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BACKGROUND: Nicotinamide mononucleotide (NMN) is the physiological circulating NAD precursor thought to elevate the cellular level of NAD+ and to ameliorate various age-related diseases. An inseparable link exists between aging and tumorigenesis, especially involving aberrant energetic metabolism and cell fate regulation in cancer cells. However, few studies have directly investigated the effects of NMN on another major ageing-related disease: tumors. METHODS: We conducted a series of cell and mouse models to evaluate the anti-tumor effect of high-dose NMN. Transmission electron microscopy and a Mito-FerroGreen-labeled immunofluorescence assay (Fe2+) were utilized to demonstrate ferroptosis. The metabolites of NAM were detected via ELISA. The expression of the proteins involved in the SIRT1-AMPK-ACC signaling were detected using a Western blot assay. RESULTS: The results showed that high-dose NMN inhibits lung adenocarcinoma growth in vitro and in vivo. Excess NAM is produced through the metabolism of high-dose NMN, whereas the overexpression of NAMPT significantly decreases intracellular NAM content, which, in turn, boosts cell proliferation. Mechanistically, high-dose NMN promotes ferroptosis through NAM-mediated SIRT1-AMPK-ACC signaling. CONCLUSIONS: This study highlights the tumor influence of NMN at high doses in the manipulation of cancer cell metabolism, providing a new perspective on clinical therapy in patients with lung adenocarcinoma.
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BACKGROUND: Lung cancer is one of the most prevalent cancers and the leading cause of cancer-related deaths worldwide; non-small cell lung cancer (NSCLC) comprises approximately 80% of all lung cancer cases. This study aimed to construct a competing endogenous RNA (ceRNA) network and identify prognostic signatures in elderly patients with NSCLC. METHODS: We extracted data from elderly patients with NSCLC from The Cancer Genome Atlas and identified differentially expressed (DE) messenger RNAs (mRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to investigate the functions of DEmRNAs. The interactions between RNAs were predicted using starBase, TargetScan, miRTarBase, and miRanda. Cytoscape version 3.0 was used to construct and visualize the lncRNA-miRNA-mRNA ceRNA network. The association between the expression levels of DERNAs in the constructed ceRNA network and overall survival was determined using the survival package in R software. Furthermore, another Gene Expression Omnibus cohort was studied to externally validate the ceRNA network. RESULTS: In total, 2865 DEmRNAs, 62 DEmiRNAs, and 131 DElncRNAs were identified. Dysregulated mRNAs are enriched in cancer-related processes and pathways. A ceRNA network was constructed using 38 miRNAs, 61 lncRNAs, and 164 mRNAs. Of these, 3 lncRNAs, 3 miRNAs, and 16 mRNAs were closely related to overall survival. The MIR99AHG-hsa-miR-31-5p-PRKCE axis has been identified as a potential ceRNA network involved in the development of NSCLC in elderly individuals. External validation of the MIR99AHG-hsa-miR-31-5p-PRKCE axis in the GSE19804 cohort showed that PRKCE was downregulated and that MIR99AHG was upregulated in the tumor tissues of elderly patients with NSCLC compared with normal lung tissues. CONCLUSIONS: This study provides novel insights into the lncRNA-miRNA-mRNA ceRNA network and reveals potential biomarkers for the diagnosis and prognosis of elderly patients with NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , MicroARNs , ARN Largo no Codificante , Humanos , Anciano , Carcinoma de Pulmón de Células no Pequeñas/genética , ARN Largo no Codificante/genética , Neoplasias Pulmonares/patología , Biomarcadores de Tumor/genética , MicroARNs/genética , ARN Mensajero/metabolismo , Redes Reguladoras de Genes , Regulación Neoplásica de la Expresión GénicaRESUMEN
