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Head and neck cancer (HNC) is mainly treated by surgery, radiotherapy, and adjuvant chemotherapy; however, the prognosis of some patients with HNC is poor because of radiotherapy and chemotherapy resistance. In recent years, antiPD1 monoclonal antibodies have shown certain efficacy, and a change of the tumor immune microenvironment is the main reason for the failure of HNC immunotherapy. The present study aimed to identify and verify that CD38, which is closely related to the prognosis of HNC, is a potential biological marker of radiotherapy and chemotherapy resistance and PD-L1 immunotherapy resistance via a comprehensive bioinformatic analysis in The Cancer Genome Atlas and Gene Expression Omnibus databases. According to the UALCAN database, the transcript level of CD38 in HNC was analyzed using cluster analysis, and the expression of CD38 mRNA in HNC was detected using the Oncomine database. The characteristics of CD38-related oncogenes were identified by gene cluster enrichment analysis in LinkedOmics. The R2 and SEER databases were used to further evaluate the prognostic significance of the CD38 gene in HNC using receiver operating characteristic curve analysis of Kaplan-Meier (KM) survival and the clinical characteristics of the subjects. The protein-protein interaction network of the top 50 genes showing significant positive correlations with CD38 in HNC was analyzed using STRING. Finally, we used a nasopharyngeal carcinoma (NPC) cell line to verify the biological function. The results showed that the levels of CD38 mRNA expression in patients with HNC were significantly higher than those in healthy controls. The levels of CD38 mRNA expression in patients with HNC of different ages, sexes, and races were significantly higher than those in the healthy controls. CD38 is an independent prognostic factor for HNC, and high expression of CD38 indicates poor prognosis. CD38 expression correlated positively with the markers of many kinds of immune cells, and correlated significantly with the expression of PD-L1. We found that the high expression of CD38 suggested a poor prognosis in the subgroup of tumors treated with chemotherapeutic drugs in the G1/S phase. We used HNC cell lines to verify that the high expression of CD38 promoted the proliferation of NPC cells and produced radiotherapy tolerance. Through comprehensive bioinformatics analysis, we suggested that CD38 is a key gene involved in radiotherapy, chemotherapy, and immune drug resistance in HNC. This study provides a reliable biomarker to predict the prognosis of patients with HNC and a reference for clinical comprehensive treatment of HNC. Individualization combined with CD38 monoclonal antibodies might provide a promising treatment strategy for this fatal disease, and this comprehensive treatment might reduce the damage to normal tissue and improve the prognosis and quality of life of patients with HNC.
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Tumor is one of the ten leading causes of death in the world. Traditional tumor treatments include surgery, radiation therapy, and chemotherapy. With the development of immune checkpoint blockade therapy targeting the programmed death 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis, the number of cancers in solid tumors has increased. Changes in the immunometabolic microenvironment have been shown to be important regulators of innate suppression of immune cell function and acquired resistance to immunotherapy. As a new target, CD38 is an enzyme that produces immunosuppressive metabolites (such as adenosine), which can be used in combination with immunotherapy to improve the clinical efficacy of tumor therapy, and can also be used as an indicator for understanding tumor immunotherapy response.
