RESUMO
AIMS: This investigation aims to elucidate the mechanism underlying sorafenib-induced ferroptosis in hepatocellular carcinoma (HCC). METHODS: The role of dual specificity phosphatase 4 (DUSP4) in sorafenib-treated HCC was investigated using comprehensive assessments both in vitro and in vivo, including Western blotting, qRT-PCR, cell viability assay, lipid reactive oxygen species (ROS) assay, immunohistochemistry, and xenograft tumor mouse model. Additionally, label-free quantitative proteomics was employed to identify potential proteins associated with DUSP4. RESULTS: Our study revealed that suppression of DUSP4 expression heightens the susceptibility of HCC cells to ferroptosis inducers, specifically sorafenib and erastin, in both in vitro and in vivo settings. Furthermore, we identified DUSP4-mediated regulation of key ferroptosis-related markers, such as ferritin light chain (FTL) and ferritin heavy chain 1 (FTH1). Notably, label-free quantitative proteomics unveiled the phosphorylation of threonine residue T148 on YTH Domain Containing 1 (YTHDC1) by DUSP4. Further investigations unraveled that YTHDC1, functioning as an mRNA nuclear export regulator, is a direct target of DUSP4, orchestrating the subcellular localization of FTL and FTH1 mRNAs. Significantly, our study highlights a strong correlation between elevated DUSP4 expression and sorafenib resistance in HCC. CONCLUSIONS: Our findings introduce DUSP4 as a negative regulator of sorafenib-induced ferroptosis. This discovery opens new avenues for the development of ferroptosis-based therapeutic strategies tailored for HCC treatment.
Assuntos
Carcinoma Hepatocelular , Fosfatases de Especificidade Dupla , Ferroptose , Neoplasias Hepáticas , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Ferroptose/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Monoéster Fosfórico Hidrolases/uso terapêutico , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Fosfatases de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/metabolismo , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismoRESUMO
BACKGROUND: Data on nail psoriasis (PsO) in China are scarce. OBJECTIVES: To provide nail PsO-related data regarding epidemiologic characteristics, manifestations, fungal infections, arthritic complaints and treatments that may facilitate improved patient management globally. METHODS: From August 2021 to August 2022, patients with nail PsO were enrolled in a prospective multicentre observational study at 25 hospitals in China. We collected and analysed data concerning nail PsO demography, clinical signs, fungal detection, arthritic symptoms and treatment. RESULTS: A total of 817 patients with nail PsO were involved, with a mean body mass index of 24.13 ± 2.93. In addition, 71.41% of the patients were male. The Nail PsO Severity Index score was weakly positively correlated with body surface area. The percentage of nail involvement was 95.29% for fingernails and 57.18% for toenails, with pitting (67.11%) and subungual hyperkeratosis (60.40%) being the most prevalent manifestations, respectively. Toenails showed a significantly higher frequency of nailfold scales, subungual hyperkeratosis and nail plate crumbling and a lower frequency of splinter haemorrhages, pitting and erythema of the lunula. A total of 13.26% of the PsO patients had onychomycosis, and 77.08% were observed in the toenails. Articular symptoms were reported by 12.17% of the patients, with the peripheral type being predominant. Significant associations between articular symptoms and nailfold swelling, subungual hyperkeratosis, nailfold scales, onycholysis and longitudinal ridges were found. Only 2.30% (20 out of 871) of patients with nail PsO received treatment. The most frequently employed therapy for cutaneous PsO with nail involvement was biologic therapy (n = 366). CONCLUSIONS: PsO showed distinct manifestations in the toenails and fingernails. Additionally, toenail PsO combined with onychomycosis requires special attention. Articular symptoms in psoriatic patients are associated with specific nail changes. It is important to research and advocate for more potent treatments for nail PsO.