In December 2019, there was an outbreak of pneumonia of unknown causes in Wuhan, China. The etiological pathogen was identified to be a novel coronavirus, named severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). The number of infected patients has markedly increased since the 2019 outbreak and COVID-19 has also proven to be highly contagious. In particular, the elderly are among the group of patients who are the most susceptible to succumbing to COVID-19 within the general population. Cross-infection in the hospital is one important route of SARS-CoV-2 transmission, where elderly patients are more susceptible to nosocomial infections due to reduced immunity. Therefore, the present study was conducted to search for ways to improve the medical management workflow in geriatric departments to ultimately reduce the risk of nosocomial infection in elderly inpatients. The present observational retrospective cohort study analysed elderly patients who were hospitalised in the Geriatric Department of the First Affiliated Hospital with Nanjing Medical University (Nanjing, China). A total of 4,066 elderly patients, who were admitted between January and March in 2019 and 2020 and then hospitalised for >48 h were selected. Among them, 3,073 (75.58%) patients hospitalised from January 2019 to March 2019 were allocated into the non-intervention group, whereas the remaining 933 (24.42%) patients hospitalised from January 2020 to March 2020 after the COVID-19 outbreak were allocated into the intervention group. Following multivariate logistic regression analysis, the risk of nosocomial infections was found to be lower in the intervention group compared with that in the non-intervention group. After age stratification and adjustment for sex, chronic disease, presence of malignant tumour and trauma, both inverse probability treatment weighting and standardised mortality ratio revealed a lower risk of nosocomial infections in the intervention group compared with that in the non-intervention group. To rule out interference caused by changes in the community floating population and social environment during this 1-year study, 93 long-stay patients in stable condition were selected as a subgroup based on 4,066 patients. The so-called floating population refers to patients who have been in hospital for <2 years. Patients aged ≥65 years were included in the geriatrics program. The incidence of nosocomial infections during the epidemic prevention and control period (24 January 2020 to 24 March 2020) and the previous period of hospitalisation (24 January 2019 to 24 March 2019) was also analysed. In the subgroup analysis, a multivariate analysis was also performed on 93 elderly patients who experienced long-term hospitalisation. The risk of nosocomial and pulmonary infections was found to be lower in the intervention group compared with that in the non-intervention group. During the pandemic, the geriatric department took active preventative measures. However, whether these measures can be normalised to reduce the risk of nosocomial infections among elderly inpatients remain unclear. In addition, the present study found that the use of an indwelling gastric tube is an independent risk factor of nosocomial pulmonary infection in elderly inpatients. However, nutritional interventions are indispensable for the long-term wellbeing of patients, especially for those with dysphagia in whom an indwelling gastric tube is the most viable method of providing enteral nutrition. To conclude, the present retrospective analysis of the selected cases showed that enacting preventative and control measures resulted in the effective control of the incidence of nosocomial infections.
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Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial pneumonia disease with no cure. Communication between injured cells is triggered and maintained by a complicated network of cytokines and their receptors. IL-19 is supported by increasing evidences for a deleterious role in respiratory diseases. However, its potential role in lung fibrosis has never been explored. Methods: Bioinformatic, immunohistochemistry and western blot analysis were used to assess the expression of IL-19 in human and mouse fibrosis lung tissues. CCK-8, transwell and flow cytometry assay were utilized to analyze the effect of IL-19 on biological behaviors of lung fibroblasts. Histopathology was used to elucidate profibrotic effect of IL-19 in vivo. Results: IL-19 was upregulated in fibrosis lung tissues. IL-19 promoted lung fibroblasts proliferation and invasion, inhibited cell apoptosis, and induced differentiation of fibroblasts to the myofibroblast phenotype, which could be revised by LY2109761, a TGF-ß/Smad signaling pathway inhibitor. Furthermore, we found that IL-19 aggravated lung fibrosis in murine bleomycin-induced lung fibrosis. Conclusions: Our results imply the profibrotic role for IL-19 through direct effects on lung fibroblasts and the potential of targeting IL-19 for therapeutic intervention in pulmonary fibrosis.