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Neoplasias , Receptor de Muerte Celular Programada 1 , Antígeno B7-H1/metabolismo , Terapia Combinada , Humanos , Inmunoterapia , Neoplasias/terapia , Receptor de Muerte Celular Programada 1/metabolismo , Microambiente TumoralRESUMEN
Background: Lung cancer remains the leading cause of cancer death worldwide, and the most subtype is lung adenocarcinoma (LUAD). Tumor-infiltrating immune cells (TIICs) greatly impact the prognosis of LUAD. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), signal via its receptor fibroblast growth factor-inducible 14 (Fn14), dysregulates immune cell recruitment within tumor environment, thus promoting the progression of autoimmune diseases and cancer. We aimed to explore its role in LUAD. Methods: The expression level of TWEAK was explored in Tumor Immune Estimation Resource 2.0 (TIMER2.0) and Oncomine databases. The Tumor Immune Dysfunction and Exclusion (TIDE) and Lung Cancer Explorer (LCE) databases were applied to evaluate the survival in correlation to TWEAK expression. TIICs were assessed with TIMER2.0 and TIDE datasets. The expression of TWEAK protein was detected in LUAD cell lines and also in tissue samples from LUAD patients via western blotting or combination with immunochemistry. Results: Our results showed that TWEAK was downregulated in LUAD tumors compared to normal tissues in TIMER2.0, Oncomine, cell lines, and clinical specimens. Poor survival was uncovered in lower TWEAK expression of LUAD patients in LCE (meta - HR = 0.84 [95% CI, 0.76-0.92]) and TCGA (Continuous Z = -1.97, p = 0.0486) and GSE13213@PRECOG (Continuous Z = -4.25, p = 2.12e - 5) in TIDE. Multiple tumor-infiltrating immune cells (TIICs) were found closely correlated with TWEAK expression in LUAD, especially hematopoietic stem cell (Rho = 0.505, p = 2.78e - 33), common lymphoid progenitor (Rho = -0.504, p = 3.79e - 33), and myeloid-derived suppressor cells (MDSCs) (Rho = -0.615, p = 1.36e - 52). Conclusion: Lower level of TWEAK was linked with poor survival and aberrant recruitment and phenotype of TIICs in LUAD, which might motivate immune escape and weaken the effects of immunotherapy.
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Adenocarcinoma del Pulmón , Citocina TWEAK , Neoplasias Pulmonares , Linfocitos Infiltrantes de Tumor , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Citocina TWEAK/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Receptores del Factor de Necrosis Tumoral/genética , Receptores del Factor de Necrosis Tumoral/metabolismo , Receptor de TWEAK/genética , Factores de Necrosis Tumoral/genéticaRESUMEN
Osteosarcoma is a big challenge on clinical treatment. The breakthrough associated with osteosarcoma in basic research and translational research depends on the reliable establishment of an animal model, whereby mice are frequently used. However, a traditional animal modeling technique like tumor cell suspension injection causes batch dynamics and large mice consumption. Here, we suggested a novel approach in establishing an orthotropic osteosarcoma model in nude mice rapidly by cell sheet culture and transplantation. Our findings demonstrated that the 143b osteosarcoma cell sheet orthotopically implanted into the nude mice could form a visible mass within 10 days, whereas it took over 15 days for a similar amount of cell suspension injection to form a visible tumor mass. Living animal imaging results showed that a tumor formation rate was 100% in the cell sheet implantation group, while it was 67% in the cell suspension injection group. The formed tumor masses were highly consistent in both growth rate and tumor size. Massive bone destruction and soft tissue mass formation were observed from the micro CT analysis, suggesting the presence of osteosarcoma. The histopathological analysis demonstrated that the orthotropic osteosarcoma model mimicked the tumor bone growth, bone destruction, and the lung metastasis. These findings imply that such a cell sheet technology could be an appropriate approach to rapidly establish a sustainable orthotropic osteosarcoma model for tumor research and reduce mice consumption.
