autophagy. In this article, we identified a natural nucleoside analogue, cordycepin, that has the ability to significantly improve lysosomal function, enhance the activity of the lysosomal representative protease cathepsin B (CTSB), and promote the expression of the functional protein lysosomal-associated membrane protein 2 (LAMP2) on the lysosomal membrane. Cordycepin then restores the damaged autophagy level of aging cells by activating the classic AMPK and mTOR-p70S6K signaling pathways, thus inhibiting cell senescence in an H2 O2 -induced stress-induced premature senescence (SIPS) cell model. This study provides new theoretical support for the further development of cordycepin and clinical antiaging drugs to inhibit cell senescence and suggests that the regulatory mechanisms of lysosomes in senescent cells should be considered when treating age-related diseases.

6.
Polit Psychol ; 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-34226776

RESUMO

Fighting the COVID-19 pandemic requires large numbers of citizens to adopt disease-preventive practices. We contend that national identification can mobilize and motivate people to engage in preventive behaviors to protect the collective, which in return would heighten national identification further. To test these reciprocal links, we conducted studies in two countries with diverse national tactics toward curbing the pandemic: (1) a two-wave longitudinal survey in China (Study 1, N = 1200), where a national goal to fight COVID-19 was clearly set, and (2) a five-wave longitudinal survey in the United States (Study 2, N = 1001), where the national leader, President Trump, rejected the severity of COVID-19 in its early stage. Results revealed that national identification was associated with an increase in disease-preventive behaviors in both countries in general. However, higher national identification was associated with greater trust in Trump's administration among politically conservative American participants, which then was associated with slower adoption of preventive behaviors. The reciprocal effect of disease-preventive behaviors on national identification was observed only in China. Overall, our findings suggest that although national identification may serve as a protective factor in curbing the pandemic, this beneficial effect was reduced in some political contexts.

7.
Aging (Albany NY) ; 13(4): 6055-6065, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33601338

RESUMO

Numerous studies have reported the important role of microRNAs (miRNAs) in human cancers. Although abnormal miR-29b expression has been linked to tumorigenesis in several cancers, its role in cholangiocarcinoma remains largely unknown. We found that miR-29b expression is frequently downregulated in human cholangiocarcinoma QBC939 cells and in clinical tumor samples. In cholangiocarcinoma patients, low miR-29b expression predicts poor overall survival. Overexpression of miR-29b in QBC939 cells inhibited proliferation, induced G1 phase cycle arrest, and promoted apoptosis. Methylation-specific PCR (MSP) analysis revealed a decreased methylation imprint at the promoter of the cell cycle inhibitor gene CDKN2B in cells overexpressing miR-29b. After identifying the DNA methyltransferase DNMT3B as a putative miR-29b target, luciferase reporter assays confirmed a suppressive effect of miR-29b on DNMT3B expression. Accordingly, we detected an inverse correlation between miR-29b and DNMT3B expression in clinical cholangiocarcinoma specimens. In QBC939 cells, DNMT3B overexpression promoted proliferation and inhibited apoptosis. DNMT3B silencing, in turn, led to increased CDKN2B expression. We also observed significant growth arrest in subcutaneous tumors formed in nude mice by QBC939 cells overexpressing miR-29b. These findings suggest miR-29b functions as a tumor suppressor in cholangiocarcinoma by relieving DNMT3B-mediated repression of CDKN2B expression.


Assuntos
Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Inibidor de Quinase Dependente de Ciclina p15/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , MicroRNAs/genética , Animais , Apoptose , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Feminino , Genes Supressores de Tumor , Humanos , Masculino , Camundongos , Camundongos Nus , Regiões Promotoras Genéticas
8.
Gastroenterol Hepatol ; 44(2): 115-124, 2021 Feb.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32980177