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Fibrosis Pulmonar Idiopática , Factor de Crecimiento Transformador beta , Animales , Bleomicina/farmacología , Fibroblastos/metabolismo , Fibrosis Pulmonar Idiopática/patología , Interleucinas/metabolismo , Pulmón/metabolismo , Ratones , Ratones Endogámicos C57BL , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Objective: To explore the role of single-nucleotide polymorphisms (SNPs) in hsa-miR-9 in non-small cell lung cancer (NSCLC). Methods: Log-rank and Cox regression analyses were conducted to assess the association of four functional SNPs of miR-9 with overall survival (OS) of Chinese patients with NSCLC. A reporter luciferase assay was performed to examine the relationship between the SNPs and transcriptional activity of miR-9. The expression of miR-9 in cells was detected by quantitative real-time PCR assay. Xenograft model was established in nude mice, which were treated with Lv-MiR-9-mimics or Lv-miR-9-inhibitor. A long noncoding RNA (lncRNA)-miR-9-messenger RNA (mRNA) competing endogenous RNA (ceRNA) network was established based on bioinformatics analyses. Results: We found that rs1501672 was associated with the prognosis of 1001 Chinese NSCLC patients (A>G, additive model: adjusted hazard ratio = 0.89, 95% confidence interval = 0.79-1.00, p = 0.056). Luciferase reporter assay showed higher luciferase activity with wild A allele than that with mutant G allele in 293T, SPC-A1, and A549 cell lines. The miR-9 level was significantly higher in lung cancer cells than normal lung cells. miR-9 was also over expressed in lung cancer tissue according to The Cancer Genome Atlas and gene expression omnibus databases. Xenograft models based on H1299 cells showed that lv-miR-9-inhibitor significantly decreased tumor growth compared with the lv-miR-9-NC group (p < 0.001). Bioinformatics analysis showed that one target gene leukemia inhibitory factor receptor and two lncRNAs (KIAA0087 and GVINP1) were associated with OS of NSCLC patients. Conclusion: The rs1501672 of miR-9 was associated with the prognosis of NSCLC patients in the Chinese population. The lncRNA-miR-9-mRNA ceRNA network revealed potential molecular biological regulation pathways and prognostic biomarkers for NSCLC.
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Carcinoma de Pulmón de Células no PequeñasRESUMEN
BACKGROUND/AIM: The prevalence of idiopathic pulmonary fibrosis (IPF) increases with age and is associated with senescence of alveolar epithelial cells (AECs). AEC senescence in pulmonary cells mediates IPF. We herein aimed to determine if YAP1 gene knockdown, a member of the Hippo/YAP signal pathway, in the bleomycin (BLM)-induced mouse model of IPF, inhibits onset of senescence of AECs and alleviates IPF. MATERIALS AND METHODS: Adeno-associated viruses (AAVs) expressing Yes-associated protein 1 (YAP1) short hairpin RNA (shRNA) were delivered into the lung of BLM-induced IPF mice via intratracheal injection, to knockdown the YAP1 gene in AECs. The mice were assigned to 4 groups: G1: control (normal mice); G2: IPF mice; G3: IPF + AAV/YAP1; G4: IPF + AAV/scramble. After 28 days, AECs were examined for senescence using H&E staining, Masson's trichrome Staining, senescence-associated ß-galactosidase (SA-ß-gal) staining, western blotting and co-immunofluorescence staining, to determine the expression of YAP1, Smad-3 and p21, in order to determine the induction of senescence of ACEs. RESULTS: The severity of IPF determined by H&E staining, Masson's staining and immunofluorescence (IF) staining was positively correlated with the senescence of AECs. Down-regulation of YAP1 expression of the Hippo-signaling pathway, determined by western blotting in AECs, alleviated pulmonary fibrosis as determined by Masson's staining. Down regulation of YAP1 expression reduced the senescence of AECs as determined by ß-galactosidase (SA-ß-gal) staining, which alleviated the clinical symptoms of IPF mice, as determined by body weight and lung index. CONCLUSION: Down-regulation of YAP1 expression in AECs inhibited AEC senescence which is thought to be the cause of IPF. Therefore, future studies can focus on inhibiting YAP1 to effectively treat IPF.