Assuntos
Doenças da Unha , Onicomicose , Psoríase , Humanos , Masculino , Feminino , Onicomicose/diagnóstico , Estudos Prospectivos , Doenças da Unha/diagnóstico , Psoríase/epidemiologia , Psoríase/terapia , Psoríase/complicações , China/epidemiologiaRESUMO
BACKGROUND: In this prospective study, we aimed to investigate the role of patient-reported dysphagia relief in predicting pathological tumor responses to neoadjuvant immunochemotherapy (NAIC) in locally advanced esophageal squamous cell carcinoma (ESCC) patients. METHODS: This study was designed as a multi-center, prospective study including ESCC patients who received NAIC in the discovery and validation cohorts. The patients' responses to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-OES 18 and QLQ-C30 were collected at multiple time points. Subsequent time point-intensive esophageal cancer-specific dysphagia trajectories were depicted using growth mixture modeling (GMM) analysis. Furthermore, univariate and multivariate binary logistic regression was used to assess the independent predictors for pathological tumor responses. RESULTS: A total of 120 patients from the discovery cohort and 42 patients from the validation cohort were included in the analysis. In the discovery cohort, 19 (22.9%) of the 83 patients achieved pCR status. In the independent validation cohort, 24 patients underwent surgery, and 9 (37.5%) patients achieved pCR status. Trajectory analysis showed that, in the pCR group, the beginning of rapid declines in the slope occurred on days 3, 6, and 9. Further multivariate analysis showed that the degree of dysphagia relief (â³dysphagia%) was the only significant independent predictor for pCR status (OR = 3.267, 95% CI 1.66-6.428, P < 0.001). The AUC value for â³dysphagia% was 0.961 (95% CI: 0.922-0.999, P < 0.001). CONCLUSION: The current study demonstrated that a longitudinal patient-reported outcome (PRO) was an easily obtained, cost-effective, and noninvasive tool for predicting tumor responses to neoadjuvant immunochemotherapy.
Assuntos
Transtornos de Deglutição , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/patologia , Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patologia , Estudos Prospectivos , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/terapia , Qualidade de Vida , Resultado do Tratamento , Terapia NeoadjuvanteRESUMO
OBJECTIVE: To construct a new pulmonary nodule diagnostic model with high diagnostic efficiency, non-invasive and simple to measure. METHODS: This study included 424 patients with radioactive pulmonary nodules who underwent preoperative 7-autoantibody (7-AAB) panel testing, CT-based AI diagnosis, and pathological diagnosis by surgical resection. The patients were randomly divided into a training set (n = 212) and a validation set (n = 212). The nomogram was developed through forward stepwise logistic regression based on the predictive factors identified by univariate and multivariate analyses in the training set and was verified internally in the verification set. RESULTS: A diagnostic nomogram was constructed based on the statistically significant variables of age as well as CT-based AI diagnostic, 7-AAB panel, and CEA test results. In the validation set, the sensitivity, specificity, positive predictive value, and AUC were 82.29%, 90.48%, 97.24%, and 0.899 (95%[CI], 0.851-0.936), respectively. The nomogram showed significantly higher sensitivity than the 7-AAB panel test result (82.29% vs. 35.88%, p < 0.001) and CEA (82.29% vs. 18.82%, p < 0.001); it also had a significantly higher specificity than AI diagnosis (90.48% vs. 69.04%, p = 0.022). For lesions with a diameter of ≤ 2 cm, the specificity of the Nomogram was higher than that of the AI diagnostic system (90.00% vs. 67.50%, p = 0.022). CONCLUSIONS: Based on the combination of a 7-AAB panel, an AI diagnostic system, and other clinical features, our Nomogram demonstrated good diagnostic performance in distinguishing lung nodules, especially those with ≤ 2 cm diameters. KEY POINTS: ⢠A novel diagnostic model of lung nodules was constructed by combining high-specific tumor markers with a high-sensitivity artificial intelligence diagnostic system. ⢠The diagnostic model has good diagnostic performance in distinguishing malignant and benign pulmonary nodules, especially for nodules smaller than 2 cm. ⢠The diagnostic model can assist the clinical decision-making of pulmonary nodules, with the advantages of high diagnostic efficiency, noninvasive, and simple measurement.