RESUMO

OBJECTIVE: Prevalence of hepatopulmonary syndrome (HPS) ranges from 4% to 47% in patients with cirrhosis. This study aimed to explore possible relationship between CX3CR1 and angiogenesis or macrophage accumulation in pathological process of HPS. MATERIAL AND METHODS: Wide-type C57Bl/6 mice were divided into WT-sham, WT-common bile duct ligation (WT-CBDL), WT-CBDL plus antibody (WT-CBDL+Ab) and WT-CBDL plus Bevacizumab. The CX3CR1GFP/GFP mice were grouping into CX3CR1 GFP/GFP-sham, CX3CR1 GFP/GFP-CBDL and CX3CR1 GFP/GFP-CBDL+Bevacizumab group. Intrapulmonary expression of Akt, pAkt, ERK, pERK, iNOS, VEGF, PDGF was measured using biological technology. Hematoxylin-eosin (H&E) staining and immunohistochemical analysis were used to evaluate changes of pulmonary tissues including pathological abnormality, angiogenesis and macrophage accumulation. RESULTS: Blockade CX3CR1 pathway inhibited angiogenesis, macrophage accumulation and pathological changes of lung tissues. Blockade of CX3CR1 pathway reduced pAkt, pERK, iNOS, PDGF and VEGF activation. CX3CR1 contributed to the process of angiogenesis and activate the pro-angiogenic factors. CX3CR1 deficiency obviously reduced the macrophage accumulation. Inhibition of VEGF by Bevacizumab improved intrapulmonary angiogenesis and pathological changes of lung tissues. Inhibition of VEGF by Bevacizumab retarded the production of pAKt, PDGF, and iNOS. Inhibition of VEGF by Bevacizumab reduced CX3CL1 production. CONCLUSION: CX3CR1 could regulate the angiogenesis and activation of pro-angiogenic factors, including pAKT, pERK, iNOS, VEGF and PDGF in the process of hepato-pulmonary syndrome. Moreover, CX3CR1 could also contribute to the macrophage accumulation.

9.
Genes (Basel) ; 11(11)2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33137935

RESUMO

BACKGROUND: We demonstrated that the transduction of Wnt11 into mesenchymal stem cells (MSCs) (MSCWnt11) promotes these cells differentiation into cardiac phenotypes. In the present study, we investigated the paracrine effects of MSCWnt11 on cardiac function and angiogenesis. METHODS AND RESULTS: Conditioned medium was collected from MSCWnt11 (CdMWnt11) and their control cells (CdMGFP). CdMWnt11, especially obtained from MSCWnt11 exposed to hypoxia, significantly promoted human umbilical vein endothelial cells (HUVECs) migration and increased capillary-like tube (CLT) formation, which was blocked by Wnt11 neutralizing antibody. Wnt11 protein was significantly higher in CdMWnt11 compared to that in CdMGFP. Directly treating HUVECs with recombinant Wnt11 protein significantly increased CLT formation, which was abrogated by treating cells with the JNK inhibitor SP600125, as well as the PKC inhibitor Calphostin-C. Moreover, the transfection of Wnt11 to HUVECs (HWnt11) significantly increased CLT formation and HUVEC migration, as well as upregulated p-pan-PKC and p-JNK expression. Injection of CdMWnt11 into the peri-infarct region in a rat acute myocardial infarction (AMI) model significantly improved cardiac function, reduced infarct size, and increased myocardial blood flow and blood vessel density in the ischemic area. CONCLUSION: Wnt11 released from MSCWnt11 increased angiogenesis and improved cardiac function via non-canonical Wnt-PKC-JNK dependent pathways.


Assuntos
Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Neovascularização Fisiológica , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , Animais , Capilares/citologia , Capilares/crescimento & desenvolvimento , Capilares/metabolismo , Células Cultivadas , Meios de Cultivo Condicionados , Modelos Animais de Doenças , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Sistema de Sinalização das MAP Quinases , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Neovascularização Fisiológica/genética , Proteína Quinase C/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Wnt/antagonistas & inibidores , Proteínas Wnt/genética , Via de Sinalização Wnt/genética
10.
Ann Ital Chir ; 91: 327-333, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32877386