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CD90, also known as Thy-1 cell surface antigen, is located on human chromosome 11q23.3, and encodes a glycosylphosphatidylinositol-linked cell surface glycoprotein. CD90 serves a key role in malignancy by regulating cell proliferation, metastasis and angiogenesis. Gastric cancer is one of the most common types of malignancy. Patients with advanced gastric cancer have a poor prognosis. CD90 plays a key role in the occurrence and progression of gastric cancer. However, the molecular mechanism of CD90 in gastric cancer is currently unclear. In order to identify the molecular mechanism by which CD90 affects the biological behavior and energy metabolism of gastric cancer cells, the present study used Cell Counting Kit-8 assays, lactate concentration determination and ATP content determination. The results demonstrated that CD90 promotes proliferation and inhibits senescence in gastric cancer cells. In addition, CD90 enhanced the invasion and migration abilities of AGS gastric cancer cells. Overexpression of CD90 resulted in the accumulation of intracellular lactic acid in AGS cells. CD90 upregulated lactate dehydrogenase levels and increased the NADPH/NADP+ ratio in AGS cells. CD90 overexpression decreased the ATP concentration in AGS cells. PI3K, PDK1, phosphorylated-AKT-Ser473, HIF-1α, MDM2 and SIRT1 levels were upregulated in CD90-overexpressing AGS cells, compared with AGS cells transfected with the empty vector. In contrast, PTEN, p53, SIRT2, SIRT3 and SIRT6 were downregulated. The results indicate that CD90 affects the biological behavior and levels of energy metabolism of gastric cancer cells by targeting the PI3K/AKT/HIF-1α signaling pathway.
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Erythropoietin-producing hepatocellular receptor A2 (EphA2) receptor tyrosine kinase plays an important role in tissue organization and homeostasis in normal organs. EphA2 is overexpressed in a variety of types of solid tumours with oncogenic functions. However, the role of EphA2 in cervical cancer (CC) is still needed to be further explored. Here, we examined the role of EphA2 by establishing a stable EphA2 knock-down CC cell lines or a stable EphA2-overexpressed CC cells lines. Overexpression of EphA2 increased cell proliferation and migration of CC while EphA2 knock-down decreased the CC tumorigenicity. In addition, EphA2 knock-down suppressed CC tumour development in the xenograft mouse model. Inhibition of EphA2 by AWL-II-41-27, EphA2-specific tyrosine kinase inhibitor, or knock-down of EphA2 decreased mRNA and protein expression of cyclin-dependent kinase (CDK) 6 in CC cells, which increased cellular susceptibility to epirubicin (EPI), an anti-cancer chemotherapy drug. A clinicopathological study of EphA2 was conducted on a cohort of 158 human CC patients. EphA2 protein expression was positively correlated with CDK6 protein expression, invasion depth, lymph node metastasis and clinicopathological stage (P < .05). This study demonstrates the oncogenic activity of EphA2 in vitro and in vivo, which provides insights into the relevant mechanisms that might lead to novel treatments for CC.
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Transformación Celular Neoplásica/genética , Quinasa 6 Dependiente de la Ciclina/genética , Regulación Neoplásica de la Expresión Génica , Receptor EphA2/genética , Neoplasias del Cuello Uterino/etiología , Neoplasias del Cuello Uterino/metabolismo , Adulto , Anciano , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Xenoinjertos , Humanos , Ratones , Persona de Mediana Edad , Clasificación del Tumor , Receptor EphA2/metabolismo , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patologíaRESUMEN
PURPOSE: Gliomas, characterized by aggressiveness and invasiveness, remain incurable after conventional therapies. The molecular mechanisms driving the progression and maintenance of glioma are still poorly understood. METHODS: The TCGA and CGGA databases were chosen for bioinformatics analysis. Gene expression profiling interactive analysis (GEPIA) was performed for differential analysis. The Kaplan-Meier method was chosen for survival analysis. Analysis of stromal and immune infiltration was performed using the ESTIMATE algorithm and xCell package. qPCR and Western blotting were performed to measure the expression of PDIA4 at the mRNA and protein levels. IHC was performed to detect the expression of PDIA4 in glioma tissues. The viability of glioma cells was evaluated by the CCK8 assay. RESULTS: In this study, we identified high PDIA4 expression in gliomas that correlated with poor prognosis. The association between IDH1 and different glioma patterns also indicated the potential biological role of PDIA4 in tumor development. Mechanistically, PDIA4 interacted with multiple immunological components to promote an immunosuppressive tumor microenvironment (TME). Knockdown of PDIA4 significantly impaired the proliferation of GBM cells. CONCLUSION: Our results confirm that PDIA4 is an efficient biomarker of gliomas, with clinical implications for prognosis and therapeutic strategies.
