RESUMO
Malnutrition is prevalent among patients with nasopharyngeal carcinoma undergoing radiotherapy. This study examined the nutritional status and incidence of radiation-induced oral mucositis (RIOM) in patients with nasopharyngeal carcinoma. A retrospective analysis was conducted to compare the incidence of RIOM, Nutritional Risk Screening (NRS) 2002 score, weight, body mass index (BMI), and hemoglobin levels in 338 patients treated with induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) or treated with CCRT alone. The IC + CCRT group exhibited an increase in weight and BMI but a decrease in hemoglobin levels after IC compared with baseline (p < 0.001). Both groups showed differences in weight at Week 0 and BMI at Weeks 0-2 of radiotherapy (p < 0.05). The IC + CCRT group experienced an increase in NRS 2002 scores from Week 2 to Week 6 (p < 0.05). The hemoglobin levels of the IC + CCRT group were consistently lower throughout radiotherapy (p < 0.001). However, no significant difference was observed in the incidence of RIOM between the two groups (p = 0.246). Patients treated with IC + CCRT exhibited a higher nutritional risk during radiotherapy. Although the incidence of Grade III RIOM was high, no significant difference was found between the groups.
Assuntos
Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/tratamento farmacológico , Estudos Retrospectivos , Estado Nutricional , Incidência , Quimiorradioterapia/efeitos adversos , Hemoglobinas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have demonstrated the ability to impede tumor cell proliferation by suppressing EGFR expression. Nonetheless, patients undergoing treatment may acquire resistance, which may occur through an EGFR-dependent (such as T790M mutation) or an EGFR-independent (such as c-Met amplification) manner. Therefore, developing dual-target inhibitors might present a potential avenue for addressing treatment-acquired resistance in patients. Herein, we designed, synthesized, and screened several novel 4-phenoxyquinazoline derivatives, aiming to identify a potent dual EGFR/c-Met inhibitor for the treatment of NSCLC, among which H-22 emerged as the most promising candidate exhibiting significant antitumor properties. Moreover, we assessed the in vitro inhibitory effect of H-22 on EGFR kinase and c-Met kinase in five cancer cell lines. In addition, a series of functional experiments (cell cycle, apoptosis assays, in vitro/in vivo animal model, etc.) were conducted to further investigate the anti-tumor mechanisms of H-22. The present study revealed that H-22 exhibited strong antitumor activity both in vitro and in vivo. Interestingly, H-22 exhibited anti-proliferative activity (2.27-3.35 µM) similar to Afatinib against all five cancer cells, with inhibitory functions against EGFRWT, EGFRL858R/T790M, and c-Met kinases at a concentration of 64.8, 305.4 and 137.4 nM, respectively. Cell cycle analysis indicated that the antiproliferative activity of H-22 was associated with its ability to cause G2/M arrest. Furthermore, in vivo data showed that H-22 could inhibit tumor growth in our xenograft models and induce apoptosis. Collectively, our findings uncovered that H-22 is a novel dual EGFR and c-Met inhibitor and a prospective anti-tumor therapeutic drug.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Humanos , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Receptores ErbB , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases , Apoptose , Resistencia a Medicamentos Antineoplásicos , Mutação , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de CélulasRESUMO
Many patients with non-small cell lung cancer (NSCLC) initially benefit from epidermal growth factor receptor (EGFR) targeted therapy. Unfortunately, varying degrees of resistance or side effects eventually develop. Overcoming and preventing the resistance and side effects of EGFR inhibitors has become a hot topic of research today. Based on the previous studies on AZD-9291, we designed and synthesized two series of 2,4-dichloro-6-methylpyrimidine derivatives, 19 compounds in total, as potential inhibitors of the EGFR kinase. The most promising compound, L-18, showed better inhibitory activity (81.9%) and selectivity against EGFRT790M/L858R kinase. In addition, L-18 showed strong antiproliferative activity against H1975 cells with an IC50 value of 0.65 ± 0.06 µM and no toxicity to normal cells (LO-2). L-18 was able to dose-dependently induce the apoptosis of H1975 cells and produced a cell-cycle-blocking effect, and it can also dose-dependently inhibit the migration and invasion of H1975 cells. L-18 also showed in vivo anticancer efficacy in H1975 cells xenograft mice. We also performed a series of in vivo and in vitro toxicological evaluations of compound L-18, which did not cause obvious injury in mice during administration. These results suggest that L-18 may be a promising drug candidate that warrants further investigation.