RESUMO

OBJECTIVE: This study aims to evaluate the execution of robot-assisted laparoscopic nephroureterectomy without repositioning the patient. METHODS: The clinical data of 9 patients who underwent robot-assisted laparoscopic nephroureterectomy between May 2017 and November 2018 were analyzed, proceeding in a single position, without repositioning the patient. This involved 5 men and 4 women, with an average age of 61.67 ± 10.37 years and an average body mass index (BMI) of 24.78 ± 3.84. We considered the duration of the intervention, the blood loss, the duration of the hospital stay, the duration of maintenance of the drainage and the follow-up on all patients, with or without complications and recurrence of the tumor. RESULTS: The intervention was completed in all 9 cases. The average duration of the intervention was 242.89 ± 13.37 minutes, the average blood loss was 166.67 ± 70.71 ml, the average hospitalization time was 2 ± 0.71 days, the average time drainage maintenance was 5.11 ± 1.05 days and the average follow-up times without complications and tumor recurrence were 12.56 ± 6.19 months. CONCLUSION: Robot-assisted laparoscopic nephroureterectomy without repositioning the patient during the procedure simplifies the procedure and shortens the duration of the procedure. It is also a safe, effective and feasible minimally invasive treatment method. KEY WORDS: Nephroureterectomy, Robot-assisted laparoscopic, Tumor recurrence, Single position, Upper tract urothelial carcinoma.


Assuntos
Laparoscopia , Nefroureterectomia , Procedimentos Cirúrgicos Robóticos , Ureter , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Posicionamento do Paciente , Resultado do Tratamento , Ureter/cirurgia
11.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(3): 358-360, 2020 Mar 30.
Artigo em Chinês | MEDLINE | ID: mdl-32376588

RESUMO

To suppress the rapid spread of coronavirus disease 2019 (COVID-19) in Hubei province, a medical rescue team consisting of 860 members was sent to E'zhou, one of the hard-hit cities in east Hubei. A total of 414 of the team members, whose core members were from Guizhou Medical University and its Affiliated Hospital, took over the full operation of Leishan hospital of E'zhou, a makeshift hospital built for treating COVID-19 patients. Under the instructions by the E'zhou Medical Team Front Command, the staff made quick responses to the surging number of patients with COVID-19 and rapidly formulated treatment plans based on the local conditions. The medical team efficiently carried out the operations and successfully completed the rescue mission. Herein the authors, as members of Guizhou Medical Team supporting COVID-19 containment in E'zhou, analyze and summarize the experiences of Guizhou Medical Team with the organization, implementation and logistic support of medical rescue operations, which may provide reference for future rescue missions in a similar scenario.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Pandemias , Pneumonia Viral , COVID-19 , China , Humanos , SARS-CoV-2
12.
Signal Transduct Target Ther ; 5(1): 13, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32296025

RESUMO

MYH9 has dual functions in tumors. However, its role in inducing tumor stemness in hepatocellular carcinoma (HCC) is not yet determined. Here, we found that MYH9 is an effective promoter of tumor stemness that facilitates hepatocellular carcinoma pathogenesis. Importantly, targeting MYH9 remarkably improved the survival of hepatocellular carcinoma-bearing mice and promoted sorafenib sensitivity of hepatocellular carcinoma cells in vivo. Mechanistic analysis suggested that MYH9 interacted with GSK3ß and reduced its protein expression by ubiquitin-mediated degradation, which therefore dysregulated the ß-catenin destruction complex and induced the downstream tumor stemness phenotype, epithelial-mesenchymal transition, and c-Jun signaling in HCC. C-Jun transcriptionally stimulated MYH9 expression and formed an MYH9/GSK3ß/ß-catenin/c-Jun feedback loop. X protein is a hepatitis B virus (HBV)-encoded key oncogenic protein that promotes HCC pathogenesis. Interestingly, we observed that HBV X protein (HBX) interacted with MYH9 and induced its expression by modulating GSK3ß/ß-catenin/c-Jun signaling. Targeting MYH9 blocked HBX-induced GSK3ß ubiquitination to activate the ß-catenin destruction complex and suppressed cancer stemness and EMT. Based on TCGA database analysis, MYH9 was found to be elevated and conferred poor prognosis for hepatocellular carcinoma patients. In clinical samples, high MYH9 expression levels predicted poor prognosis of hepatocellular carcinoma patients. These findings identify the suppression of MYH9 as an alternative approach for the effective eradication of CSC properties to inhibit cancer migration, invasion, growth, and sorafenib resistance in HCC patients. Our study demonstrated that MYH9 is a crucial therapeutic target in HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/genética , Neoplasias Hepáticas/tratamento farmacológico , Cadeias Pesadas de Miosina/genética , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Sorafenibe/farmacologia , Transativadores/genética , Ubiquitinação/efeitos dos fármacos , Proteínas Virais Reguladoras e Acessórias/genética , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/genética
13.
Biomed Pharmacother ; 123: 109780, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31901550