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The oncogenesis of cervical cancer is a multi-factor and multi-step process, and major risk factors include oncogene activation with tumor suppressor gene inactivation, viral factors, and immune factors. For example, the human papillomavirus (HPV) has been linked to the occurrence of cervical cancer. At present, the pathogenesis of cervical cancer remains unclear. Fra-1 (Fos-related antigen 1, also known as FOSL1) is a member of the Fos family and an important nuclear transcription factor that regulates normal cell growth, differentiation, and apoptosis. In the present study, we found that Fra-1 inhibited the proliferation of cervical cancer cells while also promoting apoptosis and affecting cell cycle distribution. Moreover, Fra-1 up-regulated STAT1 expression and modulated p53 signal pathway activity in cervical cancer cells. Overexpression of Fra-1 inhibited cell senescence by altering sirtuin 1 (SIRT1) expression in HeLa cells, and Fra-1 overexpression restored mitochondrial disorder and suppressed metabolic reprogramming in HeLa cells. Silencing of STAT1 impaired the inhibitory effect of Fra-1 on cervical cancer cell growth, while knock-down of STAT1 reversed the effect on cell senescence and mitochondrial dysfunction caused by Fra-1 in HeLa cells. Silencing of STAT1 also recovered metabolic reprogramming in cervical cancer cells. In summary, our results show that Fra-1 inhibited cervical cancer cell growth and the Warburg effect via STAT1-mediated regulation of the p53 signaling pathway.
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Gastric cancer (GC) is one of the most common malignant tumor types worldwide. Long non-coding RNAs (lncRNAs) have important epigenetic effects, including altering the proliferation and metastasis of malignant tumors. We used gene chip technology to search for lncRNAs that were differentially expressed in GC and metastatic lymph node tissues compared with adjacent normal tissues. The lncRNA Loc490 and the RNA-binding protein Quaking (QKI) were downregulated in GC tissues and lymph node metastases compared with normal tissues, and the levels of these two genes correlated positively with one another. Loc490 expression correlated negatively with lymph node metastasis and vein/nerve invasion, while it correlated positively with overall and disease-free survival. In vitro, Loc490 post-translationally enhanced the expression of QKI and suppressed the expression of epithelial-mesenchymal transition-related molecules. Overexpression of Loc490 inhibited GC cell proliferation, invasion and metastasis and exerted strong antitumor effects in vivo, while silencing of QKI antagonized these effects. A potential binding site between Loc490 and QKI was detected through bioinformatics analysis and confirmed through RNA immunoprecipitation and mutant analyses. Our results suggest that lncRNA Loc490 inhibits GC cell proliferation and metastasis by upregulating RNA-binding protein QKI.
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As a unique type of RNA, circular RNAs (circRNAs) are important regulators of multiple biological processes in the progression of cancer. However, the potential role of most circRNAs in breast cancer lung metastasis is still unknown. In this study, we characterized and further investigated circIQCH (hsa_circ_0104345) by analyzing the circRNA microarray profiling in our previous study. circIQCH was upregulated in breast cancer tissues, especially in the metastatic sites. CCK-8, transwell, wound-healing and mouse xenograft assays were carried out to investigate the functions of circIQCH. Knockdown of circIQCH inhibited breast cancer cell proliferation and migration to lung. Moreover, luciferase reporter assays and RNA immunoprecipitation assays were performed to elucidate the underlying molecular mechanism of circIQCH. The results showed that circIQCH sponges miR-145 and promotes breast cancer progression by upregulating DNMT3A. In summary, our study demonstrated the pivotal role of circIQCH-miR-145-DNMT3A axis in breast cancer growth and metastasis via the mechanism of competing endogenous RNAs. Thus, circIQCH could be a potential therapeutic target for breast cancer.
