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1.
Mol Ther ; 30(7): 2554-2567, 2022 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-35358687

RESUMO

Matrix stiffness promotes hepatocellular carcinoma (HCC) metastasis. This study examined the contribution of lipid metabolic reprogramming to matrix stiffness-induced HCC metastasis. HCC cells were cultured on mechanically tunable polyacrylamide gels and subjected to lipidomic analysis. The key enzyme that responded to matrix stiffness and regulated lipid metabolism was identified. The comparative lipidomic screening revealed that stearoyl-CoA desaturase 1 (SCD1) is a mechanoresponsive enzyme that reprogrammed HCC cell lipid metabolism. The genetic and pharmacological inhibition of SCD1 expression/activity altered the cellular lipid composition, which in turn impaired plasma membrane fluidity and inhibited in vitro invasive motility of HCC cells in response to high matrix stiffness. Knockdown of SCD1 suppressed HCC invasion and metastasis in vivo. Conversely, the overexpression of SCD1 or exogenous administration of its product oleic acid augmented plasma membrane fluidity and rescued in vitro invasive migration in HCC cells cultured on soft substrates, mimicking the effects imposed by high matrix stiffness. In human HCC tissues, collagen content, a marker of increasing matrix stiffness, and increased expression of SCD1 together predicted poor survival of HCC patients. An SCD1-dependent mechanoresponsive pathway that responds to increasing matrix stiffness in the tumor microenvironment promotes HCC invasion and metastasis through lipid metabolic reprogramming.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Humanos , Lipídeos , Neoplasias Hepáticas/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Microambiente Tumoral
2.
BMC Neurol ; 22(1): 124, 2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35361123

RESUMO

BACKGROUND: To study the effects of subthalamic nucleus-deep brain stimulation (STN-DBS) on autonomic dysfunctions in Parkinson's disease (PD) patients. METHODS: A total of 57 PD patients who underwent bilateral STN-DBS from March to December 2018, were retrospectively analyzed. Preplanned assessments at baseline and postoperatively at 1, 3, and 6 months also included the Scales for Outcomes in Parkinson's Disease-Autonomic questionnaire (SCOPA-Aut), the Unified Parkinson's Disease Rating Scale (UPDRS) III score, levodopa equivalent day dose (LEDD), Parkinson's Disease Quality of Life Scale (PDQ-39), the Hamilton Anxiety Rating Scale (HAMA), and the Hamilton Depression Rating Scale (HAMD). RESULTS: The SCOPA-Aut scores improved significantly [14.59% (18.32%), 24.00% (27.05%), 22.16% (27.07%), all P < 0.001] at 1 month, 3 months, and 6 months of STN-DBS, respectively. Analysis of the SCOPA-Aut sub-items showed significant improvements only in urine and thermoregulation sub-items at 6 months after surgery (P < 0.001). There was no significant correlation between improvements of SCOPA-Aut scores and improvements of PDQ-39 scores (P > 0.05) at 6 months after surgery. SCOPA-Aut scores were positively correlated with age (r = 0.428, P = 0.001); the improvements of SCCOPA-Aut scores were positively correlated with improvements of HAMA and HAMD scores (HAMA: r = 0.325, P = 0.015; HAMD: r = 0.265, P = 0.049) at 6 months after surgery. CONCLUSION: STN-DBS improved autonomic dysfunction symptoms of PD patients, and urinary and thermoregulatory sub-items of autonomic dysfunction were improved in the short-term after surgery. There was a close relationship between improved autonomic symptoms and improved anxiety and depression 6 months after surgery. We should therefore direct more attention to autonomic dysfunctions in PD involving detailed preoperative evaluations and postoperative follow-ups, to improve the quality of life of patients.


Assuntos
Estimulação Encefálica Profunda , Doença de Parkinson , Disautonomias Primárias , Núcleo Subtalâmico , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Doença de Parkinson/terapia , Qualidade de Vida , Estudos Retrospectivos , Núcleo Subtalâmico/fisiologia , Núcleo Subtalâmico/cirurgia
3.
Epilepsy Behav ; 122: 108130, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34153637