RESUMO

FAM83A is part of an 8-member protein family of unknown function and is reported to be a cancer-promoting and treatment-resistance factor in several cancers. However, its role in hepatocellular carcinoma (HCC) remains unclear. Analysis of the Cancer Genome Atlas (TCGA) showed that FAM83A mRNA expression is upregulated in HCC, as are the protein expression levels in both HCC cell lines and tissues. Clinical data have demonstrated that high FAM83A expression is positively correlated with poor progression-free survival time, thus suggesting its cancer-promoting potential. Functional analyses showed that FAM83A overexpression promoted HCC cell migration and invasion in vitro and suppressed sorafenib sensitivity. Inhibiting FAM83A reversed these results. A pulmonary metastasis model further confirmed that FAM83A promoted HCC cell metastasis in vivo. Mechanistic analyses indicated that FAM83A activated the PI3K/AKT signaling pathway, its downstream c-JUN protein, and epithelial-to-mesenchymal transition (EMT)-related protein levels, including downregulation of E-cadherin and upregulation of Vimentin and N-cadherin. Interestingly, c-JUN induced FAM83A expression by directly binding to its promoter region and thus forming a positive-feedback loop for FAM83A/PI3K/AKT/c-JUN. In conclusion, we demonstrated that FAM83A, as a cancer-metastasis promoter, accelerates migration, invasion and metastasis by activating the PI3K/AKT/c-JUN pathway and inducing its self-expression via feedback, thus forming a FAM83A/PI3K/AKT/c-JUN positive-feedback loop to activate EMT signaling and finally promote HCC migration, invasion and metastasis.


Assuntos
Carcinoma Hepatocelular/patologia , Movimento Celular , Retroalimentação Fisiológica , Neoplasias Hepáticas/patologia , Proteínas de Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Retroalimentação Fisiológica/efeitos dos fármacos , Feminino , Inativação Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Transdução de Sinais , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico
14.
Ann Transl Med ; 8(24): 1667, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33490179

RESUMO

Background: By the time they are clinically diagnosed, patients with hepatocellular carcinoma (HCC) are often at the advanced stage. DNA methylation has become a useful predictor of prognosis for cancer patients. Research on DNA methylation as a biomarker for assessing the risk of occurrence in HCC patients is limited. The purpose of this study was to develop an efficient methylation site model for predicting survival in patients with HCC. Methods: DNA methylation and gene expression profile data were extracted from The Cancer Genome Atlas (TCGA) database. Markers of DNA-methylated site in two subsets (the training subset and the test subset) were identified using a random survival forest algorithm and Cox proportional hazards regression. Then, Gene Ontology annotations were applied to investigate the functions of DNA methylation signatures. Results: A total of 37 hub genes containing 713 methylated sites were identified among the differentially methylated genes (DMGs) and differentially expressed genes (DEGs). Finally, seven methylation sites (cg12824782, cg24871714, cg18683774, cg22796509, cg19450025, cg10474350, and cg06511917) were identified. In the training group and the test group, the area under the curve predicting the survival of patients with HCC was 0.750 and 0.742, respectively. The seven methylation sites signature could be used to divide the patients in the training group into high- and low-risk subgroups [overall survival (OS): 2.81 vs. 2.11 years; log-rank test, P<0.05]. Then, the prediction ability of the model was validated in the test dataset through risk stratification (OS: 2.04 vs. 2.88 years; log-rank test, P<0.05). Functional analysis demonstrated that these signature genes were related to the activity of DNA-binding transcription activator, RNA polymerase II distal enhancer sequence-specific DNA binding, and enhancer sequence-specific DNA binding. Conclusions: The results of this study showed that the signature is useful for predicting the survival of HCC patients and thus, can facilitate treatment-related decision-making.