Assuntos
Antineoplásicos , Apoptose , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Receptores ErbB , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Pirimidinas , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Pirimidinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Apoptose/efeitos dos fármacos , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Estrutura Molecular , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB CRESUMO
BACKGROUND: Radiotherapy (RT) is the standard treatment for nasopharyngeal carcinoma (NPC). However, due to individual differences in radiosensitivity, biomarkers are needed to tailored radiotherapy to cancer patients. However, comprehensive genome-wide radiogenomic studies on them are still lacking. The aim of this study was to identify genetic variants associated with radiotherapy response in patients with NPC. METHODS: This was a largescale genome-wide association analysis (GWAS) including a total of 981 patients. 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant loci were further genotyped using MassARRAY system and TaqMan SNP assays in the validation stages of 847 patients. This study used logistic regression analysis and multiple bioinformatics tools such as PLINK, LocusZoom, LDBlockShow, GTEx, Pancan-meQTL and FUMA to examine genetic variants associated with radiotherapy efficacy in NPC. RESULTS: After genome-wide level analysis, 19 SNPs entered the validation stage (P < 1 × 10- 6), and rs11130424 ultimately showed statistical significance among these SNPs. The efficacy was better in minor allele carriers of rs11130424 than in major allele carriers. Further stratified analysis showed that the association existed in patients in the EBV-positive, smoking, and late-stage (III and IV) subgroups and in patients who underwent both concurrent chemoradiotherapy and induction/adjuvant chemotherapy. CONCLUSION: Our study showed that rs11130424 in the CACNA2D3 gene was associated with sensitivity to radiotherapy in NPC patients. TRIAL REGISTRATION NUMBER: Effect of genetic polymorphism on nasopharyngeal carcinoma chemoradiotherapy reaction, ChiCTR-OPC-14005257, Registered 18 September 2014, http://www.chictr.org.cn/showproj.aspx?proj=9546 .
Assuntos
Canais de Cálcio , Estudo de Associação Genômica Ampla , Neoplasias Nasofaríngeas , Humanos , Quimiorradioterapia , Variação Genética , Genótipo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Canais de Cálcio/genéticaRESUMO
OBJECTIVE: Chronic cerebral hypoperfusion (CCH) can cause a series of pathophysiological processes, including neuronal autophagy and apoptosis. VEGF-A has been reported to affect angiogenesis and neurogenesis in many CNS diseases. However, its effects on neuronal autophagy and apoptosis, as well as the underlying mechanisms in CCH remain unclear. METHODS: To address these issues, the CCH model was established by permanent bilateral common carotid artery occlusion (2VO). Rats were sacrificed at different stages of CCH. Hippocampal morphological and ultrastructural changes were detected using HE staining and electron microscopy. The immunoreactivities of microtubule-associated protein 1 light chain 3 (LC3) and phospho-cAMP response element binding protein (p-CREB) were examined by immunofluorescence staining. The neuronal apoptosis was detected via TUNEL staining. The levels of LC3-II, Beclin-1, Akt, p-Akt, CREB, p-CREB, Caspase-3, and Bad were accessed by Western blotting. Furthermore, mouse hippocampal HT22 neurons received the oxygen and glucose deprivation (OGD) treatment, VEGF-A treatment, and GSK690693 (an Akt inhibitor) treatment, respectively. RESULTS: LC3-II protein started to increase at 3 days of CCH, peaked at 4 weeks of CCH, then decreased. CCH increased the levels of LC3-II, Caspase-3, and Bad, and decreased the levels of p-Akt, CREB, and p-CREB, which were reversed by VEGF-A treatment. VEGF-A also improved CCH-induced neuronal ultrastructural injuries and apoptosis in the hippocampus in vitro. In HT22, the anti-apoptosis and pro-phosphorylation of VEGF-A were reversed by GSK690693. CONCLUSION: Present results provide a novel neuroprotective effect of VEGF-A in CCH that is related to the inhibition of neuronal autophagy and activation of the Akt/CREB signaling, suggesting a potential therapeutic strategy for ischemic brain damage.