RESUMO

OBJECTIVE: Hyperkinetic seizures (HKS) are characterized by complex movements that commonly occur during seizures arising from diverse cortical structures. A common semiology network may exist and analyzing the anatomo-electrical mechanisms would facilitate presurgical evaluation. Here, quantitative positron emission tomography (PET) and stereoelectroencephalography (SEEG) analysis was used to explore the underlying mechanism of HKS. METHODS: We retrospectively collected patients with epilepsy with HKS between 2014 and 2019. The interictal PET data of patients with epilepsy with HKS were compared with those of 25 healthy subjects using statistical parametric mapping to identify regions with significant hypometabolism. Then, regions of interest (ROI) for SEEG analysis were identified based on the results of PET analysis. Patients in which the ROIs were covered by intracerebral electrodes were selected for further analysis. Stereoelectroencephalography -clinical correlations with latency measurements were analyzed, and we also performed coherence analysis among ROIs both before and during HKS. RESULTS: Based on the inclusion criteria, 27 patients were analyzed. In the PET analysis, significant hypometabolism was observed in the ipsilateral dorsoanterior insular lobe, bilateral mesial frontal lobes (supplementary motor area/middle cingulate cortex, SMA/MCC), and the bilateral heads of the caudate nuclei in patients with HKS compared with the control group (p < 0.001). We selected dorsoanterior insula and SMA/MCC as ROIs for SEEG analysis. Eight patients with 23 HKS events were selected for further analysis. There was a linear correlation between the ictal involvement of both the dorsoanterior insula and SMA/MCC with the onset of HKS. Stereoelectroencephalography analysis indicated alpha range activity seemed more often associated with dorsoanterior insula and SMA/MCC involvement during HKS. CONCLUSIONS: The dorsoanterior insular lobe, mesial frontal lobes (SMA/MCC), and the bilateral heads of the caudate nuclei were probably involved in the generation of HKS. The SEEG analysis further indicated that the occurrence of HKS might be partly associated with synchronized rhythmical alpha activity between dorsoanterior insula and SMA/MCC.


Assuntos
Eletroencefalografia , Tomografia por Emissão de Pósitrons , Humanos , Redes Neurais de Computação , Estudos Retrospectivos , Convulsões/diagnóstico por imagem
4.
Epilepsy Behav ; 121(Pt A): 108028, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34058496

RESUMO

OBJECTIVE: To summarize the clinical and electrophysiological observations of epilepsy originating from the inferior perisylvian cortex, and analyze the potential epileptic networks underlying the semiological manifestations. METHODS: We retrospectively analyzed patients with refractory inferior perisylvian epilepsy (IPE) who had undergone resective surgery, and then reviewed the demographic, clinical, neuroelectrophysiological, neuroimaging, surgical, histopathological, and follow-up data of the patients from the respective medical records. The selected patients were then categorized in accordance with the results of semiological analysis. Quantitative 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) analysis was performed to investigate the underlying neural network. RESULTS: Of the 18 IPE patients assessed in this study, ipsilateral frontotemporal epileptic discharges or its onsets were the dominant interictal or ictal scalp EEG observations. In addition, oroalimentary or manual automatism was the most frequently documented manifestation, followed by facial tonic or clonic movements. Moreover, the semiological analysis identified and classified the patients into 2 patterns, and the PET statistical analyses conducted on these 2 groups revealed differences in the neural network between them. CONCLUSION: Inferior perisylvian epilepsy possesses semiological manifestations similar to those of mesial temporal lobe epilepsy or rolandic opercular epilepsy, hence these conditions should be carefully differentiated. Performing lesionectomy or cortectomy, sparing the mesial temporal structures, was found to be an effective and safe treatment modality for IPE.


Assuntos
Epilepsia do Lobo Frontal , Epilepsia do Lobo Temporal , Eletroencefalografia , Fluordesoxiglucose F18 , Humanos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Estudos Retrospectivos , Resultado do Tratamento
5.
Mol Cancer ; 18(1): 105, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31153371

RESUMO

BACKGROUND: Recently, the dysregulation of circular RNA (circRNA) have been shown to have important regulatory roles in cancer development and progression, including hepatocellular carcinoma (HCC). However, the roles of most circRNAs in HCC are still unknown. METHODS: The expression of circular tripartite motif containing 33-12 (circTRIM33-12) in HCC tissues and cell lines was detected by qRT-PCR. The role of circTRIM33-12 in HCC progression was assessed by western blotting, CCK-8, flow cytometry, transwell and a subcutaneous tumor mouse assays both in vitro and in vivo. In vivo circRNA precipitation, RNA immunoprecipitation, luciferase reporter assays were performed to evaluate the interaction between circTRIM33-12 and miR-191. RESULTS: Here, we found that circTRIM33-12, is downregulated in HCC tissues and cell lines. The downregulation of circTRIM33-12 in HCC was significantly correlated with malignant characteristics and served as an independent risk factor for the overall survival (OS) and recurrence-free survival (RFS) of patients with HCC after surgery. The reduced expression of circTRIM33-12 in HCC cells increases tumor proliferation, migration, invasion and immune evasion. Mechanistically, we demonstrated that circTRIM33-12 upregulated TET1 expression by sponging miR-191, resulting in significantly reduced 5-hydroxymethylcytosine (5hmC) levels in HCC cells. CONCLUSIONS: These results reveal the important role of circTRIM33-12 in the proliferation, migration, invasion and immune evasion abilities of HCC cells and provide a new perspective on circRNAs in HCC progression.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , MicroRNAs/genética , Oxigenases de Função Mista/genética , Proteínas Proto-Oncogênicas/genética , RNA Circular/genética , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Masculino , Invasividade Neoplásica , Transplante de Neoplasias , Prognóstico , Análise de Sobrevida
6.
Int J Hyperthermia ; 36(1): 253-263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30701994