15.
Onco Targets Ther ; 12: 10717-10726, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827329

RESUMO

Background: Previous studies indicated that long noncoding RNAs (lncRNAs) played vital roles in the development and progression of hepatocellular carcinoma (HCC). Recently, downregulation of lncRNA RP5­833A20.1 has been observed in HCC tissues. However, the underlying mechanism by which RP5­833A20.1 regulates the proliferation and apoptosis in HCC has not been investigated. Thus, this study aimed to investigate the role of RP5­833A20.1 in the progression of HCC. Methods: The levels of RP5­833A20.1 in 30 pairs of HCC tissues and adjacent normal tissues were detected by RT-qPCR. In addition, the effects of RP5­833A20.1 on cell proliferation, apoptosis and invasion were evaluated by CCK-8, flow cytometric, transwell assays, respectively. Meanwhile, the dual-luciferase reporter system assay was used to explore the interaction of RP5­833A20.1 and miR-18a-5p in HCC. Results: The level of RP5­833A20.1 was significantly downregulated in HCC tissues and HCC cell lines. Downregulation of RP5­833A20.1 markedly promoted the proliferation and invasion of Bel-7402 cells. In addition, overexpression of RP5­833A20.1 notably inhibited the proliferation and invasion of Huh7 cells. Moreover, overexpression of RP5­833A20.1 obviously induced the apoptosis of Huh7 cells via increasing the levels of Bax and active caspase 3, and decreasing the levels of Bcl-2, p-Akt and p-ERK. Meanwhile, in vivo experiments performed also indicated that overexpression of RP5-833A20.1 could inhibit the tumorigenesis of subcutaneous Huh7 xenograft in nude mice. Furthermore, bioinformatics and luciferase reporter assay identified that RP5-833A20.1 functioned as a competing endogenous RNA (ceRNA) for miR-18a-5p in HCC. Conclusion: In this study, we found that RP5­833A20.1 was downregulated in HCC tissues. In addition, RP5-833A20.1 could suppress the tumorigenesis in HCC through inhibiting Akt/ERK pathway by acting as a ceRNA for miR-18a-5p. Therefore, RP5-833A20.1 might be a valuable and potential biomarker and therapeutic target for the treatment of HCC.

16.
Drug Des Devel Ther ; 13: 3949-3961, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819369

RESUMO

Objective: Osteoarthritis (OA) is characterized by progressive matrix destruction of articular cartilage. This study aimed to investigate the potential antioxidative and chondroprotective effects and underlying mechanism of Icariin (ICA) in interleukin-1 beta (IL-1ß)-induced extracellular matrix (ECM) degradation of OA cartilage. Methods: Human chondrocyte cell line HC-A was treated with different doses of ICA, and then MTT assay and PI staining were used to estimate ICA-induced chondrocyte apoptosis. Intracellular ROS and superoxide dismutase (SOD) and glutathione peroxidase (GPX) were measured after treatment by IL-1ß with or without ICA. The mRNA and protein expression levels of redox transcription factor Nrf2 and the downstream effector SOD-1, SOD-2, NQO-1 and HO-1 were assayed to explore the detailed mechanism by which ICA alleviates ECM degradation. Finally, to expound the role of Nrf2 in ICA-mediated chondroprotection, we specifically depleted Nrf2 in human chondrocytes and then pretreated them with ICA followed by IL-1ß. Results: ICA had no cytotoxic effects on human chondrocytes and 10-9 M was selected as the optimum concentration. ROS induced by IL-1ß could drastically activate matrix-degrading proteases and ICA could significantly rescue the matrix degradation and excess ROS generation caused by IL-1ß. We observed that ICA activated the Nrf2/ARE pathway, consequently upregulating the generation of GPX and SOD. Ablation of Nrf2 abrogated the chondroprotective and antioxidative effects of ICA in IL-1ß-treated chondrocytes. Conclusion: ICA alleviates IL-1ß-induced matrix degradation and eliminates ROS by activating the Nrf2/ARE pathway.


