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BACKGROUND: Inhibition of Serum Amyloid A-like 1 (SAAL1) expression could inhibit cancer progression and improve the prognosis of cancer patients. At present, the correlation between SAAL1 and lung adenocarcinoma (LAC) remains unclear. Therefore, this study surveyed the worth and pathway of SAAL1 in LAC progression and immunity. METHODS: Bioinformatics and immunohistochemistry were used to identify the SAAL1 expression in LAC. The roles of SAAL1 expression in the existence values of LAC patients were explored, and the nomograms were constructed. Clinical values of SAAL1 co-expressed genes were evaluated by COX regression, survival, and Receiver operating characteristic (ROC) analysis. EDU and western blotting methods were used to inquiry the functions and pathways of the SAAL1 in cell growths. The correlation between the SAAL1 level and immune microenvironment was visualized using correlation research. RESULTS: SAAL1 level was elevated in LAC tissues, and was observed in cancer tissues of dead patients. SAAL1 overexpression had something to do with shorter overall survival, progression-free interval, and disease-specific survival in LAC. The area under the curve of SAAL1 was 0.902 in normal tissues and cancer tissues. Inhibition of SAAL1 expression could inhibit cancer cell proliferation, which may be related to the decreased expression of cyclin D1 and Bcl-2 proteins. In LAC, SAAL1 level had something to do with stromal, immune, and estimate scores, and correlated with macrophages, T cells, Th2 cells, CD8 T cells, NK CD56dim cells, DC, eosinophils, NK CD56bright cells, pDC, iDC, cytotoxic cells, Tgd, aDC cells, B cells, Tcm, and TFH levels. SAAL1 overexpression had something to do with existence values and the immunity in LAC. CONCLUSIONS: Inhibition of SAAL1 expression could regulate cancer growth via cyclin D1 and Bcl-2. SAAL1 is a promising prognostic biomarker in LAC patients.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Ciclina D1 , Prognóstico , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/genética , Microambiente TumoralRESUMO
Immunotherapy can improve the survival of patients with advanced lung squamous cell carcinoma (LUSC). T cytotoxic cells are one of the main members of the immune microenvironment. Herein, we aimed to identify the roles of T-cell cytotoxic markers interleukin 18 (IL18) receptor 1 (IL18R1) in the LUSC progression using bioinformatics, clinical tissue specimen, and cell experiment. We assessed the association between the IL18R1 expression and immune infiltration and IL18R1-related competing RNA network. The IL18R1 expression was downregulated in the LUSC tissues. The IL18R1 expression downregulation was associated with diagnosis and short overall survival and disease-specific survival, and it was also an independent risk factor for dismal survival time in LUSC. IL18R1-related nomograms predicted the survival time of patients with LUSC. IL18R1 overexpression inhibited the proliferation, migration, and invasion of LUSC cells. The IL18R1 expression was significantly associated with the microenvironment (stromal, immune, and estimate scores), immune cells (such as the T cells, cytotoxic cells, CD8 T cells), and immune cell markers (such as the CD8A, PD-1, and CTLA4) in LUSC. AC091563.1 and RBPMS-AS1 downregulation was positively associated with the IL18R1 expression, negatively associated with the miR-128-3p expression, and associated with short disease-specific survival and progression in LUSC. In conclusion, IL18R1 was significantly downregulated and associated with the prognosis and immune microenvironment. IL18R1 overexpression inhibits the growth and migration of cancer cells in LUSC. Furthermore, AC091563.1 and RBPMS-AS1 might compete with IL18R1 to bind miR-128-3p for participating in LUSC progression. These results showed that IL18R1 is a biomarker for evaluating the prognosis of patients with LUSC.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , MicroRNAs , Humanos , Regulação para Baixo , Prognóstico , Complexo CD3 , Subunidade alfa de Receptor de Interleucina-18 , Neoplasias Pulmonares/genética , Proliferação de Células , Pulmão , MicroRNAs/genética , Microambiente TumoralRESUMO
OBJECTIVE: T cell receptor-associated transmembrane adaptor 1 (TRAT1) is one of the hub genes regulating T cell receptors (TCRs). Herein, the roles of TRAT1 in the prognosis and immune microenvironment of non-small cell lung cancer (NSCLC) were investigated. METHODS: The expression and prognosis values of TRAT1 in NSCLC, and the relationship between TRAT1 expression levels and cancer immune cell infiltration was identified via the TIMER, UALCAN, TISIDB, and other databases. The mechanism of TRAT1 in NSCLC was analyzed using gene set enrichment analysis (GSEA). RESULTS: The expression level of TRAT1 was decreased in NSCLC tissues. Low TRAT1 expression was associated with shorter overall survival of patients with NSCLC and was related to gender, smoking, and tumor grade. TRAT1 was involved in regulating immune response, TCR signaling pathway, PI3K/AKT, and other processes. TRAT1 expression levels were positively correlated with immune cell infiltration in NSCLC. CONCLUSION: Down-regulation of TRAT1 expression was associated with an unfavorable prognosis and immune infiltration of NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Regulação para Baixo , Neoplasias Pulmonares/genética , Fosfatidilinositol 3-Quinases , Fumar , Microambiente Tumoral/genéticaRESUMO