RESUMO
BACKGROUND: Genetic variants associated with acute side effects of radiotherapy in nasopharyngeal carcinoma (NPC) remain largely unknown. METHODS: We performed a two-stage genome-wide association analysis including a total of 1084 patients, where 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant variants were then validated in an independent cohort of 765 patients using the MassARRAY system. Gene mapping, linkage disequilibrium, genome-wide association analysis, and polygenic risk score were conducted or calculated using FUMA, LDBlockShow, PLINK, and PRSice software programs, respectively. RESULTS: Five SNPs (rs6711678, rs4848597, rs4848598, rs2091255, and rs584547) showed statistical significance after validation. Radiotherapy toxicity was more serious in mutant minor allele carriers of all five SNPs. Stratified analysis further indicated that rs6711678, rs4848597, rs4848598, and rs2091255 correlated with skin toxicity in patients of EBV positive, late stage (III and IV), receiving both concurrent chemoradiotherapy and induction/adjuvant chemotherapy, and with OR values ranging from 1.92 to 2.66. For rs584547, high occurrence of dysphagia was found in A allele carriers in both the discovery (P = 1.27 × 10- 6, OR = 1.55) and validation (P = 0.002, OR = 4.20) cohorts. Furthermore, prediction models integrating both genetic and clinical factors for skin reaction and dysphagia were established. The area under curve (AUC) value of receiver operating characteristic (ROC) curves were 0.657 (skin reaction) and 0.788 (dysphagia). CONCLUSIONS: Rs6711678, rs4848597, rs4848598, and rs2091255 on chromosome 2q14.2 and rs584547 were found to be novel risk loci for skin toxicity and dysphagia in NPC patients receiving radiotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Register (registration number: ChiCTR-OPC-14005257 and CTXY-140007-2).
Assuntos
Transtornos de Deglutição , Neoplasias Nasofaríngeas , Quimiorradioterapia , Transtornos de Deglutição/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/radioterapiaRESUMO
BACKGROUND: Glioblastoma is the most common primary malignant brain tumor. Because of the limited understanding of its pathogenesis, the prognosis of glioblastoma remains poor. This study was conducted to explore potential competing endogenous RNA (ceRNA) network chains and biomarkers in glioblastoma by performing integrated bioinformatics analysis. METHODS: Transcriptome expression data from The Cancer Genome Atlas database and Gene Expression Omnibus were analyzed to identify differentially expressed genes between glioblastoma and normal tissues. Biological pathways potentially associated with the differentially expressed genes were explored by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis, and a protein-protein interaction network was established using the STRING database and Cytoscape. Survival analysis using Gene Expression Profiling Interactive Analysis was based on the Kaplan-Meier curve method. A ceRNA network chain was established using the intersection method to align data from four databases (miRTarBase, miRcode, TargetScan, and lncBace2.0), and expression differences and correlations were verified by quantitative reverse-transcription polymerase chain reaction analysis and by determining the Pearson correlation coefficient. Additionally, an MTS assay and the wound-healing and transwell assays were performed to evaluate the effects of complement C1s (C1S) on the viability and migration and invasion abilities of glioblastoma cells, respectively. RESULTS: We detected 2842 differentially expressed (DE) mRNAs, 2577 DE long non-coding RNAs (lncRNAs), and 309 DE microRNAs (miRNAs) that were dysregulated in glioblastoma. The final ceRNA network consisted of six specific lncRNAs, four miRNAs, and four mRNAs. Among them, four DE mRNAs and one DE lncRNA were correlated with overall survival (p < 0.05). C1S was significantly correlated with overall survival (p= 0.015). In functional assays, knockdown of C1S inhibited the proliferation and invasion of glioblastoma cell lines. CONCLUSIONS: We established four ceRNA networks that may influence the occurrence and development of glioblastoma. Among them, the MIR155HG/has-miR-129-5p/C1S axis is a potential marker and therapeutic target for glioblastoma. Knockdown of C1S inhibited the proliferation, migration, and invasion of glioblastoma cells. These findings clarify the role of the ceRNA regulatory network in glioblastoma and provide a foundation for further research.