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Células Epiteliales Alveolares/metabolismo , Fibrosis Pulmonar Idiopática/genética , Factores de Transcripción/metabolismo , Animales , Senescencia Celular , Modelos Animales de Enfermedad , Humanos , Fibrosis Pulmonar Idiopática/patología , Masculino , Ratones , Transducción de Señal , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND: Autophagy is a double-edged sword during the initiation and progression of multiple tumors. The Hippo pathway effector YAP has been proved to be involved in autophagy processes. The present study aimed to investigate how YAP regulates cell proliferation via autophagy in lung adenocarcinomas (LUAD). METHODS: Data of LUAD chip GSE43458 was obtained from Gene Expression Omnibus (GEO). RT-qPCR and Western blot were performed to assess YAP expression in LUAD cell lines. CCK-8 assay, xenograft tumor model, immunochemistry and GFP-mRFP-LC3 fusion proteins were utilized to evaluate the effect of YAP on autophagy of LUAD cells in vitro and in vivo. Autophagy inhibitor treatment and rescue experiments were carried out to elucidate the mechanism by which YAP manipulates autophagy in LUAD cells. RESULTS: YAP was significantly overexpressed in samples of LUAD patients and its expression level is related to 5-year survival. YAP manipulated the proliferation and autophagy in A549 and H1299 LUAD cells. YAP could induce activation of Akt/mTOR signaling pathway via suppressing PTEN in a Hippo-pathway-dependent manner. 3-Methyladenine impeded autophagy flux and promoted the proliferation in vitro and in vivo. CONCLUSIONS: Hippo pathway critical transcriptional coactivators YAP manipulates the proliferation of lung adenocarcinoma, which is regulated by PTEN/AKT/mTOR autophagic signaling.
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BACKGROUND Chemotherapy is widely used in gastric cancer treatment, but multidrug resistance remains a leading cause of chemotherapy failure. Trop2 is highly expressed in gastric tumor tissues and greatly influences cancer progression. However, little is known about the relationship between Trop2 and drug resistance in gastric cancer. MATERIAL AND METHODS In the present study, Trop2 was knocked down in BGC823 cells and overexpressed in HGC27. CCK-8 assay was performed to explore the relationship of Trop2 expression and cell proliferation treated with anticancer drugs. Flow cytometry was performed to assess the relationship between Trop2 and cell apoptosis after chemotherapy. Subcutaneous xenograft models were generated to explore the curative effect of DDP to GC in vivo. MRP1 and Notch1 expressions were assessed by Western blot. RESULTS Trop2 decreased cell proliferation inhibition and apoptosis after chemotherapeutic treatments. DDP showed stronger therapeutic effects on Trop2-knockdown tumor than control in vivo. MRP1 and Notch1 signaling pathway were confirmed to participate in Trop2-induced drug resistance. CONCLUSIONS Our findings suggest that Trop2 promotes the resistance of gastric cancer to chemotherapy by activating the Notch1 pathway.
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Antígenos de Neoplasias/genética , Moléculas de Adhesión Celular/genética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Antígenos de Neoplasias/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Moléculas de Adhesión Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos , Humanos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , ARN Largo no Codificante/metabolismo , ARN Interferente Pequeño/farmacología , Receptor Notch1/deficiencia , Receptor Notch1/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND AND OBJECTIVE: This study aimed to identify miRNA as potential diagnostic biomarkers for silica-related pulmonary fibrosis (SPF). METHODS: We first performed a comprehensive miRNA-seq screening in PBL of eight subjects exposed to silica dust (four individuals with SPF and four healthy controls). The promising miRNA were then evaluated in the first-stage validation using an independent GEO data set (GSE80555) of 6 subjects (3 individuals with SPF and 3 healthy controls), followed by a second-stage validation using 120 subjects exposed to silica dust (60 individuals with SPF and 60 healthy controls). RESULTS: Thirty-five miRNA showed strong expression differences in miRNA-seq screening, while miRNA-4508 (P = 9.52 × 10-3 ) was retained as a candidate after the first-stage validation (GSE80555), which was further confirmed in the second-stage validation with similar and strong effect (P = 9.93 × 10-17 ). ROC analysis showed that miRNA-4508 could distinguish SPF cases from healthy controls with high AUC (0.886), with sensitivity of 81.7% and specificity of 86.7%. In addition, the miRNA-4508 upstream rs6576457 mutant A allele exhibited a strong association with susceptibility to SPF (OR = 1.64, 95% CI = 1.20-2.23, P = 0.002), while eQTL analysis revealed a potential association between different genotypes of rs6576457 and miRNA-4508 expression (P = 0.068) in 60 healthy subjects with silica dust exposure. CONCLUSION: miRNA-4508 may be a potential diagnostic marker for SPF, and rs6576457, a functional variant of miRNA-4508, may affect SPF susceptibility. The detailed mechanism of action of this miRNA remains to be elucidated.