Assuntos
Neoplasias Pulmonares , Nódulos Pulmonares Múltiplos , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgia , Inteligência Artificial , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Nódulos Pulmonares Múltiplos/cirurgia , Autoanticorpos , Tomografia Computadorizada por Raios X/métodos , Estudos RetrospectivosRESUMO
Translational reprogramming is part of the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress, which acts to the advantage of cancer growth and development in different stress conditions, but the mechanism of ER stress-related translational reprogramming in colorectal carcinoma (CRC) progression remains unclear. Here, we identified that Krüppel-like factor 16 (KLF16) can promote CRC progression and stress tolerance through translational reprogramming. The expression of KLF16 was upregulated in CRC tissues and associated with poor prognosis for CRC patients. We found that ER stress inducers can recruit KLF16 to the nucleolus and increase its interaction with two essential proteins for nucleolar homeostasis: nucleophosmin1 (NPM1) and fibrillarin (FBL). Moreover, knockdown of KLF16 can dysregulate nucleolar homeostasis in CRC cells. Translation-reporter system and polysome profiling assays further showed that KLF16 can effectively promote cap-independent translation of ATF4, which can enhance ER-phagy and the proliferation of CRC cells. Overall, our study unveils a previously unrecognized role for KLF16 as an ER stress regulator through mediating translational reprogramming to enhance the stress tolerance of CRC cells and provides a potential therapeutic vulnerability.
Assuntos
Neoplasias Colorretais , Fatores de Transcrição Kruppel-Like , Resposta a Proteínas não Dobradas , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Estresse do Retículo Endoplasmático/genética , Homeostase , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismoRESUMO
Previous reports have confirmed that saponins (ginsenosides) derived from Panax ginseng. C. A. Meyer exerted obvious memory-enhancing and antiaging effects, and the simpler the structure of ginsenosides, the better the biological activity. In this work, we aimed to explore the therapeutic effect and underlying molecular mechanism of 20(S)-protopanaxatriol (PPT), the aglycone of panaxatriol-type ginsenosides, by establishing D-galactose (D-gal)-induced subacute brain aging model in mice. The results showed that PPT treatment (10 and 20 mg/kg) for 4 weeks could significantly restore the D-gal (800 mg/kg for 8 weeks)-induced impaired memory function, choline dysfunction, and redox system imbalance in mice. Meanwhile, PPT also significantly reduced the histopathological changes caused by D-gal exposure. Moreover, PPT could increase TFEB/LAMP2 protein expression to promote mitochondrial autophagic flow. Importantly, the results from molecular docking showed that PPT had good binding ability with LAMP2 and TFEB, suggesting that TFEB/LAMP2 might play an important role in PPT to alleviate D-gal-caused brain aging.