RESUMO
Gliomas are a group of brain cancers with high mortality and morbidity. Understanding the molecular mechanisms is important for the prevention or treatment of gliomas. The present study was to investigate the effects and mechanisms of long noncoding RNA TRPM2-AS in gliomas proliferation, migration, and invasion. We first compared the levels of TRPM2-AS in 111 patients with glioma to that of the normal control group by a quantitative polymerase chain reaction. The results indicated a significant increase of TRPM2-AS in patients with glioma (2.43 folds of control, p = .0135). MTT methods, wound healing assays, transwell analysis, and clone formation analysis indicated the overexpression of TRPM2-AS promoted the proliferation, migration, and invasion of U251 and U87 cells, while downregulation of TRPM2-AS inhibited the cell proliferation, migration, and invasion significantly (p < .05). To further uncover the mechanisms, bioinformatics analysis was conducted on the expression profiles, GSE40687 and GSE4290, from the Gene Expression Omnibus database. One hundred fifty-six genes were differentially expressed in both datasets (FC > 2.0; p = .05). Among these differentially expressed genes, the level of RGS4 messenger RNA was drastically regulated by TRPM2-AS. Further western-blot analysis indicated the increase of RGS4 protein expression and decrease of p-JNK/JNK and p-c-Jun/c-Jun ratio after TRPM2-AS overexpression. On the other hand, inhibition of TRPM2-AS by small interfering RNA suppressed the expression of RGS4 and promoted the ratios of p-JNK/JNK and p-c-Jun/c-Jun. The present work indicated the mechanisms of the participation of TRPM2-AS in the progression of gliomas might, at least partly, be related to JNK, c-Jun, and RGS4. Our work provided new insights into the underlying mechanisms of glioma cellular functions.
Assuntos
Neoplasias Encefálicas/enzimologia , Movimento Celular , Proliferação de Células , Glioma/enzimologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Proteínas RGS/metabolismo , RNA Longo não Codificante/metabolismo , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Fosforilação , Proteínas RGS/genética , RNA Longo não Codificante/genética , Transdução de SinaisRESUMO
OBJECTIVE: Atherosclerosis is a chronic inflammatory disease which is responsible for many clinical manifestations. The present study was to investigate the anti-inflammatory functions and mechanisms of TNK1 in atherosclerosis. METHODS: The ApoE(-/-) mice and human carotid endarterectomy (CEA) atherosclerotic plaques were used to investigate the differential expression of TNK1. The ApoE(-/-) mice were fed with high-fat diet (HFD) or normal-fat diet (NFD) for 8 weeks; the aorta was separated and stained with oil red O to evaluate the formation of atherosclerosis. TNK1 in mice aorta was measured by qPCR. The human CEA were obtained and identified as ruptured and stable plaques. The level of TNK1 was measured by qPCR and Western-blot staining. Further studies were conducted in THP-1 cells to explore the anti-inflammatory effects of TNK1. We induced the formation of macrophages by incubating THP-1 cells with PMA (phorbol 12-myristate 13-acetate). Afterwards, oxidized low-density lipoprotein (oxLDL) was used to stimulate the inflammation, and the secretion of inflammatory factors was measured by ELISA and qPCR. The levels of TNK1, total STAT1 and Tyk2, and the phosphorylation of STAT1 and Tyk2 were measured by western blot to uncover the mechanisms of TNK1. RESULTS: The oil red O staining indicated obvious deposition of lipid on the aorta of ApoE(-/-) mice after 8-week HFD treatment. The TNK1 level was much higher in both the HFD-fed ApoE(-/-) mice aorta arch and the ruptured human CEA plaques. We found that TNK1 was highly expressed in THP-1 cells, compared to other atherosclerotic related cells (HUVEC, HBMEC, and HA-VSMC), indicating TNK1 might be involved in the inflammation. Suppressing the expression of TNK1 by shTNK1 inhibited the oxLDL-induced secretion of inflammatory factors, such as IL-12, IL-6, and TNF-α. ShTNK1 also inhibited the uptake of lipid and decreased the cellular cholesterol content in THP-1 cells. Furthermore, the shTNK1 suppressed the oxLDL-induced phosphorylation of Tyk2 and STAT1. CONCLUSION: TNK1 participated in the inflammation in atherosclerosis. shTNK1 suppressed the oxLDL-induced inflammation and lipid deposition in THP-1 cells. The mechanism might be related to the Tyk2/STAT signal pathway.