Assuntos
Elementos de Resposta Antioxidante/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/farmacologia , Interleucina-1beta/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Células Cultivadas , Condrócitos/metabolismo , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/química , Flavonoides/química , Humanos , Interleucina-1beta/metabolismo , Conformação Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
17.
Theranostics ; 9(25): 7583-7598, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695788

RESUMO

Cancer stem cells (CSCs) are the key factor in determining cancer recurrence, metastasis, chemoresistance and patient prognosis in hepatocellular carcinoma (HCC). The role of miR-5188 in cancer stemness has never been documented. In this study, we investigated the clinical and biological roles of miR-5188 in HCC. Methods: MiRNA expression in HCC was analyzed by bioinformatics analysis and in situ hybridization. The biological effect of miR-5188 was demonstrated in both in vitro and in vivo studies through the ectopic expression of miR-5188. The target gene and molecular pathway of miR-5188 were characterized using bioinformatics tools, dual-luciferase reporter assays, gene knockdown, and rescue experiments. Results: MiR-5188 was shown to be upregulated and confer poor prognosis in HCC patient data from TCGA database. MiR-5188 was subsequently identified as a significant inducer of cancer stemness that promotes HCC pathogenesis. Specifically, the targeting of miR-5188 by its antagomir markedly prolonged the survival time of HCC-bearing mice and improved HCC cell chemosensitivity in vivo. Mechanistic analysis indicated that miR-5188 directly targets FOXO1, which interacts with ß-catenin in the cytoplasm to reduce the nuclear translocation of ß-catenin and promotes the activation of Wnt signaling and downstream tumor stemness, EMT, and c-Jun. Moreover, c-Jun transcriptionally activates miR-5188 expression, forming a positive feedback loop. Interestingly, the miR-5188-FOXO1/ß-catenin-c-Jun feedback loop was induced by hepatitis X protein (HBX) through Wnt signaling and participated in the HBX-induced pathogenesis of HCC. Finally, analyses of transcriptomics data and our clinical data supported the significance of the abnormal expression of the miR-5188 pathway in HCC pathogenesis. Conclusions: These findings present the inhibition of miR-5188 as a novel strategy for the efficient elimination of CSCs to prevent tumor metastasis, recurrence and chemoresistance in patients with hepatocellular carcinoma. Our study highlights the importance of miR-5188 as a tumor stemness inducer that acts as a potential target for HCC treatment.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proteína Forkhead Box O1/metabolismo , Neoplasias Hepáticas/metabolismo , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Transativadores/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo , beta Catenina/metabolismo , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/fisiologia , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Recidiva Local de Neoplasia/metabolismo , Via de Sinalização Wnt/fisiologia
18.
Aging (Albany NY) ; 11(22): 10697-10710, 2019 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-31761784

RESUMO

Mitogen-activated protein kinase kinase 4 (MAP2K4) is a member of the mitogen-activated protein kinase (MAPK) activator family. MAPK signaling plays a significant role in cell proliferation, differentiation, transcriptional regulation, and development. However, specific function and mechanism of MAP2K4 in breast cancer have not been clarified. According to our study, overexpressed MAP2K4 in breast cancer cells increased proliferation, migration, and invasion in vivo and in vitro, while MAP2K4 knockdown restored the effects. Subsequent mechanistic analyses demonstrated that MAP2K4 promoted cell proliferation, migration, and invasion by activating phosphoinositide-3-kinase (PI3K)/AKT signaling, the downstream proteins, c-JUN, the G1/S cell cycle, and the epithelial-to-mesenchymal transition (EMT). Meanwhile, MAP2K4 interacted with Vimentin and further propagated the malignant phenotype. Furthermore, patients with high MAP2K4 and Vimentin expression levels had poorer overall survival rates than those with low expression levels of both proteins. Our studies demonstrated that MAP2K4 has the potential to serve as an oncogene in breast cancer and it activates the phosphorylated PI3K/AKT signaling pathway to activate downstream cycle-associated proteins and EMT signals while interacting with Vimentin to promote breast cancer cells proliferation, migration, and invasion. In our study, MAP2K4 and Vimentin co-expression is confirmed to be an unfavorable factor in breast cancer.