Assuntos
Ginsenosídeos , Panax , Camundongos , Animais , Ginsenosídeos/farmacologia , Galactose/efeitos adversos , Simulação de Acoplamento Molecular , Envelhecimento , Encéfalo/metabolismo , Panax/químicaRESUMO
BACKGROUND: Circular RNAs (circRNAs) regulate various biological activities and have been shown to play crucial roles in hepatocellular carcinoma (HCC) progression. However, only a few coding circRNAs have been identified in cancers, and their roles in HCC remain elusive. This study aimed to identify coding circRNAs and explore their function in HCC. METHODS: CircMAP3K4 was selected from the CIRCpedia database. We performed a series of experiments to determine the characteristics and coding capacity of circMAP3K4. We then used in vivo and in vitro assays to investigate the biological function and mechanism of circMAP3K4 and its protein product, circMAP3K4-455aa, in HCC. RESULTS: We found circMAP3K4 to be an upregulated circRNA with coding potential in HCC. IGF2BP1 recognized the circMAP3K4 N6-methyladenosine modification and promoted its translation into circMAP3K4-455aa. Functionally, circMAP3K4-455aa prevented cisplatin-induced apoptosis in HCC cells by interacting with AIF, thus protecting AIF from cleavage and decreasing its nuclear distribution. Moreover, circMAP3K4-455aa was degraded through the ubiquitin-proteasome E3 ligase MIB1 pathway. Clinically, a high level of circMAP3K4 is an independent prognostic factor for adverse overall survival and adverse disease-free survival of HCC patients. CONCLUSIONS: CircMAP3K4 is a highly expressed circRNA in HCC. Driven by m6A modification, circMAP3K4 encoded circMAP3K4-455aa, protected HCC cells from cisplatin exposure, and predicted worse prognosis of HCC patients. Targeting circMAP3K4-455aa may provide a new therapeutic strategy for HCC patients, especially for those with chemoresistance. CircMAP3K4 is a highly expressed circRNA in HCC. Driven by m6A modification, IGF2BP1 facilitates circMAP3K4 peptide translation, then the circMAP3K4 peptide inhibits AIF cleavage and nuclear distribution, preventing HCC cells from cell death under stress and promoting HCC progression.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Adenosina/análogos & derivados , Apoptose , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/patologia , PeptídeosRESUMO
Pathogenic dental plaque biofilms are universal and harmful, which can result in oral infections and systemic diseases. Many conventional therapeutic methods have proven insufficient or ineffective against plaque biofilms. Therefore, new strategies are urgently needed. Fusobacterium nucleatum (F. nucleatum), a periodontal pathogen associated with a variety of oral and systemic diseases, is thought to be central to the development and structure of dental plaques. Here, ultra-small gold nanoclusters (AuNCs) were prepared. They exhibited potent antibacterial activity against F. nucleatum through enhanced destruction of bacterial membranes and generation of reactive oxygen species. Furthermore, due to their excellent penetration, the AuNCs could inhibit biofilm formation and destroy mature biofilms in vitro. Their antibiofilm efficacy was further confirmed in a mouse model, where they reduced biofilm accumulation and ameliorated inflammation. Meanwhile, the disruption of oral and gut microbiota caused by colonization of oral F. nucleatum could be partially restored through AuNCs treatment. Therefore, AuNCs could be considered as promising antibiofilm agents and have great potential in the clinical treatment of dental plaque.
Assuntos
Placa Dentária , Fusobacterium nucleatum , Animais , Camundongos , Ouro/farmacologia , Placa Dentária/tratamento farmacológico , Biofilmes , Antibacterianos/farmacologiaRESUMO
BACKGROUND: Lysophosphatidic acid (LPA) and its receptors play a key role in regulating cancer progression. Upregulation of LPA receptor 2 (LPAR2) plays a role in carcinogenesis; however, the exact role of LPAR2 in tumors remains elusive. This study aims to explore the correlation between LPAR2 expression with tumor prognosis and immune infiltration in pan-cancers. MATERIALS AND METHODS: The expression of LPAR2 in pan-cancers was analyzed using the Online Cancer Microarray Database (Oncomine), Tumor Immune Estimation Resource (TIMER), and UALCAN databases. The effects of LPAR2 on the clinical prognosis in pan-cancer were examined using the Kaplan-Meier plotter (KM plotter) as well as Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, and Human Protein Atlas (HPA) databases. Moreover, the R software program was applied for validation of expression and prognostic value of LPAR2 in tumor patients in the Cancer Genome Atlas (TCGA) dataset and the Gene Expression Omnibus (GEO) database. The relationship between the expression level of LPAR2 and the clinical and molecular criteria of head and neck squamous cell carcinoma (HNSC) and kidney renal clear cell carcinoma (KIRC) was analyzed using UALCAN, whereas the relationship between LPAR2 expression and prognosis in patients with HNSC and KIRC with different clinical characteristics was examined using the KM plotter. Furthermore, the correlation between LPAR2 expression and tumor immune infiltration was examined using TIMER. The correlation between LPAR2 expression and gene markers of tumor immune infiltrates was analyzed using TIMER and GEPIA. In addition, the cBioPortal for Cancer Genomics was used to calculate the mutations, methylations, and altered neighbor genes of LPAR2. RESULTS: The expression of LPAR2 was significantly correlated with the outcome of multiple types of cancer, especially HNSC and KIRC. Furthermore, high expression of LPAR2 was significantly associated with various immune markers in the immune cell subsets of HNSC and KIRC. CONCLUSIONS: High expression of LPAR2 plays significantly different prognostic roles in HNSC and KIRC possibly owing to its association with different immune markers. LPAR2 is correlated with tumor immune cell infiltration and is a valuable prognostic biomarker for HNSC and KIRC. However, further experiments are required to validate these findings.