The roles and mechanisms of T-cell receptor (TCR)-associated transmembrane adaptor 1 (TRAT1) in lung adenocarcinoma (LAC) have not yet been reported in the relevant literature. Therefore, this study aimed to understand the roles and mechanisms of TRAT1 in LAC using bioinformatics and in vitro experiments. TRAT1 expression levels in LAC samples were analysed using various databases. TRAT1 co-expressed genes were acquired by the correlation analysis of LAC tissues. The functional mechanisms and protein network of TRAT1 co-expressed genes were analysed using bioinformatics analysis. The expression of TRAT1 was activated in LAC cells, and the roles of TRAT1 overexpression in the growth and migration of cancer cells was investigated using flow cytometry, Cell Counting Kit-8 (CCK-8), and migration and invasion assays. The relationship between TRAT1 overexpression, the immune microenvironment, and RNA modification was evaluated using correlation analysis. TRAT1 expression levels were significantly abnormal at multiple mutation sites and were related to the prognosis of LAC. TRAT1 co-expressed genes were involved in cell proliferation, adhesion, and differentiation, and TRAT1 overexpression significantly inhibited cell viability, migration, and invasion and promoted apoptosis of A549 and H1299 cells, which might be related to the TCR, B cell receptor (BCR), MAPK, and other pathways. TRAT1 expression levels were significantly correlated with the ESTIMATE, immune, and stromal scores in the LAC microenvironment. Additionally, TRAT1 expression levels were significantly correlated with the populations of B cells, CD8 T cells, cytotoxic cells, and other immune cells. TRAT1 overexpression was significantly correlated with the expression of immune cell markers (such as PDCD1, CD2, CD3E) and genes involved in RNA modification (such as ALKBH1, ALKBH3, ALKBH5). In conclusions, TRAT1 overexpression inhibited the growth and migration of LAC cells, thereby delaying cancer progression, and was correlated with the LAC microenvironment and RNA modifications.
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The tumor microenvironment (TME) plays an important regulatory role in the progression of non-small cell lung cancer (NSCLC). Mesenchymal stem cells (MSCs) in the TME might contribute to the occurrence and development of cancer. This study evaluates the role of differentially expressed genes (DEGs) of MSCs and the development of NSCLC and develops a prognostic risk model to assess the therapeutic responses. The DEGs in MSCs from lung tissues and from normal tissues were analyzed using GEO2R. The functions and mechanisms of the DEGs were analyzed using the Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Additionally, the Cancer Genome Atlas (TCGA) database was used to determine the expression levels of the DEGs of MSCs in the NSCLC tissues. The prognostic factors of NSCLC related to MSCs were screened by survival analysis, meta-analysis, Cox regression analysis, and a prognostic risk model and nomogram was developed. The signaling mechanisms and immune roles that risk model participate in NSCLC development were determined via Gene Set Enrichment Analysis and CIBERSORT analysis. Compared to the normal tissues, 161 DEGs were identified in the MSCs of the lung tissues. These DEGs were associated with mechanisms, such as DNA replication, nuclear division, and homologous recombination. The overexpression of DDIT4, IL6, ITGA11, MME, MSX2, POSTN, and TRPA1 were associated with dismal prognosis of NSCLC patients. A high-risk score based on the prognostic risk model indicated the dismal prognosis of NSCLC patients. The nomogram showed that the age, clinical stage, and risk score affected the prognosis of NSCLC patients. Further, the high-risk model was associated with signaling mechanisms, such as the ECM-receptor interaction pathways, cytokine-cytokine receptor interaction, and MAPK pathways, involved in the progression of NSCLC and was also related to the components of the immune system, such as macrophages M0, T follicular helper cells, regulatory T cells. Therefore, the risk model and nomogram that was constructed on the basis of MSC-related factors such as POSTN, TRPA1, and DDIT4 could facilitate the discovery of target molecules that participate in the progression of NSCLC, which might also serve as new candidate markers for evaluating the prognosis of NSCLC patients.