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Neoplasias de la Mama/genética , Metilasas de Modificación del ADN/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , ARN Circular/metabolismo , Regulación hacia Arriba/genética , Animales , Progresión de la Enfermedad , Femenino , Ratones , Ratones Endogámicos BALB C , ARN Circular/genética , Células Tumorales CultivadasRESUMEN
In contrast to normal cells, cancer cells typically undergo metabolic reprogramming. Studies have shown that oncogenes play an important role in this metabolic reprogramming. CD38 is a multifunctional transmembrane protein that is expressed abnormally in a variety of tumor types. To investigate the effect and possible mechanism of CD38 in cervical cancer cells and to provide a new therapeutic target for the treatment of cervical cancer, the present study identified that CD38 is involved in regulating cell metabolism in cervical cancer cells. Liquid chromatographytandem mass spectrometry and bioinformatic analyses revealed that differentially abundant proteins in CD38overexpressed cervical cancer cells (CaSkiCD38 and HeLaCD38) are predominantly involved in glycolytic pathways, oxidative phosphorylation and the NAD/NADH metabolic process. Further experiments using an ATP test kit and lactate test kit revealed that CD38 promotes glucose consumption, increases lactate accumulation and increases ATP production. In addition, CD38 increases the phosphorylation of phosphatidylserine/threonine kinase (AKT), mechanistic target of rapamycin (mTOR) and phosphatidylinositol4,5bisphosphate 3kinase (PI3K), which play a key role in tumor metabolism. Furthermore, it was found that the energy metabolism of cervical cancer cells was inhibited following treatment with the mTOR inhibitor rapamycin. In conclusion, the results of the present study suggested that CD38 regulates the metabolism of cervical cancer cells by regulating the PI3K/AKT/mTOR pathway, which may be a candidate target for the treatment of cervical cancer.
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ADP-Ribosil Ciclasa 1/metabolismo , Metabolismo Energético/fisiología , Glicoproteínas de Membrana/metabolismo , Neoplasias del Cuello Uterino/patología , Metabolismo Energético/efectos de los fármacos , Femenino , Células HeLa , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias del Cuello Uterino/tratamiento farmacológicoRESUMEN
Protein tyrosine phosphatase H-type receptor (PTPRH) gene encodes a gastric cancer associated protein, which exerts its biological function through tyrosine phosphorylation in the post-translational COOH- terminal region. PTPRH is abnormally expressed in a variety of tumors, and its biological function is closely related to the occurrence, development and prognosis of tumors.
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Neoplasias Gástricas , Humanos , Fosforilación , Proteínas Tirosina Fosfatasas , Proteínas , TirosinaRESUMEN
Nasopharyngeal carcinoma (NPC) is a common pattern of regional malignancy in the south of China, especially in Guangdong province. The development of computerized tomography (CT) technology and the improvement of radiotherapy scheme can improve the survival rate of NPC patients. However, the prevalence and recurrence rate of NPC are increasing every year. It is urgent for us to uncover the molecular mechanism of NPC. In this study, we used scientific information retrieval from the GEO (gene expression omnibus) database to download the GSE12452, which contained 41 samples, including 31 nasopharyngeal carcinoma samples and 10 control samples. With the help of GO (gene ontology) analysis, KEGG (kyoto encyclopedia of genes and genomes) analysis, PPI (protein-protein interaction) network model construction, and WGCNA (weighted gene co-expression network analysis), we found 6896 differentially expressed genes, which affected the biological processes included cell cycle process, DNA metabolic process, DNA repairing, immune response, cell activation, regulation of immune system process, inflammatory response. The 20 hub genes present in front of us are SYK, PIK3CG, FYN, ACACB, LRRK2, RIPK4, RAC2, PIK3CD, PTPRC, LCR, RAD51, MAD2L1, CDK1, PCNA, GMPS, CCNB1, GAPDH, CCNA2, RFC4, TOP2A. In the future, these are the areas where we need to focus on the molecular mechanism of NPC.