Assuntos
Aterosclerose/metabolismo , Inflamação/metabolismo , Proteínas Tirosina Quinases/metabolismo , Fator de Transcrição STAT1/metabolismo , TYK2 Quinase/metabolismo , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/imunologia , Western Blotting , Ensaio de Imunoadsorção Enzimática , Humanos , Inflamação/imunologia , Masculino , Camundongos , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/metabolismo , Proteínas Tirosina Quinases/genética , Fator de Transcrição STAT1/genética , Células THP-1 , TYK2 Quinase/genéticaRESUMO
Increasing evidence indicates that long noncoding RNAs play important roles in development and progression of various cancers. Zinc finger antisense 1 is a novel long noncoding RNA whose clinical significance, biological function, and underlying mechanism are still undetermined in glioma. In this study, we reported that zinc finger antisense 1 expression was markedly upregulated in glioma and tightly correlated with clinical stage. Moreover, patients with high zinc finger antisense 1 expression had shorter survival. Multivariate Cox regression analysis provided a clue that, probably, zinc finger antisense 1 level could serve as an independent prognostic factor for glioma. Functionally, zinc finger antisense 1 acted as an oncogene in glioma because its knockdown could promote apoptosis and significantly inhibit cell proliferation, migration, and invasion. Furthermore, zinc finger antisense 1 silencing could result in cell cycle arrest at the G0/G1 phase and correspondingly decrease the percentage of S phase cells in both U87 and U251 cell lines. Moreover, it was found that silenced zinc finger antisense 1 could impair migration and invasion by inhibiting the epithelial-mesenchymal transition through reducing the expression of MMP2, MMP9, N-cadherin, Integrin ß1, ZEB1, Twist, and Snail as well as increasing E-cadherin level in glioma. Taken together, our data identified that zinc finger antisense 1 might act as a valuable prognostic biomarker and potential therapeutic target for glioma.
Assuntos
Proliferação de Células/genética , Glioma/genética , Prognóstico , RNA Longo não Codificante/genética , Adulto , Idoso , Apoptose/genética , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Proteínas de Neoplasias/biossínteseRESUMO
Objective. The present study was performed to investigate the effects and mechanisms of miR-99a on LPS-induced endothelial cell inflammation, as well as the regulation of NF-κB on miR-99a production. Methods and Results. ELISA showed that LPS treatment significantly promoted the secretion of inflammatory factors (TNF-α, IL-6, IL-1ß, and MCP-1). LPS treatment also inhibited miR-99a production and promoted mTOR expression and NF-κB nuclear translocation. Overexpression of miR-99a suppressed the LPS-induced TNF-α, IL-6, IL-1ß, and MCP-1 overproduction, mTOR upregulation, and NF-κB nuclear translocation. The PROMO software analysis indicated NF-κB binding site in the -1643 to -1652 region of miR-99a promoter. Dual luciferase reporter analysis, electrophoretic mobility shift assays (EMSA), and chromosome immunoprecipitation (ChIP) assays demonstrated that NF-κB promoted the transcription of miR-99a by binding to the -1643 to -1652 region of miR-99a promoter. Further studies on HUVECs verified the regulatory effects of NF-κB on miR-99a production. Conclusion. MiR-99a inhibited the LPS-induced HUVECs inflammation via inhibition of the mTOR/NF-κB signal. NF-κB promoted miR-99a production by binding to the -1643 to -1652 region of miR-99a promoter. Considering the importance of endothelial inflammation on cardiovascular diseases, such as atherosclerosis, our results may provide a new insight into the pathogenesis and therapy of atherosclerosis.