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Lung ischemia-reperfusion (IR) occurs in many circumstances and leads to impaired lung function. The NACHT, LRR and PYD domains-containing protein 3 (Nlrp3) inflammasome is reportedly activated during lung IR. Mcc950 is a recently developed Nlrp3 inhibitor. The aim of our study was to test the efficacy of Mcc950 on lung IR injury and to investigate the role of reactive oxygen species (ROS) in Nlrp3 inflammasome activation using a murine lung IR model. The results of the current study confirmed that Nlrp3 was upregulated and activated during lung IR, and inhibiting oxidative stress by the ROS scavenger edaravone attenuated Nlrp3 inflammasome activation. Mcc950 pretreatment significantly alleviated IR-induced lung injury by reducing production of the proinflammatory cytokines Il-1ß and Il-18 and inhibiting neutrophil infiltration and cell apoptosis. Protein coimmunoprecipitation revealed that Mcc950 partially blocked the interaction between Nlrp3 and Nek7 (NimA-related protein kinase 7). Therefore, we conclude that ROS-dependent activation of the Nlrp3 inflammasome contributed to lung IR injury. Mcc950 significantly reduced lung IR injury by blocking Nlrp3 inflammasome activation, and the mechanism was partially attributed to inhibition of the interaction between Nlrp3 and Nek7. Thus, Mcc950 is a promising treatment for the prevention of lung IR injury.
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Anti-Inflamatórios/uso terapêutico , Inflamassomos/antagonistas & inibidores , Lesão Pulmonar/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Pneumonia/tratamento farmacológico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Inflamassomos/análise , Inflamassomos/imunologia , Interleucina-18/análise , Interleucina-18/imunologia , Interleucina-1beta/análise , Interleucina-1beta/imunologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/patologia , Masculino , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/análise , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Infiltração de Neutrófilos/efeitos dos fármacos , Pneumonia/imunologia , Pneumonia/patologia , Espécies Reativas de Oxigênio/imunologia , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologiaRESUMO
14-3-3ζ is overexpressed in several cancers, including esophageal squamous cell carcinoma (ESCC), and plays an important role in tumorigenesis. However, the mechanisms underlying its tumorigenesis remain unclear. Here we report that 14-3-3ζ was upregulated in ESCC tumors, compared with adjacent normal tissues; 14-3-3ζ levels were positively correlated with ESCC lymph node metastasis and recurrence. Overexpression of 14-3-3ζ promoted the tumor growth and invasion of ESCC in vitro and in vivo, whereas depletion of 14-3-3ζ suppressed these effects. Moreover, 14-3-3ζ reduces expression of genes mediating S1P/S1PR2 signaling, and this effect is mediated through activation of NF- κ B. Taken together, 14-3-3ζ contributes to ESCC tumorigenesis and progression through repressing S1PR2 signaling and may act as a new therapeutic target for ESCC.
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Proteínas 14-3-3/metabolismo , Regulação para Baixo , Carcinoma de Células Escamosas do Esôfago/patologia , NF-kappa B/metabolismo , Receptores de Lisoesfingolipídeo/genética , Transdução de Sinais , Linhagem Celular Tumoral , Proliferação de Células , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Receptores de Esfingosina-1-FosfatoRESUMO
The association between atrial fibrillation (AF) after coronary artery bypass grafting (CABG) and the surgical techniques selected has been extensively reported. However, no consistent results were obtained. In the present study, a meta-analysis was conducted by searching the electronic databases PubMed, Embase, Web of Science, and Cochrane to identify the association of post-CABG AF with on-pump (conventional CABG, cCABG) or off-pump CABG (OPCABG). Outcomes from randomized clinical trials (RCTs) and propensity score matching (PSM) trials were pooled by using the fixed-effect or the random-effect modeling method, and verified by the quality-effect modeling method. There were 35 studies with 36 independent reports that met the inclusion criteria and were eventually included in our meta-analysis. The total odds ratio (OR) of the incidence of post-CABG AF between OPCABG and cCABG was 0.80 (95% CI 0.71-0.91). The 25 randomized clinical trials (RCTs) had an OR of 0.69 (95% CI 0.56-0.86), while the OR of the 11 PSM trials was 0.88 (95% CI 0.77-1.00). Twenty-six studies involving the patients at a mean age no more than 65 years showed an OR of 0.76 (95% CI 0.64-0.90), whereas 10 studies with patients greater than 65 years old showed an OR of 0.90 (95% CI 0.78-1.05). The results of this meta-analysis suggest that OPCAB surgery may reduce the incidence of post-CABG AF when compared to cCABG and that younger patients may benefit more from OPCAB and have a lower incidence of post-CABG AF.