Assuntos
Carcinoma de Células Renais , Neoplasias de Cabeça e Pescoço , Neoplasias Renais , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Humanos , Rim/metabolismo , Rim/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Prognóstico , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/genéticaRESUMO
Clinically, patients with urothelial carcinoma of the bladder (UCB) with tumor metastasis are incurable. To find new therapeutic strategies, the mechanisms underlying UCB invasion and metastasis should be further investigated. In this study, zinc finger and homeobox 3 (ZHX3) was first screened as a critical oncogenic factor associated with poor prognosis in a UCB dataset from The Cancer Genome Atlas (TCGA). These results were also confirmed in a large cohort of clinical UCB clinical samples. Next, we found that ZHX3 could promote the migration and invasion capacities of UCB cells both in vitro and in vivo. Mechanistically, coimmunoprecipitation (coIP) and mass spectrometry (MS) analysis indicated that ZHX3 was a target of tripartite motif 21 (TRIM21), which mediates its ubiquitination, and subsequent degradation. Notably, RNA-seq analysis showed that ZHX3 repressed the expression of regulator of G protein signaling 2 (RGS2). Generally, our results suggest that ZHX3 plays an oncogenic role in UCB pathogenesis and might serve as a novel therapeutic target for UCB.
Assuntos
Carcinoma de Células de Transição/metabolismo , Proteínas de Homeodomínio/metabolismo , Proteínas RGS/metabolismo , Proteínas Repressoras/metabolismo , Ribonucleoproteínas/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Animais , Carcinoma de Células de Transição/etiologia , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/secundário , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Regulação para Baixo , Feminino , Proteínas de Homeodomínio/genética , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , Prognóstico , Proteínas RGS/genética , RNA Interferente Pequeno , Proteínas Repressoras/genética , Ubiquitinação , Regulação para Cima , Neoplasias da Bexiga Urinária/etiologia , Neoplasias da Bexiga Urinária/patologia , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
BACKGROUND: Plasma cell-free DNA (cfDNA) methylation has shown promising results in the early detection of multiple cancers recently. Here, we conducted a study to investigate the performance of cfDNA methylation in the early detection of esophageal cancer (ESCA). METHODS: Specific methylation markers for ESCA were identified and optimized based on esophageal tumor and paired adjacent tissues (n = 24). Age-matched participants with ESCA (n = 85), benign esophageal diseases (n = 10), and healthy controls (n = 125) were randomized into the training and test sets to develop a classifier to differentiate ESCA from healthy controls and benign esophageal disease. The classifier was further validated in an independent plasma cohort of ESCA patients (n = 83) and healthy controls (n = 98). RESULTS: In total, 921 differentially methylated regions (DMRs) between tumor and adjacent tissues were identified. The early detection classifier based on those DMRs was first developed and tested in plasma samples, discriminating ESCA patients from benign and healthy controls with a sensitivity of 76.2% (60.5-87.9%) and a specificity of 94.1% (85.7-98.4%) in the test set. The performance of the classifier was consistent irrespective of sex, age, and pathological diagnosis (P > 0.05). In the independent plasma validation cohort, similar performance was observed with a sensitivity of 74.7% (64.0-83.6%) and a specificity of 95.9% (89.9-98.9%). Sensitivity for stage 0-II was 58.8% (44.2-72.4%). CONCLUSION: We demonstrated that the cfDNA methylation patterns could distinguish ESCAs from healthy individuals and benign esophageal diseases with promising sensitivity and specificity. Further prospective evaluation of the classifier in the early detection of ESCAs in high-risk individuals is warranted.