Assuntos
Células Endoteliais da Veia Umbilical Humana/metabolismo , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Sítios de Ligação , Quimiocina CCL2/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Ensaio de Imunoadsorção Enzimática , Células HEK293 , Histonas/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , MicroRNAs/genética , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas/genética , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Emerging studies show that long noncoding RNAs (lncRNAs) have important roles in carcinogenesis. lncRNA ZEB1 antisense 1 (ZEB1-AS1) is a novel lncRNA, whose clinical significance, biological function, and underlying mechanism remains unclear in glioma. Here, we found that ZEB1-AS1 was highly expressed in glioma tissues, being closely related to clinical stage of glioma. Moreover, patients with high ZEB1-AS1 levels had poor prognoses, with the evidence provided by multivariate Cox regression analysis indicating that ZEB1-AS1 expression could serve as an independent prognostic factor in glioma patients. Functionally, silencing of ZEB1-AS1 could significantly inhibit cell proliferation, migration, and invasion, as well as promote apoptosis. Knockdown of ZEB1-AS1 significantly induced the G0/G1 phase arrest and correspondingly decreased the percentage of S phase cells. Further analysis indicated that ZEB1-AS1 could regulate the cell cycle by inhibiting the expression of G1/S transition key regulators, such as Cyclin D1 and CDK2. Furthermore, ZEB1-AS1 functioned as an important regulator of migration and invasion via activating epithelial to mesenchymal transition (EMT) through up-regulating the expression of ZEB1, MMP2, MMP9, N-cadherin, and Integrin-ß1 as well as decreasing E-cadherin levels in the metastatic progression of glioma. Additionally, forced down-regulation of ZEB1-AS1 could dramatically promote apoptosis by increasing the expression level of Bax and reducing Bcl-2 expression in glioma. Taken together, our data suggest that ZEB1-AS1 may serve as a new prognostic biomarker and therapeutic target of glioma.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , RNA Longo não Codificante/genética , Adulto , Apoptose , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Caderinas/genética , Caderinas/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Ciclina D1/genética , Ciclina D1/metabolismo , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Transição Epitelial-Mesenquimal , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular , Glioma/genética , Glioma/patologia , Humanos , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , RNA Longo não Codificante/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismoRESUMO
We aimed to investigate the association between gene co-expression modules and responses to neoadjuvant chemotherapy in breast cancer by using a systematic biological approach. The gene expression profiles and clinico-pathological data of 508 (discovery set) and 740 (validation set) patients with breast cancer who received neoadjuvant chemotherapy were analyzed. Weighted gene co-expression network analysis was performed and identified seven co-regulated gene modules. Each module and gene signature were evaluated with logistic regression models for pathological complete response (pCR). The association between modules and pCR in each intrinsic molecular subtype was also investigated. Two transcriptional modules were correlated with tumor grade, estrogen receptor status, progesterone receptor status, and chemotherapy response in breast cancer. One module that constitutes upregulated cell proliferation genes was associated with a high probability for pCR in the whole (odds ratio (OR) = 5.20 and 3.45 in the discovery and validation datasets, respectively), luminal B, and basal-like subtypes. The prognostic potentials of novel genes, such as MELK, and pCR-related genes, such as ESR1 and TOP2A, were identified. The upregulation of another gene co-expression module was associated with weak chemotherapy responses (OR = 0.19 and 0.33 in the discovery and validation datasets, respectively). The novel gene CA12 was identified as a potential prognostic indicator in this module. A systems biology network-based approach may facilitate the discovery of biomarkers for predicting chemotherapy responses in breast cancer and contribute in developing personalized medicines.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Transcriptoma , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Neoplasias da Mama/tratamento farmacológico , Análise por Conglomerados , Biologia Computacional , Bases de Dados de Ácidos Nucleicos , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Terapia Neoadjuvante , Gradação de Tumores , Estadiamento de Neoplasias , Razão de Chances , Curva ROC , Resultado do TratamentoRESUMO
MicroRNA-184 (miR-184) is found to be significantly deregulated in human cancers associated with tumorigenesis and progression. In this study, we aimed to investigate the role and mechanism of miR-184 expression in epithelial ovarian cancer (EOC). Relative expression of miR-184 was measured by quantificational real-time polymerase chain reaction assay (qRT-PCR) in 80 EOC patients. Kaplan-Meier curve and the log-rank test were conducted to detect the prognostic value of miR-184. Function assays including cell proliferation, apoptosis and inflammation were further explored in vitro. We found that miR-184 was down-regulated in EOC tissues and cell lines compared with paired non-cancerous tissues and IOSE, respectively. Moreover, miR-184 was expressed at significantly lower levels in late-stage (III/IV) EOC tissues. Cox regression multivariate analysis indicated that miR-184 and FIGO stage were independent prognostic indicators for EOC patients. Patients with high miR-184 level achieved significantly a higher 5-year survival rate compared with low level group (P < 0.001). Functional assays showed that miR-184 over-expression could suppress EOC cell proliferation as well as inflammation and induce apoptosis in vitro. Altogether, our results suggest that miR-184 together with pathologic diagnosis is critical for prognosis determination in EOC patients and help select treatment strategy.