RESUMO

BACKGROUND: Microscopic residual tumor often occurs after thermal ablation for medium-large hepatocellular carcinoma (HCC), leading to early aggressive recurrence or late relapse during follow-up. The mechanism how microscopic residual HCC cells survive sublethal heat stress and develop rapid outgrowth remains poorly understood. METHODS: HCC cells were exposed to sublethal heat treatment and co-cultured with conditioned media from activated HSCs (HSC-CM). Changes of cell proliferation, parameters of cell autophagy and activation of signaling pathways in heat-treated residual HCC cells were analyzed. An HCC orthotopic model was subjected to partial thermal ablation and antitumor effects of a combined treatment regimen were studied. RESULTS: HCC cells survived sublethal heat stress via activation of autophagy. HSC-CM enhanced autophagic survival within 24 h and then promoted proliferation of heat-treated residual HCC cells through HGF/c-Met signaling. Inhibition of autophagy or c-Met increased apoptosis of heat-treated residual HCC cells and reversed the protective effect of HSC-CM. HGF modulated biological status in autophagic survival or proliferation of heat-treated residual HCC through HGF/c-Met/ERK signaling and downstream components of ATG5/Beclin1 or cyclinD1. In an animal model, inhibiting autophagy in combination with c-Met inhibitor significantly thwarted tumor progression of residual HCC after incomplete thermal ablation via the suppressed autophagy, the decreased proliferation and the increased apoptosis. CONCLUSIONS: Activated HSCs promote progression of residual HCC cells after sublethal heat treatment from autophagic survival to proliferation via HGF/c-Met signaling. A combined treatment regimen of inhibiting autophagy and c-Met signaling could be used to suppress tumor progression of residual HCC after incomplete thermal ablation.


Assuntos
Carcinoma Hepatocelular/genética , Células Estreladas do Fígado/metabolismo , Neoplasias Hepáticas/genética , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Humanos
7.
Med Sci Monit ; 25: 4716-4722, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31281179

RESUMO

BACKGROUND A growing body of evidence suggests that systemic lupus erythematosus (SLE) may result in reversible cognitive dysfunction. Vitamin D is considered important for neurons. The therapeutic effect of vitamin D was evaluated in a rat model of SLE. MATERIAL AND METHODS There were 20 male MRL/lpr mice randomly divided into the SLE model group and the vitamin D group, in addition, 10 male C57BL 6J mice were used as the control (CON) group. Vitamin D was administered intraperitoneally (2 µg/kg) for 4 weeks. After 4 weeks of continuing intervention, we tested the cognitive function using the Morris water maze. The expression of vitamin D receptor (VDR), amyloid-ß, caspase-3, and Bcl-2 were detected by western blot analysis. RESULTS In the present study, we observed that vitamin D treatment alleviated neurobehavioral deficits in the mice with SLE. At the molecular levels, administration of vitamin D activated the expression of VDR and reduced the number of dead cells in the CA1 region of the hippocampus as well as regulated caspase-3 and Bcl-2 expression. CONCLUSIONS In conclusion, our results indicated that vitamin D played a protective role by suppressing inflammatory cytokines, thereby ultimately inhibiting the progression of apoptosis in a mouse model of SLE. Vitamin D may be promising as a protective intervention in SLE with cognitive dysfunction, and more and more experiments are warranted for its clinical testing in the near future.


Assuntos
Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Vitamina D/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Animais , Caspase 3/metabolismo , Citocinas/metabolismo , Hipocampo/patologia , Mediadores da Inflamação/metabolismo , Interferon gama/metabolismo , Interleucina-2/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fatores de Tempo , Vitamina D/farmacologia
8.
J Transl Med ; 16(1): 302, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30400797