Assuntos
Ácidos Nucleicos Livres , Neoplasias Esofágicas , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Metilação de DNA , Detecção Precoce de Câncer , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/genética , HumanosRESUMO
BACKGROUND: Metastasis causes the vast majority of colorectal carcinoma (CRC)-related deaths. However, little is known about the specific traits and underlying mechanisms of metastasis-initiating cells in primary CRC. And whether or not circular RNAs (circRNAs) take part in this particular event remain not adequately stated yet. METHODS: A screening method based on Transwell assay was first applied to build CRC subgroups with different metastatic potential. High throughput RNA sequencing was used to find out novel metastatic drivers in CRC metastasis-initiating step. A series of in vitro and in vivo assays were further applied to elucidate the functions and underlying molecular mechanisms of circRNAs in CRC metastasis. RESULTS: A circRNA consisting of exon 8-11 of LONP2, termed as circLONP2, was upregulated in metastasis-initiating CRC subgroups. Aberrant higher expression of circLONP2 was observed in primary CRC tissues with established metastasis, and along the invasive margin in metastatic site. High expression of circLONP2 predicted unfavorable overall survival. Functional studies revealed that circLONP2 could enhance the invasiveness of CRC cells in vitro, and targeting circLONP2 through anti-sense oligonucleotide (ASO) dramatically reduced the penetrance of metastasis to foreign organs in vivo. Mechanically, circLONP2 directly interacted with and promoted the processing of primary microRNA-17 (pri-miR-17), through recruiting DiGeorge syndrome critical region gene 8 (DGCR8) and Drosha complex in DDX1-dependent manner. Meanwhile, upregulated mature miR-17-5p could be assembled into exosomes and internalized by neighboring cells to enhance their aggressiveness. CONCLUSIONS: Our data indicate that circLONP2 acts as key metastasis-initiating molecule during CRC progression through modulating the intracellular maturation and intercellular transfer of miR-17, resulting in dissemination of metastasis-initiating ability in primary site and acceleration of metastasis formation in foreign organs. circLONP2 could serve as an effective prognostic predictor and/or novel anti-metastasis therapeutic target in CRC treatment.
Assuntos
Neoplasias Colorretais/patologia , RNA Helicases DEAD-box/metabolismo , Exossomos/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/secundário , MicroRNAs/genética , RNA Circular/genética , Proteases Dependentes de ATP/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , RNA Helicases DEAD-box/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Nus , Invasividade Neoplásica , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Glucose-6-phosphate dehydrogenase (G6PD) deficiency has been revealed to be involved in the efficacy to anti-cancer therapy but the mechanism remains unclear. We aimed to investigate the anti-cancer mechanism of G6PD deficiency. In our study, dehydroepiandrosterone (DHEA) and shRNA technology were used for inhibiting the activity of G6PD of cervical cancer cells. Peak Force QNM Atomic Force Microscopy was used to assess the changes of topography and biomechanical properties of cells and detect the effects on living cells in a natural aqueous environment. Flow cytometry was used to detect the apoptosis and reactive oxygen species (ROS) generation. Scanning electron microscopy was used to observe cell morphology. Moreover, a laser scanning confocal microscope was used to observe the alterations in cytoskeleton to explore the involved mechanism. When G6PD was inhibited by DHEA or RNA interference, the abnormal Young's modulus and increased roughness of cell membrane were observed in HeLa cells, as well as the idioblasts. Simultaneously, G6PD deficiency resulted in decreased HeLa cells migration and proliferation ability but increased ROS generation inducing apoptosis. What's more, the inhibition of G6PD activity caused the disorganization of microfilaments and microtubules of cytoskeletons and cell shrinkage. Our results indicated the anti-cervix cancer mechanism of G6PD deficiency may be involved with the decreased cancer cells migration and proliferation ability as a result of abnormal reorganization of cell cytoskeleton and abnormal biomechanical properties caused by the increased ROS. Suppression of G6PD may be a promising strategy in developing novel therapeutic methods for cervical cancer.