Assuntos
Apoptose/fisiologia , Biomarcadores Tumorais/análise , Proliferação de Células , Inflamação/patologia , MicroRNAs/análise , MicroRNAs/fisiologia , Neoplasias Epiteliais e Glandulares/diagnóstico , Neoplasias Ovarianas/diagnóstico , Apoptose/genética , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Citocinas/metabolismo , Feminino , Humanos , Inflamação/genética , MicroRNAs/genética , Pessoa de Meia-Idade , Prognóstico , TransfecçãoRESUMO
Bacoside A (gypenoside, Gyp) is a potent bioactive compound derived from Gynostemma pentaphyllum, known to exert inhibitory effects on various malignant tumors. However, the effects of Gyp on glioma as well as the underlying mechanisms remain unclear. In the present study, we first conducted a comprehensive investigation into the anti-glioma potential of gypenosides using network pharmacology to identify potential glioma-related targets. Protein-protein interaction networks were assembled, and GO and KEGG enrichment analyses were performed for shared targets. Experimental validation involved assessing the viability of U251 and U87 cell lines using the MTS method. Furthermore, trans-well and scratch migration assays evaluated the cell migration, while flow cytometry and Hoechst 33342 staining were utilized for apoptosis assessment. The study also monitored changes in autophagy flow through fluorescence microscopy. The expression levels of proteins pertinent to migration, apoptosis, and autophagy were tested using Western blotting. Findings revealed that Gyp upregulated apoptosis-related proteins (Bax and cleaved caspase-9), downregulated anti-apoptotic protein Bcl-2, and migration-associated matrix metalloproteinases (MMP-2 and MMP-9). Furthermore, autophagy-related proteins (Beclin1 and LC3 II) were upregulated, and p62 protein expression was downregulated. Gyp displayed considerable potential in suppressing glioma progression by inhibiting cell proliferation, invasion, and migration and promoting apoptosis and autophagy. Gyp may offer potential clinical therapeutic choices in glioma management.
Assuntos
Apoptose , Glioma , Saponinas , Triterpenos , Humanos , Glioma/tratamento farmacológico , Glioma/patologia , Proteínas Reguladoras de Apoptose/metabolismo , Proliferação de Células , Autofagia , Linhagem Celular TumoralRESUMO
BACKGROUND: Facing the significant challenge of overcoming drug resistance in cancer treatment, particularly resistance caused by mutations in epidermal growth factor receptor (EGFR), the aim of our study was to identify potent EGFR inhibitors effective against the T790M/C797S/L858R mutant, a key player in resistance mechanisms. METHODS: Our integrated in silico approach harnessed machine learning, virtual screening, and activity evaluation techniques to screen 5105 compounds from three libraries, aiming to find candidates capable of overcoming the resistance conferred by the T790M and C797S mutations within EGFR. This methodical process narrowed the search down to six promising compounds for further examination. RESULTS: Kinase assays identified three compounds to which the T790M/C797S/L858R mutant exhibited increased sensitivity compared to the T790M/L858R mutant, highlighting the potential efficacy of these compounds against resistance mechanisms. Among them, T001-10027877 exhibited dual inhibitory effects, with IC50 values of 4.34 µM against EGFRT790M/C797S/L858R and 1.27 µM against EGFRT790M/L858R. Further investigations into the antiproliferative effects in H1975, A549, H460 and Ba/F3-EGFRL858/T790M/C797S cancer cells revealed that T001-10027877 was the most potent anticancer agent among the tested compounds. Additionally, the induction of H1975 cell apoptosis and cell cycle arrest by T001-10027877 were confirmed, elucidating its mechanism of action. CONCLUSIONS: This study highlights the efficacy of combining computational techniques with bioactivity assessments in the quest for novel antiproliferative agents targeting complex EGFR mutations. In particular, T001-10027877 has great potential for overcoming EGFR-mediated resistance and merits further in vivo exploration. Our findings contribute valuable insights into the development of next-generation anticancer therapies, demonstrating the power of an integrated drug discovery approach.