RESUMO

BACKGROUND: Incomplete thermal ablation may induce invasiveness of hepatocellular carcinoma (HCC). Here, we investigated whether activated hepatic stellate cells (HSCs) would accelerate the progression of residual HCC after sublethal heat treatment, and thus sought to identify the potential targets. METHODS: Hepatocellular carcinoma cells were exposed to sublethal heat treatment and then cultured with the conditioned medium from activated HSCs (HSC-CM). The cell proliferation, migration, invasion and parameters of epithelial-mesenchymal transition (EMT) were analyzed. In vivo tumor progression of heat-treated residual HCC cells inoculated with activated HSCs was studied in nude mice. RESULTS: HSC-CM significantly enhanced the proliferation, motility, invasion, prominent EMT activation and decreased apoptosis of heat-exposed residual HCC cells. These increased malignant phenotypes were markedly attenuated by neutralizing periostin (POSTN) in HSC-CM. Furthermore, exogenous POSTN administration exerted the similar effects of HSC-CM on heat-treated residual HCC cells. POSTN induced the prominent activation of p52Shc and ERK1/2 via integrin ß1 in heat-exposed residual HCC cells. Vitamin D analog calcipotriol blocked POSTN secretion from activated HSCs. Calcipotriol plus cisplatin significantly suppressed the activated HSCs-enhanced tumor progression of heat-treated residual HCC cells via the inhibited POSTN expression and the increased apoptosis. CONCLUSIONS: Activated HSCs promote the tumor progression of heat-treated residual HCC through the release of POSTN, which could be inhibited by calcipotriol. Calcipotriol plus cisplatin could be used to thwart the accelerated progression of residual HCC after suboptimal heat treatment.


Assuntos
Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Moléculas de Adesão Celular/metabolismo , Progressão da Doença , Células Estreladas do Fígado/metabolismo , Hipertermia Induzida , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Animais , Apoptose/efeitos dos fármacos , Calcitriol/análogos & derivados , Calcitriol/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Ativação Enzimática/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Biológicos , Invasividade Neoplásica , Receptores de Calcitriol/metabolismo , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismo , Ensaio Tumoral de Célula-Tronco
9.
BMC Cancer ; 18(1): 901, 2018 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-30227844

RESUMO

BACKGROUND: Accelerated malignant behaviors induced by insufficient thermal ablation have been increasingly reported, however, the exact mechanisms are still unclear. Here, we investigated the importance of the extracellular matrix (ECM) in modulating the progression of residual hepatocellular carcinoma (HCC) after heat treatment. METHODS: Heat-exposed residual HCC cells were cultured in different ECM gels. We used basement membrane gel (Matrigel) to simulate the normal microenvironment and collagen I to model the pathological stromal ECM. The alterations of morphology and parameters of proliferation, epithelial-mesenchymal transition (EMT) and stemness were analyzed in vitro and in vivo. RESULTS: Increased collagen I deposition was observed at the periablational zone after incomplete RFA of HCC in a xenograft model. The markers of cell proliferation, EMT, motility and progenitor-like traits of heat-exposed residual HCC cells were significantly induced by collagen I as compared to Matrigel (p values all < 0.05). Importantly, collagen I induced the activation of ERK phosphorylation in heat-exposed residual HCC cells. ERK1/2 inhibitor reversed the collagen I-promoted ERK phosphorylation, cell proliferative, protrusive and spindle-like appearance of heat-treated residual HCC cells in vitro. Moreover, collagen I promoted the in vivo tumor progression of heat-exposed residual HCC cells, and sorafenib markedly reversed the collagen I-mediated protumor effects. CONCLUSIONS: Our findings demonstrate that collagen I could enhance the aggressive progression of residual HCC cells after suboptimal heat treatment and sorafenib may be a treatment approach to thwart this process.


Assuntos
Carcinoma Hepatocelular/terapia , Colágeno Tipo I/genética , Hipertermia Induzida/métodos , Neoplasias Hepáticas/terapia , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Ablação por Cateter , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Matriz Extracelular/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Sorafenibe , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Cancer Sci ; 108(9): 1778-1786, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28699238

RESUMO

Aggravated behaviors of hepatocellular carcinoma (HCC) will occur after inadequate thermal ablation. However, its underlying mechanisms are not fully understood. Here, we assessed whether the increased matrix stiffness after thermal ablation could promote the progression of residual HCC. Heat-treated residual HCC cells were cultured on tailorable 3D gel with different matrix stiffness, simulating the changed physical environment after thermal ablation, and then the mechanical alterations of matrix stiffness on cell phenotypes were explored. Increased stiffness was found to significantly promote the proliferation of the heat-treated residual HCC cells when the cells were cultured on stiffer versus soft supports, which was associated with stiffness-dependent regulation of ERK phosphorylation. Heat-exposed HCC cells cultured on stiffer supports showed enhanced motility. More importantly, vitamin K1 reduced stiffness-dependent residual HCC cell proliferation by inhibiting ERK phosphorylation and suppressed the in vivo tumor growth, which was further enhanced by combining with sorafenib. Increased matrix stiffness promotes the progression of heat-treated residual HCC cells, proposing a new mechanism of an altered biomechanical environment after thermal ablation accelerates HCC development. Vitamin K1 plus sorafenib can reverse this protumor effect.