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Biología Computacional/métodos , Carcinoma Nasofaríngeo/genética , Pueblo Asiatico/genética , Macrodatos , Carcinoma Hepatocelular/genética , China , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/genética , Ontología de Genes , Redes Reguladoras de Genes/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Nasofaríngeas/genética , Recurrencia Local de Neoplasia/genética , Mapas de Interacción de ProteínasRESUMEN
Nasopharyngeal carcinoma (NPC) is the most common malignant tumor type in Southern China and SouthEast Asia. Cluster of differentiation (CD)38 is highly expressed in the human immune system and participates in the activation of T, natural killer and plasma cells mediated by CD2 and CD3 through synergistic action. CD38 is a type II transmembrane glycoprotein, which was observed to mediate diverse activities, including signal transduction, cell adhesion and cyclic ADPribose synthesis. However, the significance of CD38 in NPC biological behavior and cellular energy metabolism has not been examined. In order to elucidate the effect of CD38 on the biological behavior of NPC cells, stable CD38overexpressed NPC cell lines were established. It was demonstrated that CD38 promoted NPC cell proliferation with Cell Counting Kit8 and colony formation assays. It was also indicated that CD38 inhibited cell senescence, and promoted cell metastasis. Furthermore, it was determined that CD38 promoted the conversion of cells to the S phase and decreased the content of reactive oxygen species and Ca2+. Additionally, cell metabolism assays demonstrated that CD38 increased the concentration of ATP, lactic acid, cyclic adenosine monophosphate and human ADP/acrp30 concentration in NPC cells. To investigate the possible mechanism, bioinformatics analysis and mass spectrometry technology was used to determine the most notably changing molecule and signaling pathways, and it was determined and verified that CD38 regulated the metabolicassociated signaling pathways associated with tumor protein 53, hypoxia inducible factor1α and sirtuin 1. The present results indicated that CD38 may serve a carcinogenic role in NPC by regulating metabolicassociated signaling pathways.
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ADP-Ribosil Ciclasa 1/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Carcinoma Nasofaríngeo/genética , Proteína p53 Supresora de Tumor/genética , ADP-Ribosil Ciclasa 1/inmunología , ADP-Ribosil Ciclasa 1/metabolismo , Adenosina Trifosfato/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Metabolismo Energético/genética , Metabolismo Energético/inmunología , Regulación Neoplásica de la Expresión Génica , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/inmunología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Ácido Láctico/inmunología , Ácido Láctico/metabolismo , Carcinoma Nasofaríngeo/inmunología , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Sirtuina 1/genética , Sirtuina 1/inmunología , Sirtuina 1/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Proteína p53 Supresora de Tumor/inmunología , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Accurate measurement of strain is one of the most important issues for high temperature environments. We present a highly integrated all-fiber sensor to achieve precise measurements of strain/high-pressure, which consists of a fiber Bragg grating (FBG) inscribed by an 800 nm femtosecond laser cascaded with a micro extrinsic Fabryâ»Perot (FP) cavity fabricated by the 157 nm laser micromachining technique. FBG is sensitive to temperature, but insensitive to strain/pressure, whereas the FP is sensitive to strain/pressure, but has a small dependence on temperature. Therefore, such a cascaded sensor could be used for dual-parameter measurement and can work well at high temperatures. Experimental results indicate that this device exhibits a good strain characteristic at high temperatures and excellent high-pressure performance at room temperature. Due to its highly sensitive wavelength response, the proposed sensor will have remarkable potential applications in dual parameter sensing in harsh environments.