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MicroARNs , Fibrosis Pulmonar , Dióxido de Silicio/inmunología , Adulto , Estudios de Casos y Controles , Femenino , Marcadores Genéticos/inmunología , Predisposición Genética a la Enfermedad , Humanos , Linfocitos/inmunología , Masculino , MicroARNs/genética , MicroARNs/inmunología , Fibrosis Pulmonar/diagnóstico , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/inmunología , Curva ROC , Reproducibilidad de los ResultadosRESUMEN
Due to their high heterogeneity and complex tumor microenvironment, the treatment of solid tumors by CAR-T cell technology is limited. This study developed bi-specific Trop2/PD-L1 specific third-generation CAR-T cells by lentiviral infection. The specific killing ability of the bi-specific CAR-T cells against Trop2+ and PD-L1+ expressed on the gastric cancer cell line by CCK-8 assay, was confirmed in vitro. The killing ability of bi-specific Trop2/PD-L1 CAR-T cells was higher than that of mono-specific CAR-T cells (Trop2 CAR-T and PD-L1 CAR-T) and the independent control group (CD19-CAR-T and CIK). The bi-specific Trop2/PD-L1 CAR-T cells produced IFN-γ and IL-2 in response to the overexpression of Trop2 and PD-L1 in gastric cancer cells through ELASA assay. The levels of cytokines (IFN-γ and IL-2) released by bi-specific Trop2/PD-L1 CAR-T cells were the highest among all other types of CAR-T cells and the independent control group. To further demonstrate the ability of bi-specific Trop2/PD-L1 CAR-T cells in vivo, this study testified to the anti-tumor effect of several types of CAR-T cells through a xenograft model bearing human gastric tumors. The results indicated that bi-specific Trop2/PD-L1 CAR-T cells can significantly reduce the tumor growth through intratumoral injection, with a higher inhibition effect than Trop2 specific CAR-T cells and the independent control group (CD19-CAR-T and untreated group). These results suggest that novel bi-specific Trop2/PD-L1 CAR-T cells are able to target Trop2/PD-L1 and checkpoint blockade, and reveal the killing effect on gastric cancer, therefore improving the killing effect of CAR-T cells in solid tumors.
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Hepatocellular carcinoma (HCC) is one of the most mortality-causing solid cancers globally and the second largest cause of death among malignancies. Oxaliplatin, a platinum-based drug, has been widely utilized in the treatment of malignancies such as colorectal cancer and hepatocellular carcinoma, yet its usage is limited because of severe side effects of cytotoxicity to normal tissues. c-Met, a receptor tyrosine kinase, is expressed aberrantly on the surface of HCC. The purpose of this study was to synthesise a humanized antibody against c-Met (anti-c-Met IgG) and conjugate it to oxaliplatin to develop a novel antibody-drug conjugate (ADC). Anti-c-Met IgG was detected to be loaded with ~4.35 moles oxaliplatin per mole of antibody. ELISA and FCM confirmed that ADC retained a high and selective binding affinity for c-Met protein and c-Met-positive HepG2 cells. In vitro, the cytotoxicity tests and biological function assay indicated that ADC showed much higher cytotoxicity and functioning in c-Met-positive HepG2 cells, compared with shMet-HepG2 cells expressing lower levels of c-Met. Furthermore, compared with free oxaliplatin, ADC significantly improved cytotoxicity to c-Met-positive tumours and avoided off-target cell toxicity in vivo. In conclusion, by targeting c-Met-expressing hepatoma cells, ADC can provide a platform to reduce drug toxicity and improve drug efficacy in vitro and in vivo.