Assuntos
Carcinoma Hepatocelular/patologia , Matriz Extracelular/patologia , Neoplasias Hepáticas Experimentais/patologia , Animais , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Terapia Combinada , Progressão da Doença , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Hipertermia Induzida , Neoplasias Hepáticas Experimentais/terapia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasia Residual , Células-Tronco Neoplásicas/fisiologia , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Fenilureia/farmacologia , Transdução de Sinais , Sorafenibe , Vitamina K 1/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Magn Reson Imaging ; 45(1): 270-280, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27299302

RESUMO

PURPOSE: To investigate the effectiveness of intravoxel incoherent motion (IVIM) in the assessment of the therapeutic efficacy of sorafenib in an orthotopic hepatocellular carcinoma (HCC) xenograft model. MATERIALS AND METHODS: Thirty-five HCC nude mouse models were established. IVIM was performed on a 1.5T MR scanner at baseline (n = 5) and serially at 7, 14, and 21 days after sorafenib treatment. The apparent diffusion coefficient (ADCtotal ), true diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) at these timepoints were measured and compared between the treated (n = 15) and control group (n = 15). Differences in measurements among different timepoints were evaluated. Correlations between IVIM parameters and histologic features including necrotic fraction (NF) and microvessel density (MVD) were analyzed. RESULTS: Compared to the control group, ADCtotal and D were significantly higher at each timepoint (P = 0.009), while f significantly decreased at 7 days (P = 0.009) and increased at 21 days (P = 0.028) in the treated group. Serial measurements in the treated group showed that both ADCtotal and D increased significantly at 7, 14, and 21 days compared to baseline (P < 0.05), while f significantly declined at 7 days (P = 0.016) and increased at 21 days (P = 0.009). Significant correlations were found between ADCtotal and NF (r = 0.811, P < 0.001), D and NF (r = 0.838, P < 0.001), and between f and NF (r = 0.528, P = 0.017) in the treated group. CONCLUSION: IVIM may provide useful biomarkers for evaluating the therapeutic effects of sorafenib on HCC. LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:270-280.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/tratamento farmacológico , Imagem de Difusão por Ressonância Magnética/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Angiografia por Ressonância Magnética/métodos , Neovascularização Patológica/diagnóstico por imagem , Neovascularização Patológica/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Inibidores da Angiogênese/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Movimento (Física) , Neovascularização Patológica/patologia , Niacinamida/administração & dosagem , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sorafenibe , Resultado do Tratamento
12.
Hepatology ; 62(4): 1201-14, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25998839

RESUMO

UNLABELLED: Hepatocellular carcinoma (HCC) is the third-most lethal cancer worldwide. Understanding the molecular pathogenesis of HCC recurrence and metastasis is the key to improve patients' prognosis. In this study, we report that protein tyrosine phosphatase receptor S (PTPRS) is significantly down-regulated in nearly 80% of HCCs, and its expression negatively correlates with aggressive pathological features, such as larger tumor size and advanced stage. In addition, PTPRS deficiency is independently associated with shorter survival and increased recurrence in patients, although 16.7% of HCCs show intratumor heterogeneous expression of PTPRS. Restoration of wild-type, but not mutant, PTPRS expression significantly inhibits HCC cell migration and invasion in vitro as well as lung metastasis in vivo, whereas knockdown of its expression significantly promotes invasion and metastasis. Notably, PTPRS-regulated HCC invasiveness is accompanied by typical changes of epithelial-mesenchymal transition (EMT). Moreover, PTPRS forms a complex with epithermal growth factor receptor (EGFR) and regulates its tyrosine residues' phosphorylation. Ectopic expression of EGFR reverses the metastasis-inhibiting effects of PTPRS, whereas silencing of EGFR or inhibiting phosphorylation of key molecules in EGFR downstream pathways reinhibits EMT and metastasis caused by PTPRS down-regulation. Meanwhile, promoter hypermethylation of PTPRS is frequently detected in HCC samples and cell lines. Treatment with a demethylation agent, 5-aza-2'-deoxycytidine, recovers PTPRS expression in a dose-dependent manner. CONCLUSIONS: Epigenetic inactivation of PTPRS may increase phosphorylation and activity of EGFR signaling to promote EMT and metastasis in HCC.


Assuntos
Carcinoma Hepatocelular/secundário , Regulação para Baixo , Transição Epitelial-Mesenquimal , Receptores ErbB/fisiologia , Neoplasias Hepáticas/patologia , Metástase Neoplásica , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/fisiologia , Humanos , Receptores de Fatores de Crescimento , Células Tumorais Cultivadas
13.
Hepatology ; 62(6): 1804-16, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26340507