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The Fip1-like1 (FIP1L1)-platelet-derived growth factor receptor alpha (PDGFRA) (F/P) oncogene can cause chronic eosinophilic leukemia (CEL), but requires IL-5 cytokine participation. In this study, we investigate the mechanism of F/P in collaboration with IL-5 in CEL. The results showed that Lyn, a key effector in the IL-5-motivated eosinophil production, is extensively activated in F/P-positive CEL cells. Lyn can associate and phosphorylate IL-5 receptor α (IL-5RA) in F/P-positive cells. Moreover, the activation of Lyn and IL-5R kinase were strengthened when the cells were stimulated by IL-5. Lyn inhibition in F/P-positive CEL cells attenuated cellular proliferation, induced apoptosis, and blocked cell migration and major basic protein (MBP) release. We identified the FIP1L1-PDGFRA/JAK2/Lyn/Akt complex in the F/P-expressing cells which can be disrupted by dual inhibition of JAK2 and Lyn, repressing cell proliferation in both EOL-1(F/P-positive human eosinophilic cell line) and imatinib-resistance (IR) cells. Altogether, our data demonstrate that Lyn is a vital downstream kinase activated by F/P converged with IL-5 signals in CEL cells. Lyn activate and expand IL-5RA intracellular signaling through FIP1L1-PDGFRA/JAK2/Lyn/Akt network complex, provoking eosinophils proliferation and exaggerated activation manifested as CEL.
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DNA demethylases of the TET family function as tumor suppressors in various human cancers, but their pathogenic contributions and mechanisms of action in gastric carcinogenesis and progression remain unclear. Here, we report that TET is transcriptionally upregulated in gastric cancer, where it correlates with poor prognosis. Mechanistic investigations revealed that TET facilitated gastric carcinogenesis through a noncoding function of the 3'UTR, which interacted with miR-26. This interaction resulted in sequestration of miR-26 from its target EZH2, which released the suppression on EZH2, and thereby led to EZH2 overexpression in gastric cancer. Our findings uncover a novel noncoding function for TET family proteins in facilitating gastric carcinogenesis. Cancer Res; 77(22); 6069-82. ©2017 AACR.
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Proteínas de Unión al ADN/genética , Dioxigenasas/genética , Proteína Potenciadora del Homólogo Zeste 2/genética , MicroARNs/genética , Oxigenasas de Función Mixta/genética , Proteínas Proto-Oncogénicas/genética , Neoplasias Gástricas/genética , Regiones no Traducidas 3'/genética , Animales , Línea Celular Tumoral , Estudios de Cohortes , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Estimación de Kaplan-Meier , Ratones Endogámicos BALB C , Ratones Desnudos , Interferencia de ARN , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Trasplante HeterólogoRESUMEN
BACKGROUND: Peritoneal carcinomatosis (PC) is an important cause of morbidity and mortality among patients with gastric cancer. Thus, it is important to identify an ideal biomarker for PC. METHODS: Plasma and ascites samples were collected from gastric cancer patients with PC and a control group. Lysophosphatidic acid (LPA) levels were tested and analyzed. RESULTS: The plasma LPA levels of gastric cancer patients with PC were significantly higher than those in gastric cancer patients after radical resection (p = 0.046) and healthy volunteers (p < 0.001). Besides, plasma LPA levels were statistically lower after chemotherapy in gastric cancer patients with PC (p = 0.028). Furthermore, the ascites LPA levels were significantly higher in gastric cancer patients with peritoneal carcinomatosis than those in liver cirrhosis patients (p < 0.001). Moreover, ascites LPA levels were statistically lower after intraperitoneal chemotherapy injection than before (p < 0.001). In addition, the plasma LPA levels were significantly associated with serum CA125 levels (p = 0.032) and TNM stage in gastric cancer patients (p = 0.009). Individuals with plasma LPA levels >20,000 ng/mL had significantly worse overall survival (OS) than those with plasma LPA levels <20,000 ng/mL group (p = 0.006). In addition the group with ascites LPA levels >24,000 ng/mL showed significantly worse progression-free survival (PFS) and OS (p < 0.001 in PFS and OS). CONCLUSIONS: This study demonstrated that LPA levels in plasma and ascites may be useful diagnostic biomarkers for PC of gastric cancer and that higher levels are associated with poor prognosis.