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Recently, long noncoding RNAs (lncRNAs) have been shown to play significant regulatory roles in human tumorigenesis. However, the biological function of lncRNAs in cholangiocarcinoma (CCA) remains largely unknown. In this study, DANCR was shown to be significantly upregulated in CCA. DANCR regulated the proliferation and migration of CCA cells in vitro. Moreover, downregulation of DANCR suppressed CCA cells proliferation in vivo. RNA-seq revealed that DANCR knockdown preferentially affected genes linked with cell proliferation and cell differentiation. Furthermore, mechanistic investigation validated that DANCR could bind EZH2 and modulate the histone methylation of promoter of FBP1, thereby regulating CCA cells growth and migration. Taken together, these results demonstrated the significant roles of DANCR in CCA and may provide a theoretical basis for clinical diagnosis and treatment of CCA.
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Neoplasias de los Conductos Biliares/metabolismo , Carcinogénesis/genética , Movimiento Celular/genética , Proliferación Celular/genética , Colangiocarcinoma/metabolismo , Epigénesis Genética , ARN Largo no Codificante/metabolismo , Animales , Neoplasias de los Conductos Biliares/patología , Línea Celular Tumoral , Colangiocarcinoma/patología , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Fructosa-Bifosfatasa/metabolismo , Técnicas de Silenciamiento del Gen , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , ARN Largo no Codificante/genética , Transfección , Carga Tumoral/genéticaRESUMEN
Gastric cancer is one of the most common types of human cancer, and it is additionally one of the leading causes of cancerassociated mortality worldwide. Previous studies have suggested that interleukin (IL)10 may contribute to the pathogenesis of gastric cancer. However, the underlying mechanisms remain unclear. In the present study, it was observed that the expression of IL10 was significantly upregulated in gastric tumor tissues and serum samples of patients with gastric cancer. Furthermore, IL10 was increased in the cell culture supernatant of cancerassociated macrophages (CAMs). Treatment with cell culture supernatant from CAMs induced a significant increase in proliferation and migration, while it suppressed apoptosis, in MGC803 and BGC823 gastric cancer cells. Notably, application of an inhibitory IL10 antibody partially blocked the cell culture supernatant of CAMinduced oncogenic effects. RNAsequencing analysis was then performed to identify the differentially expressed genes in MGC803 cells treated with IL10. Based on the sequencing results and in vitro analysis, it was demonstrated that IL10induced carcinogenic behaviors in MGC803 cells were potentially mediated by activation of the cMet/STAT3 signaling pathway. In conclusion, the present results demonstrated that IL10 secreted by CAMs may be involved in the pathogenesis of gastric cancer, suggesting that IL10 may serve as a potential therapeutic target for the treatment of gastric cancer.
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Biomarcadores de Tumor/metabolismo , Proliferación Celular , Interleucina-10/metabolismo , Macrófagos/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Factor de Transcripción STAT3/metabolismo , Neoplasias Gástricas/patología , Anciano , Apoptosis , Estudios de Casos y Controles , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Macrófagos/patología , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias Gástricas/metabolismo , Células Tumorales CultivadasRESUMEN
Background: As reported by numerous research studies, the expression levels of SNHG1 (small nucleolar RNA host gene 1) are increased in different kinds of tumours, revealing that SNHG1 is likely to perform a crucial function in cancer prevalence and progression. Moreover, a mounting degree of evidence suggests that increased SNHG1 expression also has an association with poor medical outcomes among cancer patients. Materials and methods: Collection of qualifying research studies was performed through the retrieval of keywords in PubMed and Web of Science, up to March 20, 2018. This quantitative meta-analysis was carried out using Stata SE12.0 software and aimed at exploring the connection between the expression level of SNHG1 and clinicopathology. Results: Ten research studies, involving an aggregate of 715 patients, met the inclusion criteria. As suggested by the findings of the current meta-analysis, with regard to prognosis, the patients with high expression of SNHG1 had poorer overall survival (OS) (HR =3.36, 95% CI: 2.42, 4.67) and, with regard to their clinicopathology, increased SNHG1 was associated with advanced TNM stage (RR =1.88, 95% CI: 1.58, 2.24), poorly differentiated histological grade (RR =1.38, 95% CI:1.09, 1.76), and positive lymph node metastasis (RR =1.80, 95% CI: 1.42, 2.29). Conclusion: As revealed by this meta-analysis, elevated SNHG1 expression is typical in various types of cancer. In addition, elevated SNHG1 expression is likely to function as an advanced predictive element of poor prognosis and lymph node metastasis in various cancer types. Nonetheless, to date, it remains essential to carry out larger-size and better-designed research studies for the confirmation of our findings.