RESUMO

UNLABELLED: The molecular pathogenesis of intrahepatic cholangiocarcinoma (iCCA) is poorly understood, and its incidence continues to increase worldwide. Deficiency of mitogen-activated protein kinase kinase kinase 4 (MAP3K4) has been reported to induce the epithelial-mesenchymal transition (EMT) process of placental and embryonic development, yet its role in human cancer remains unknown. MAP3K4 has somatic mutation in iCCA so we sequenced all exons of MAP3K4 in 124 iCCA patients. We identified nine somatic mutations in 10 (8.06%) patients, especially in those with lymph node metastasis and intrahepatic metastasis. We also showed that messenger RNA and protein levels of MAP3K4 were significantly reduced in iCCA versus paired nontumor tissues. Furthermore, knockdown of MAP3K4 in cholangiocarcinoma cells markedly enhanced cell proliferation and invasiveness in vitro and tumor progression in vivo, accompanied by a typical EMT process. In contrast, overexpression of MAP3K4 in cholangiocarcinoma cells obviously reversed EMT and inhibited cell invasion. Mechanistically, MAP3K4 functioned as a negative regulator of EMT in iCCA by antagonizing the activity of the p38/nuclear factor κB/snail pathway. We found that the tumor-inhibitory effect of MAP3K4 was abolished by inactivating mutations. Clinically, a tissue microarray study containing 322 iCCA samples from patients revealed that low MAP3K4 expression in iCCA positively correlated with aggressive tumor characteristics, such as vascular invasion and intrahepatic or lymph node metastases, and was independently associated with poor survival and increased recurrence after curative surgery. CONCLUSIONS: MAP3K4, significantly down-regulated, frequently mutated, and potently regulating the EMT process in iCCA, was a putative tumor suppressor of iCCA.


Assuntos
Neoplasias dos Ductos Biliares/enzimologia , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/enzimologia , Colangiocarcinoma/patologia , Transição Epitelial-Mesenquimal , MAP Quinase Quinase Quinase 4/deficiência , Humanos , Invasividade Neoplásica
14.
Tumour Biol ; 36(11): 8413-24, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26022159

RESUMO

Robo1 is a member of the Robo immunoglobulin superfamily of proteins, and it plays an important role in angiogenesis and cancer. In this study, we investigate the role of roundabout 1 (Robo1) in tumor angiogenesis in hepatocellular carcinoma (HCC). Firstly, the relationship between Robo1 expression on tumors and patient's survival and endothelial cells in tumor blood vessels and patient's survival was studied. Secondly, Robo1 was overexpressed or knocked down in human umbilical vein endothelial cells (HUVECs). Cell proliferation, motility, and tube formation were compared in HUVEC with different Robo1 expression. Also, HUVECs with different Robo1 expression were mixed with HCCLM3 and HepG2 hepatoma cells and then implanted in a nude mouse model to examine the effects of Robo1 in endothelial cells on tumor growth and angiogenesis. Cell motility-related molecules were studied to investigate the potential mechanism how Robo1 promoted tumor angiogenesis in HCC. The disease-free survival of the patients with high Robo1 expression in tumoral endothelial cells was significantly shorter than that of those with low expression (P = 0.021). Overexpression of Robo1 in HUVECs resulted in increased proliferation, motility, and tube formation in vitro. In the implanted mixture of tumor cells and HUVECs with an increased Robo1 expression, tumor growth and microvessel density were enhanced compared with controls. Robo1 promoted cell division cycle 42 (Cdc42) expression in HUVECs, and a distorted actin cytoskeleton in HUVECs was observed when Robo1 expression was suppressed. In conclusion, Robo1 promoted angiogenesis in HCC mediated by Cdc42.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Neovascularização Patológica/genética , Proteínas do Tecido Nervoso/biossíntese , Receptores Imunológicos/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Animais , Carcinoma Hepatocelular/patologia , Movimento Celular/genética , Proliferação de Células/genética , Proteínas do Citoesqueleto , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Proteínas do Tecido Nervoso/genética , Receptores Imunológicos/genética , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas rho de Ligação ao GTP , Proteínas Roundabout
15.
Tumour Biol ; 36(4): 2763-71, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25480415

RESUMO

The loss of 5-hydroxymethylcytosine (5-hmC) has been identified as an epigenetic hallmark in several malignancies. However, its role in intrahepatic cholangiocarcinoma (ICC) is still unknown. Our study aims to investigate the level of 5-hmC in diagnosis and prognosis prediction of ICC. The 5-hmC levels were detected using dot blot, tissue microarray technique and immunohistochemical method, and the correlation between 5-hmC level and ICC clinicopathological parameters was analysed. Compared with matched liver tissues, most of ICC tissues presented with the loss of 5-hmC. Furthermore, the subgroups of cirrhotic and poor differentiation tissues showed the lowest level of 5-hmC. We found that 5-hmC level in non-elevated ICC patients was significantly related to lymph node metastasis and TNM stage and not related to vessel invasion, sex, age, HBV, cirrhosis or degree of differentiation. ICC patients with high TNM stage (stages III and IV) and lymph node metastases had significantly lower 5-hmC level than those with low TNM stage (stages I and II) and no lymph node metastases. Further analysis showed that low 5-hmC level is significantly correlated with worse overall survival (OS) and disease-free survival (DFS). Importantly, multivariate analysis indicated that 5-hmC level, tumour diameter, lymphatic metastasis and tumour differentiation could be used as independent prognostic factors for ICC. The loss of 5-hmC is implicated in the progression of ICC. Our results can contribute to the diagnostic ability and postoperative surveillance of ICC patients.