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Fibrilação Atrial/diagnóstico , Ponte de Artéria Coronária sem Circulação Extracorpórea/efeitos adversos , Idoso , Fibrilação Atrial/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Pontuação de Propensão , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND AND AIMS: Infections related to pemetrexed have been reported in clinical trials. It is not yet clear whether this drug increases infection risk or not. This meta-analysis assessed the overall incidence and risk of severe infections (≥ grade 3) associated with the use of pemetrexed in non-small-cell lung cancer patients. METHODS: The databases of PubMed, Embase, and the Cochrane Library were searched for relevant studies published up to December 2015. Eligible studies included randomized controlled trials (RCTs) of pemetrexed for non-small-cell lung cancer patients that reported grade 3-5 infection and febrile neutropenia. Summary incidence rates, relative risks (RRs) and 95% confidence intervals (CIs) were calculated by using either random-effects or fixed-effects models, according to the heterogeneity of the included studies. RESULTS: Seven randomized controlled trials were included, comprising 1848 patients. The incidence of severe infection and febrile neutropenia due to pemetrexed was 5.7% (95% CI: 3.2-8.3%) and 1.3% (95% CI: 0.7-2.0%), respectively. The use of pemetrexed was associated with an increased risk of severe infection (RR 1.61, 95% CI: 1.07-2.44, P = .02) and febrile neutropenia (RR 4.28, 95% CI: 1.08-17.01, P = .04). CONCLUSION: The use of pemetrexed was associated with an increased risk of developing severe infections and febrile neutropenia in non-small-cell lung cancer patients. Frequent clinical monitoring and management of infections should be emphasized during pemetrexed treatment. More studies are needed to reveal the mechanism of the increased risk of severe infections.
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Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Pemetrexede/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , RiscoRESUMO
X-box binding protein 1 (XBP1) was found to be overexpressed in glioma and breast cancers, suggesting that XBP1 might act as a potent oncogenic protein. However, the clinical significance and biological role of XBP1 in esophageal squamous cell carcinoma (ESCC) remain unknown. In this study, we report that XBP1 is markedly overexpressed in ESCC cell lines and clinical samples. XBP1 overexpression was significantly correlated with ESCC tumor stage, lymph node metastasis and poor outcome. A functional study demonstrated that XBP1 promoted cell growth and cell invasion both in vitro and in vivo. Further study found that the XBP1-mediated invasion and proliferation of cancer cells requires the up-regulation of matrix metalloproteinase-9 (MMP-9). Importantly, a significant correlation between XBP1 and MMP-9 levels was observed in ESCC clinical samples. Our findings demonstrate that XBP1 is an oncogene that plays an important role in the development of ESCC by activating MMP-9 expression.
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14-3-3ζ has been identified as a putative oncogene in several cancers, including non-small cell lung cancer (NSCLC). However, the mechanisms underlying its functions remain undefined. In this study, we show that overexpression of 14-3-3ζ was frequently detected in lung adenocarcinoma (LuAC) tissues and was significantly associated with lymph node metastasis and poor outcome. Functional studies demonstrated that 14-3-3ζ promoted migration and invasion in A549 cells, both of which were effectively inhibited when 14-3-3ζ was silenced with short hairpin RNA (shRNA). Furthermore, 14-3-3ζ-mediated invasion of cancer cells was found to upregulate Snail through the activation of atypical protein kinase C (aPKC). Activation of aPKCζ mediates this effect by stimulating NF-κB signaling. Our results identify a specific pathway by which 14-3-3ζ induces tumor invasion and provide insight into potential therapeutic approaches to target 14-3-3ζ-associated lung adenocarcinoma.
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Proteínas 14-3-3/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , NF-kappa B/metabolismo , Proteína Quinase C/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/metabolismo , Proteínas 14-3-3/genética , Células A549 , Adenocarcinoma , Adenocarcinoma de Pulmão , Proliferação de Células , Ativação Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Invasividade Neoplásica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para CimaRESUMO
Hepatocyte growth factor has been identified as a lymphangiogenic factor in experimental animal models. However, the correlation between hepatocyte growth factor or c-Met expression and lymphangiogenesis in human spontaneous tumors has been rarely reported, and the distribution pattern of c-Met on tumor-related lymphatic vessels remains to be further investigated. Lymphatic vessel density, lymphatic invasion, the expression of hepatocyte growth factor, c-Met, and vascular endothelial growth factor C proteins were evaluated by immunohistochemistry in 76 cases of oral squamous cell carcinoma. The distribution of c-Met on lymphatic endothelium was examined. High expression of c-Met in tumor cells was significantly associated with advanced clinical stage (P = .045), high expression of vascular endothelial growth factor-C (P < .001), higher peritumoral lymphatic vessel density (P = .003), higher incidence of peritumoral lymphatic invasion (P = .032), and positive lymph node status (P = .005), in spite of its negative expression on most lymphatic vessels. Patients with high-c-Met expression tumors exhibited shorter overall survival and disease-free survival (P < .001 and P = .010, respectively). Taken together, our results provide indirect evidence for an association and possible regulatory link of c-Met with the lymphangiogenic factor, vascular endothelial growth factor C, and, by extension, with lymphangiogenesis and lymph node metastasis, suggesting important prognostic significance of c-Met for patients with oral squamous cell carcinoma.