Assuntos
Neoplasias da Mama/patologia , MAP Quinase Quinase 4/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Vimentina/metabolismo , Animais , Neoplasias da Mama/metabolismo , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Transdução de Sinais/fisiologia
19.
World J Gastroenterol ; 25(30): 4222-4234, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31435175

RESUMO

BACKGROUND: Liver fibrosis is a refractory disease whose persistence can eventually induce cirrhosis or even liver cancer. Early liver fibrosis is reversible by intervention. As a member of the transforming growth factor-beta (TGF-ß) superfamily, bone morphogenetic protein 7 (BMP7) has anti-liver fibrosis functions. However, little is known about BMP7 expression changes and its potential regulatory mechanism as well as the relationship between BMP7 and TGF-ß during liver fibrosis. In addition, the mechanism underlying the anti-liver fibrosis function of BMP7 needs to be further explored. AIM: To investigate changes in the dynamic expression of BMP7 during liver fibrosis, interactions between BMP7 and TGF-ß1, and possible mechanisms underlying the anti-liver fibrosis function of BMP7. METHODS: Changes in BMP7 expression during liver fibrosis and the interaction between BMP7 and TGF-ß1 in mice were observed. Exogenous BMP7 was used to treat mouse primary hepatic stellate cells (HSCs) to observe its effect on activation, migration, and proliferation of HSCs and explore the possible mechanism underlying the anti-liver fibrosis function of BMP7. Mice with liver fibrosis received exogenous BMP7 intervention to observe improvement of liver fibrosis by using Masson's trichrome staining and detecting the expression of the HSC activation indicator alpha-smooth muscle actin (α-SMA) and the collagen formation associated protein type I collagen (Col I). Changes in the dynamic expression of BMP7 during liver fibrosis in the human body were further observed. RESULTS: In the process of liver fibrosis induced by carbon tetrachloride (CCl4) in mice, BMP7 protein expression first increased, followed by a decrease; there was a similar trend in the human body. This process was accompanied by a sustained increase in TGF-ß1 protein expression. In vitro experiment results showed that TGF-ß1 inhibited BMP7 expression in a time- and dose-dependent manner. In contrast, high doses of exogenous BMP7 inhibited TGF-ß1-induced activation, migration, and proliferation of HSCs; this inhibitory effect was associated with upregulation of pSmad1/5/8 and downregulation of phosphorylation of Smad3 and p38 by BMP7. In vivo experiment results showed that exogenous BMP7 improved liver fibrosis in mice. CONCLUSION: During liver fibrosis, BMP7 protein expression first increases and then decreases. This changing trend is associated with inhibition of BMP7 expression by sustained upregulation of TGF-ß1 in a time- and dose-dependent manner. Exogenous BMP7 could selectively regulate TGF-ß/Smad pathway-associated factors to inhibit activation, migration, and proliferation of HSCs and exert anti-liver fibrosis functions. Exogenous BMP7 has the potential to be used as an anti-liver fibrosis drug.


Assuntos
Proteína Morfogenética Óssea 7/metabolismo , Células Estreladas do Fígado/patologia , Cirrose Hepática/patologia , Fígado/patologia , Administração Oral , Animais , Proteína Morfogenética Óssea 7/administração & dosagem , Tetracloreto de Carbono/toxicidade , Células Cultivadas , Regulação para Baixo , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Fígado/citologia , Fígado/efeitos dos fármacos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Camundongos , Fosforilação , Cultura Primária de Células , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima
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