Assuntos
Neoplasias dos Ductos Biliares/diagnóstico , Colangiocarcinoma/diagnóstico , Citosina/análogos & derivados , Prognóstico , 5-Metilcitosina/análogos & derivados , Adolescente , Adulto , Idoso , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Citosina/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade
16.
J Low Genit Tract Dis ; 19(1): 46-54, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24914885

RESUMO

OBJECTIVE: The current study aimed to investigate the molecular basis of cervical cancer development using a microarray to identify the differentially expressed genes. This study also aimed to detect apoptosis genes and proteins to find those genes most aberrantly expressed in cervical cancer and to explore the cause of Uighur cervical cancer. METHODS: An analysis of gene expression profiles obtained from cervical cancer cases was performed. Total RNA was prepared from 10 samples of cervical carcinoma and normal cervix and was hybridized to Affymetrix oligonucleotide microarrays with probe sets complementary to more than 20,000 transcripts. Several genes of the apoptosis pathway, which were differentially regulated, included BCL2, BCLXL, and c-IAP1. These were validated by quantitative reverse transcription-polymerase chain reaction and immunohistochemical staining on an independent set of cancer and control specimens. RESULTS: Unsupervised hierarchical clustering of the expression data readily distinguished the normal cervix from cancer. Supervised analysis of gene expression data identified 1,326 and 1,432 genes that were upregulated and downregulated, respectively; a set of genes belonging to the apoptosis pathways were upregulated or downregulated in patients with cervical cancer. BCL2, BCLXL, and c-IAP1 were found to be upregulated in late-stage cancer compared to early-stage cancer. CONCLUSIONS: These findings provide a new understanding of the gene expression profile in cervical cancer. BCL2, BCLXL, and c-IAP1 might be involved in cancer progression. The pathway analysis of expression data showed that the BCL2, BCLXL, and c-IAP1 genes were coordinately differentially regulated between cancer and normal cases. Our results may serve as basis for further development of biomarkers for the diagnosis and treatment of cervical cancer.


Assuntos
Apoptose , Perfilação da Expressão Gênica , Neoplasias do Colo do Útero/patologia , Feminino , Humanos , Análise em Microsséries , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real
17.
MedComm (2020) ; 5(5): e550, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38645662

RESUMO

Three-dimensional (3D) echocardiography is an emerging technique for assessing right ventricular (RV) volume and function, but 3D-RV normal values from a large Chinese population are still lacking. The aim of the present study was to establish normal values of 3D-RV volume and function in healthy Chinese volunteers. A total of 1117 Han Chinese volunteers from 28 laboratories in 20 provinces of China were enrolled, and 3D-RV images of 747 volunteers with optimal image quality were ultimately analyzed by a core laboratory. Both vendor-dependent and vendor-independent software platforms were used to analyze the 3D-RV images. We found that men had larger RV volumes than women did in the whole population, even after indexing to body surface area, and older individuals had smaller RV volumes. The normal RV volume was significantly smaller than that recommended by the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines in both sexes. There were significant differences in 3D-RV measurements between the two vendor ultrasound systems and the different software platforms. The echocardiographic measurements in normal Chinese adults II study revealed normal 3D-RV volume and function in a large Chinese population, and there were significant differences between the sexes, ages, races, and vendor groups. Thus, normal 3D-RV values should be stratified by sex, age, race, and vendor.

18.
Angiogenesis ; 16(4): 809-20, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23716000

RESUMO

Antiangiogenic therapy, specially sorafenib, has become the standard of care for patients with advanced hepatocellular carcinoma (HCC), however, the improvement in survival time is not satisfactory. Previous studies have found that, in some circumstances, antiangiogenic therapy promoted tumor metastasis and the mechanistic studies were mainly focus on cancer-cell-autonomous manners. In two experimental metastasis models with tail-vein injection with hepatoma cells and an orthotopic HCC mouse model, we found that pretreatment with two vascular endothelial growth factor receptor (VEGFR) inhibitors, sunitinib and sorafenib, facilitated tumor cell survival in blood stream and promoted lung metastasis from tumors that were subsequently incubated after drug discontinuation, indicating that host response joined into the pro-metastatic effects. An antibody microarray identified that interleukin (IL)-12b was decreased in the peripheral blood of the mice treated with the two VEGFR inhibitors. IL-12b suppression in macrophages and dendritic cells from host organs was found to play a crucial role in treatment-induced metastasis. Supplement with recombinant mouse IL-12b or restoration of IL-12b expression in the host by zoledronic acid, which was previously reported to enhance IL-12 expression in vitro and in vivo, alleviated the metastasis-promoting effects of sunitinib and sorafenib. These studies suggest that host response to VEGFR inhibitors facilitates HCC metastasis and restoration of IL-12b expression could translate into clinical benefits.