RESUMO
BACKGROUND: Lactate dehydrogenase (LDH) has emerged as a promising biomarker for cancer. However, the current understanding of LDH and circulating LDH expression in thymic epithelial tumour (TET) is lacking. METHODS: A comprehensive literature review and meta-analysis were performed to evaluate the clinical significance of circulating LDH levels in patients with TET. Circulating LDH levels were measured using a laboratory analyser (Cobas8000, Roche, Basel, Switzerland). The maximum standardised uptake value (SUVmax) was determined in patients who underwent whole-body 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). Multiplex immunohistochemistry (IHC) was performed using a commercially available kit (Opal 6-plex Detection Kit, Akoya Biosciences, Marlborough, MA, USA) and slide scanner (Slideview VS200, Olympus, Tokyo, Japan). All statistical analyses were performed using SPSS (IBM Corp., Armonk, NY, USA) and Prism version 9.0 (GraphPad Inc., San Diego, CA, USA). Differences with p < 0.05 were considered to be statistically significant. RESULTS: Meta-analysis revealed that elevated circulating serum levels of LDH predicted poor prognosis in patients with TET. Circulating levels of LDH were analysed in the serum of 313 patients with TET and 87 with benign mediastinal mass. The mean circulating LDH level in patients with thymic carcinoma (TC) was significantly higher than that in those with thymoma (TM) and the benign group (p < 0.001). Expression levels of circulating LDH were significantly reduced in postoperative samples compared with that in preoperative samples (p < 0.05). Receiver operating characteristic (ROC) curve analysis for diagnosing TC yielded an area under the curve of 0.74, with a sensitivity of 54 % and specificity of 86 %. Furthermore, patients with TC exhibited higher 18F-FDG PET/CT SUVmax values compared to those with TM. Correlation analysis demonstrated a positive association between SUVmax values and circulating LDH levels. In addition, the percentages of LDH-positive cells in TC and type B1 TM tissues were higher than those in other subtypes of TM, and a significant positive correlation between the percentages of LDH-positive and CD20-positive cells was detected in patients with TET (p < 0.05). CONCLUSION: Circulating serum LDH level may serve as a non-invasive biomarker for the diagnosis and prognosis of TET. The relationship between LDH expression and immune cell infiltration merits further regarding its application in companion diagnosis for immunotherapy.
Assuntos
Neoplasias Epiteliais e Glandulares , Timoma , Neoplasias do Timo , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18/metabolismo , L-Lactato Desidrogenase , Neoplasias do Timo/diagnóstico , Neoplasias Epiteliais e Glandulares/diagnóstico , Biomarcadores , Estudos RetrospectivosRESUMO
Finding novel therapeutic modalities, improving drug delivery efficiency and targeting, and reducing the immune escape of tumor cells are currently hot topics in the field of tumor therapy. Bacterial therapeutics have proven highly effective in preventing tumor spread and recurrence, used alone or in combination with traditional therapies. In recent years, a growing number of researchers have significantly improved the targeting and penetration of bacteria by using genetic engineering technology, which has received widespread attention in the field of tumor therapy. In this paper, we provide an overview and assessment of the advancements made in the field of tumor therapy using genetically engineered bacteria. We cover three major aspects: the development of engineered bacteria, their integration with other therapeutic techniques, and the current state of clinical trials. Lastly, we discuss the limitations and challenges that are currently being faced in the utilization of engineered bacteria for tumor therapy.
Assuntos
Bactérias , Engenharia Genética , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Animais , Bactérias/genética , Imunoterapia/métodos , Sistemas de Liberação de MedicamentosRESUMO
Long noncoding RNAs (lncRNAs) represent a large subgroup of RNA transcripts that lack the function of coding proteins and may be essential universal genes involved in carcinogenesis and metastasis. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNAMALAT1) is overexpressed in various human tumors, including gliomas. However, the biological function and molecular mechanism of action of lncRNA-MALAT1 in gliomas have not yet been systematically elucidated. Accumulating evidence suggests that the abnormal expression of lncRNA-MALAT1 in gliomas is associated with various physical properties of the glioma, such as tumor growth, metastasis, apoptosis, drug resistance, and prognosis. Furthermore, lncRNAs, as tumor progression and prognostic markers in gliomas, may affect tumorigenesis, proliferation of glioma stem cells, and drug resistance. In this review, we summarize the knowledge on the biological functions and prognostic value of lncRNA-MALAT1 in gliomas. This mini-review aims to deepen the understanding of lncRNA-MALAT1 as a novel potential therapeutic target for the individualized precision treatment of gliomas.