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To investigate the associations between the functional single nucleotide polymorphisms (SNPs) in the miR-125 family and the survival of non-small cell lung cancer (NSCLC) patients, we systematically selected six functional SNPs located in three pre-miRNAs (miR-125a, miR-125b-1, miR-125b-2). Cox proportional hazard regression analyses were conducted to estimate the crude and adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs). Reporter gene luciferase assay was performed to examine the relationship between the SNPs and transcriptive activity of the miRNAs. The expression of miRNAs in different cells was detected using quantitative real-time PCR assay. We found that rs2241490 (upstream of miR-125b-1, G > A, adjusted HR = 1.24, 95%CI = 1.05-1.48, P = 0.014, in dominant model; adjusted HR = 1.18, 95%CI = 1.03-1.35, P = 0.014, in additive model), rs512932 (upstream of miR-125b-1, A > G, dominant model: adjusted HR = 1.25, 95%CI = 1.05-1.48, P = 0.013) and rs8111742 (upstream of miR-125a, G > A, dominant model: adjusted HR = 0.84, 95%CI = 0.71-1.00, P = 0.047) were associated with the prognosis of 1001 Chinese NSCLC patients. The combined analysis of the three SNPs related the number of risk alleles (rs2241490-A, rs512932-G and rs8111742-G) to death risk of NSCLC in a locus-dosage mode (P for trend <0.001). Furthermore, luciferase reporter gene assay showed significantly higher levels of luciferase activity with rs512932 variant G than that with A allele in 293T, SPC-A1 and A549 cell lines. Besides, miR-125b was highly expressed in lung cancer cells than the normal lung cell. Our study indicated that genetic variations in miR-125 family were implicated in the survival of NSCLC patients. Larger population-based and functional studies are needed to verify these findings.
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Pueblo Asiatico/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Neoplasias Pulmonares/mortalidad , MicroARNs/genética , Polimorfismo de Nucleótido Simple , Regulación hacia Arriba , Células A549 , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Pulmonares/genética , Masculino , Pronóstico , Análisis de SupervivenciaRESUMEN
OBJECTIVES: In a genome-wide association study, we discovered chromosome 12q15 (defined as rs73329476) as a silica-related pneumoconiosis susceptibility region. However, the causal variants in this region have not yet been reported. METHODS: We systematically screened eight potentially functional single-neucleotide polymorphism (SNPs) in the genes near rs73329476 (carboxypeptidase M (CPM) and cleavage and polyadenylation specific factor 6 (CPSF6)) in a case-control study including 177 cases with silicosis and 204 healthy controls, matched to cases with years of silica dust exposure. We evaluated the associations between these eight SNPs and the development of silicosis. Luciferase reporter gene assays were performed to test the effects of selected SNP on the activity of CPM in the promoter. In addition, a two-stage case-control study was performed to investigate the expression differences of the two genes in peripheral blood leucocytes from a total of 64 cases with silicosis and 64 healthy controls with similar years of silica dust exposure as the cases. RESULTS: We found a strong association between the mutant rs12812500 G allele and the susceptibility of silicosis (OR=1.45, 95% CI 1.03 to 2.04, p=0.034), while luciferase reporter gene assays indicated that the mutant G allele of rs12812500 is strongly associated with increased luciferase levels compared with the wild-type C allele (p<0.01). Moreover, the mRNA (peripheral blood leucocytes) expression of the CPM gene was significantly higher in subjects with silicosis compared with healthy controls. CONCLUSIONS: The rs12812500 variant of the CPM gene may increase silicosis susceptibility by affecting the expression of CPM, which may contribute to silicosis susceptibility with biological plausibility.