Assuntos
Glucosefosfato Desidrogenase/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Neoplasias do Colo do Útero/enzimologia , Neoplasias do Colo do Útero/patologia , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Apoptose/efeitos dos fármacos , Fenômenos Biomecânicos/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Desidroepiandrosterona/farmacologia , Módulo de Elasticidade , Inibidores Enzimáticos/farmacologia , Feminino , Técnicas de Silenciamento de Genes , Inativação Gênica/efeitos dos fármacos , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Células HeLa , Humanos , Imageamento Tridimensional , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Plasmídeos/metabolismo , Pseudópodes/efeitos dos fármacos , Pseudópodes/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , TransfecçãoRESUMO
Chromobox homolog 8 (CBX8), also known as human polycomb 8, is a repressor that maintains the transcriptionally repressive state in various cellular genes, and has been reported to promote tumorigenesis. In the present study, we examined CBX8 expression in eight pairs of muscle invasive bladder cancer tissues and adjacent non-tumor tissues, and found that CBX8 was frequently upregulated in muscle invasive bladder cancer tissues when compared to adjacent non-tumor tissues. Analysis showed that high expression of CBX8 in 152 muscle invasive bladder cancer specimens was associated with progression of the T, N, and M stages (P = 0.004, 0.005, <0.001, respectively). Furthermore, Kaplan-Meier survival analysis and log-rank test showed that muscle invasive bladder cancer patients with high CBX8 expression had a poor rate of overall survival (P < 0.001) and 5-year recurrence-free survival (P < 0.001) compared to patients with low CBX8 expression. High CBX8 expression predicted poor overall survival and 5-year recurrence-free survival in T and N stages of muscle invasive bladder cancer patients. Moreover, knockdown of CBX8 inhibited cell proliferation of urothelial carcinoma of the bladder both in vitro and in vivo. In addition, CBX8 depletion resulted in cell cycle delay of urothelial carcinoma cells of the bladder at the G2/M phase by the p53 pathway. The data suggest that high expression of CBX8 plays a critical oncogenic role in aggressiveness of urothelial carcinoma cells of the bladder through promoting cancer cell proliferation by repressing the p53 pathway, and CBX8 could be used as a novel predictor for muscle invasive bladder cancer patients.
Assuntos
Neoplasias Musculares/genética , Complexo Repressor Polycomb 1/genética , Proteína Supressora de Tumor p53/genética , Neoplasias da Bexiga Urinária/genética , Idoso , Animais , Apoptose/genética , Carcinogênese/genética , Proliferação de Células/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasias Musculares/patologia , Neoplasias Musculares/secundário , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND This study aimed to investigate the role of miR-184 in the proliferation and apoptosis of keratinocyte (HaCaT cells). MATERIAL AND METHODS HaCaT cells were cultured in a growth medium. The miR-184 was transfected with siRNA, then cell viability and apoptosis were assayed by MTT and flow cytometry, respectively. The colony-forming efficacy of HaCaT cells were detected as well. mRNA expressions of basic fibroblast growth factor (bFGF) and transforming growth factor (TGF)-ß1 were measured with RT-PCR. The expressions of apoptosis-related proteins caspase-3 and Bcl-x in HaCaT cells were determined by Western blot. RESULTS After miR-184 was transfected with siRNA, cell viability and colony forming ability decreased significantly, and apoptosis was significantly increased. The expressions of growth factors TGF-ß1 and bFGF mRNAs, as well as apoptosis-related proteins Bcl-x, in HaCaT cells declined significantly after miR-184 was transfected with siRNA. In addition, the expression of pro-apoptotic protein caspase-3 increased significantly. CONCLUSIONS Our results suggest distinct roles of miR-184 during the growth, proliferation, and apoptosis of keratinocytes.