Assuntos
Inibidores da Angiogênese/toxicidade , Carcinoma Hepatocelular/secundário , Indóis/toxicidade , Subunidade p40 da Interleucina-12/fisiologia , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/secundário , Niacinamida/análogos & derivados , Compostos de Fenilureia/toxicidade , Pirróis/toxicidade , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Animais , Carcinoma Hepatocelular/irrigação sanguínea , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Difosfonatos/uso terapêutico , Xenoenxertos , Humanos , Imidazóis/uso terapêutico , Terapia de Imunossupressão , Indóis/administração & dosagem , Indóis/farmacologia , Subunidade p40 da Interleucina-12/deficiência , Subunidade p40 da Interleucina-12/genética , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/irrigação sanguínea , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Transplante de Neoplasias , Células Neoplásicas Circulantes , Neovascularização Patológica/tratamento farmacológico , Niacinamida/administração & dosagem , Niacinamida/farmacologia , Niacinamida/toxicidade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacologia , Pirróis/administração & dosagem , Pirróis/farmacologia , Sorafenibe , Sunitinibe , Ácido Zoledrônico
19.
Ann Surg Oncol ; 20(3): 929-37, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23203407

RESUMO

BACKGROUND: Presurgery serum osteopontin (OPN) level has been demonstrated to correlate to tumor recurrence and survival of hepatocellular carcinoma (HCC) patients. This study investigated the postoperative dynamic changes of serum OPN level and its clinical significance in HCC patients. METHODS: Presurgery serum OPN levels were measured by enzyme-linked immunosorbent assay in cohort A of 179 HCC patients and were compared with the multiple controls including different kinds of liver diseases and healthy individuals. In cohort B of 110 patients with resectable HCCs, besides preoperative assays, serum OPN was monitored at 1 week, 1, and ≥2 months after operation. RESULTS: The baseline presurgery serum OPN of HCC patients was significantly higher than that of the patients with the other kinds of liver diseases (p < 0.0001). The prognostic values of presurgery serum OPN level in HCC patients were further confirmed. The postsurgery OPN levels were significantly elevated within 1 week after HCC resection, then decreased at 1 month and reached the nadir later than 2 months after operations. It increased again at the time of tumor recurrence, then declined after the second removal of recurrent HCCs. Moreover, postoperative OPN in α-fetoprotein-negative and -positive HCC patients had the same changing pattern; it only correlated to liver function and C-reactive protein level. CONCLUSIONS: After a transient fluctuation, serum OPN levels significantly decrease after curative resection of HCCs. Postoperative serum OPN could serve as a surrogate serologic biomarker for monitoring treatment response and tumor recurrence after HCC resection, including α-fetoprotein-negative ones.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/sangue , Hepatite B/sangue , Neoplasias Hepáticas/sangue , Recidiva Local de Neoplasia/diagnóstico , Osteopontina/sangue , Proteína C-Reativa/metabolismo , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Hepatectomia , Hepatite B/cirurgia , Hepatite B/virologia , Vírus da Hepatite B/patogenicidade , Humanos , Técnicas Imunoenzimáticas , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Estadiamento de Neoplasias , Período Pós-Operatório , Prognóstico , alfa-Fetoproteínas/metabolismo
20.
Medicine (Baltimore) ; 102(32): e34574, 2023 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-37565870

RESUMO

This study aimed to explore the safety and effectiveness of rehabilitation treatment for stroke patients with muscular call vein thrombosis (MCVT) in the lower limbs. A total of 173 patients were recruited with stroke complicated by MCVT, including 130 who received rehabilitation training and 43 who did not receive rehabilitation training. The t test and chi-square test were used to analyze the basic data of the 2 groups. There were no significant differences in the Fugl-Meyer Assessment scores between 2 groups at the beginning of recruitment (P = .149). There was a significant difference in the Fugl-Meyer Assessment scores of the lower limbs in patients with MCVT after 3 weeks of rehabilitation treatment (P < .001), and there was a significant difference in the rate of MCVT recanalization and extension between the 2 groups (χ2 = 11.646, P = 0001). Combined with anticoagulation therapy, rehabilitation training did not increase the thrombosis progression of MCVT and was effective in the recovery of lower limb motor function in stroke patients.


Assuntos
Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Trombose Venosa , Humanos , Extremidade Inferior , Trombose Venosa/complicações , Resultado do Tratamento , Recuperação de Função Fisiológica , Extremidade Superior
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