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Metaloendopeptidasas/genética , Exposición Profesional/efectos adversos , Neumoconiosis/genética , Dióxido de Silicio/toxicidad , Estudios de Casos y Controles , China , Proteínas Ligadas a GPI/genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Modelos Logísticos , Neumoconiosis/etiología , Polimorfismo de Nucleótido SimpleRESUMEN
Long noncoding RNAs (lncRNAs) have been classically defined as regulatory RNA members >200 nucleotides in length, without detectable openreading frames to encode proteins. Previous studies have demonstrated that lncRNAs serve critical roles in multiple cancer types. Colon cancerassociated transcript 1 (CCAT1), a novel cancerassociated lncRNA, is significantly overexpressed in a number of malignancies. Functionally, as an oncogenic lncRNA, CCAT1 is involved in proliferation, migration, cell cycle progression, apoptosis, chemoresistance and other biological processes of cancer cells through complex regulation mechanisms in the cytoplasm or nucleus. In clinical applications, CCAT1 is additionally positively associated with histological differentiation, tumour node metastasis stage, vascular invasion, overall survival and recurrencefree survival, which demonstrates its important role as a diagnostic and prognostic marker in cancer. The present review summarises the current research progress of the oncogenic potential and clinical uses of CCAT1 in various human cancer types.
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Neoplasias del Colon/genética , Neoplasias del Colon/patología , ARN Largo no Codificante/genética , Apoptosis/genética , Carcinogénesis/genética , Diferenciación Celular/genética , Movimiento Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Oncogenes/genética , PronósticoRESUMEN
Cholangiocarcinoma (CCA) is the most common biliary tract malignancy, with a low survival rate and limited treatment options. Long non-coding RNAs (lncRNAs) have recently been verified to have significant regulatory functions in many kinds of human cancers. It was discovered in this study that the lncRNA PVT1, whose expression is significantly elevated in CCA, could be a molecular marker of CCA. Experiments indicated that PVT1 knockdown greatly inhibited cell migration and proliferation in vitro and in vivo. According to RNA sequencing (RNA-seq) analysis, PVT1 knockdown dramatically influenced target genes associated with cell angiogenesis, cell proliferation, and the apoptotic process. RNA immunoprecipitation (RIP) analysis demonstrated that, by binding to epigenetic modification complexes (PRC2), PVT1 could adjust the histone methylation of the promoter of ANGPTL4 (angiopoietin-like 4) and, thus, promote cell growth, migration, and apoptosis progression. The data verified the significant functions of PVT1 in CCA oncogenesis, and they suggested that PVT1 could be a target for CCA intervention.
RESUMEN
Cholangiocarcinoma (CCA) is the as the most frequently observed biliary tract malignancy, which has low survival rate in addition to constrained treatment options; nevertheless, the fundamental molecular phenomenon underlying malignant progression of CCA is quite ambiguous. Recently long non-coding RNAs (lncRNAs) have been found to have significant regulatory functions in several human cancers. Herein, we have figured out that lncRNA SNHG1, with substantially enhanced expression in CCA, is capable of acting as the oncogenic molecule of CCA. As revealed by our data, SNHG1 knockdown extensively inhibited CCA cell migration as well as proliferation in vitro and in vivo. In addition, in accordance with the findings of the RNA-Seq analysis, SNHG1 knockdown exhibited a significant impact on the target genes that were linked to cell migration and regulation of cell proliferation, in addition to the apoptotic phenomenon. In a mechanistic manner, we also showed that SNHG1 bound to the histone methyltransferase enhancer of the zeste homolog 2 (EZH2, which is regarded as the catalytic subunit of the polycomb repressive complex 2 (PRC2), which is an extremely conserved protein complex regulating gene expression with the help of methylating lysine 27 on histone H3), specifying the histone alteration pattern on the target genes, including CDKN1A, and, as a result, altered the CCA cell biology. These data verified a major function of the epigenetic regulation of SNHG1 in CCA oncogenesis, in addition to its likely function as a target for CCA interruption.