Assuntos
Queratinócitos/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismo , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/metabolismo , Caspase 3/metabolismo , Linhagem Celular , Proliferação de Células/genética , Sobrevivência Celular/genética , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Transfecção , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
OBJECTIVE: We have reported "heat-sensitization" responses during suspended moxibustion, whose occurrence is associated with significantly better therapeutic effects. The present study aimed to characterize the electrophysiological features of this interesting phenomenon with high-density electroencephalography (EEG). METHODS: We performed EEG recording in a group of patients with chronic low back pain before, during, and after moxibustion treatment at DU3. RESULTS: 12 out of 25 subjects experienced strong heat-sensitization during moxibustion, which was accompanied by increased power spectral densities (PSDs) at the theta, alpha, and beta frequency bands. The scalp topographies of averaged power indicated that the theta and beta PSD changes were most obvious in fronto-central regions, whereas those of the alpha band were more global. In addition, nonsensitized and sensitized groups showed distinct activity patterns, with heat-sensitization inducing increased phase coherence at the theta and beta ranges. CONCLUSIONS: These data were the first objective evidence of heat-sensitization responses during suspended moxibustion, which were characterized by widespread oscillatory changes in scalp EEG.
Assuntos
Encéfalo/fisiologia , Temperatura Alta , Dor Lombar/terapia , Moxibustão/métodos , Sensação/fisiologia , Adulto , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To systematically evaluate the effectiveness and safety of heat-sensitive moxibustion (HSM) on asthma. METHODS: Large databases in China and overseas were searched by electronic and manual means to collect information on randomized controlled trials (RCTs). Two evaluators independently extracted data and evaluated the quality of RCTs according to Cochrane Review Handbook v5.0. RevMan v5.0.20 was used for statistical analyses. RESULTS: Fourteen RCTs involving 637 patients were collected. Thirteen RCTs compared the effects of HSM and Western Medicine. After 3-month treatment and after 6-month follow-up, there was no significant difference in effective rate [relative risk (RR) = 1.01, 95% CI (0.92, 1.12), and 1.12, (0-93, 1.36), respectively], in the asthma control test score of asthma symptoms [weighted mean difference (WMD) = - 1.54, 95% CI (- 3.54, 0.47), and 1.41, (- 0.48, 3.29), respectively] and in the forced expiratory volume in 1 second (FEV1) and peak expiratory flow (PEF). One RCT compared the effect of HSM with warm-suspended moxibustion. After 6-month follow-up, there was a significant difference in FEV1 and PEF [WMD = 0.51, 95% CI (0.10, 0.92), and 1.78, (1.06, 2.50), respectively]. After 3-month treatment, there was no significant difference between the two groups. One RCT compared the effect of HSM with acupoint application. After 3-month treatment, there was no significant difference in the effective rate [RR = 0.68, 95% CI (0.42, 1.12)]. CONCLUSION: HSM did not show superiority to conventional Western Medicine and acupoint application in terms of curative effects, and may be superior to warm-suspended moxibustion with regard to long-term curative effects. Because of low quality of the included RCTs, this conclusion must be bolstered with higher-quality RCTs.