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1.
Cell Calcium ; 102: 102527, 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-35026540

RESUMO

CACNA1E is a gene encoding the ion-conducting α1 subunit of R-type voltage-dependent calcium channels, whose roles in tumorigenesis remain to be determined. We previously showed that CACNA1E was significantly mutated in patients with non-small cell lung cancer (NSCLC) who were long-term exposed to household air pollution, with a mutation rate of 19% (15 of 79 cases). Here we showed that CACNA1E was also mutated in 207 (12.8%) of the 1616 patients with NSCLC in The Cancer Genome Atlas (TCGA) datasets. At mRNA and protein levels, CACNA1E was elevated in tumor tissues compared to counterpart non-tumoral lung tissues in NSCLCs of the public datasets and our settings, and its expression level was inversely associated with clinical outcome of the patients. Overexpression of wild type (WT) or A275S or R249G mutant CACNA1E transcripts promoted NSCLC cell proliferation with activation of epidermal growth factor receptor (EGFR) signaling pathway, whereas knockdown of this gene exerted inhibitory effects on NSCLC cells in vitro and in vivo. CACNA1E increased current density and Ca2+ entrance, whereas calcium channel blockers inhibited NSCLC cell proliferation. These data indicate that CACNA1E is required for NSCLC cell proliferation, and blockade of this oncoprotein may have therapeutic potentials for this deadly disease.

2.
Life (Basel) ; 11(12)2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34947813

RESUMO

The development of cancer is a multistep and complex process involving interactions between tumor cells and the tumor microenvironment (TME). C-X-C chemokine ligand 13 (CXCL13) and its receptor, CXCR5, make crucial contributions to this process by triggering intracellular signaling cascades in malignant cells and modulating the sophisticated TME in an autocrine or paracrine fashion. The CXCL13/CXCR5 axis has a dominant role in B cell recruitment and tertiary lymphoid structure formation, which activate immune responses against some tumors. In most cancer types, the CXCL13/CXCR5 axis mediates pro-neoplastic immune reactions by recruiting suppressive immune cells into tumor tissues. Tobacco smoke and haze (smohaze) and the carcinogen benzo(a)pyrene induce the secretion of CXCL13 by lung epithelial cells, which contributes to environmental lung carcinogenesis. Interestingly, the knockout of CXCL13 inhibits benzo(a)pyrene-induced lung cancer and azoxymethane/dextran sodium sulfate-induced colorectal cancer in mice. Thus, a better understanding of the context-dependent functions of the CXCL13/CXCR5 axis in tumor tissue and the TME is required to design an efficient immune-based therapy. In this review, we summarize the molecular events and TME alterations caused by CXCL13/CXCR5 and briefly discuss the potentials of agents targeting this axis in different malignant tumors.

3.
Signal Transduct Target Ther ; 6(1): 405, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34795208

RESUMO

Thalidomide induces γ-globin expression in erythroid progenitor cells, but its efficacy on patients with transfusion-dependent ß-thalassemia (TDT) remains unclear. In this phase 2, multi-center, randomized, double-blind clinical trial, we aimed to determine the safety and efficacy of thalidomide in TDT patients. A hundred patients of 14 years or older were randomly assigned to receive placebo or thalidomide for 12 weeks, followed by an extension phase of at least 36 weeks. The primary endpoint was the change of hemoglobin (Hb) level in the patients. The secondary endpoints included the red blood cell (RBC) units transfused and adverse effects. In the placebo-controlled period, Hb concentrations in patients treated with thalidomide achieved a median elevation of 14.0 (range, 2.5 to 37.5) g/L, whereas Hb in patients treated with placebo did not significantly change. Within the 12 weeks, the mean RBC transfusion volume for patients treated with thalidomide and placebo was 5.4 ± 5.0 U and 10.3 ± 6.4 U, respectively (P < 0.001). Adverse events of drowsiness, dizziness, fatigue, pyrexia, sore throat, and rash were more common with thalidomide than placebo. In the extension phase, treatment with thalidomide for 24 weeks resulted in a sustainable increase in Hb concentrations which reached 104.9 ± 19.0 g/L, without blood transfusion. Significant increase in Hb concentration and reduction in RBC transfusions were associated with non ß0/ß0 and HBS1L-MYB (rs9399137 C/T, C/C; rs4895441 A/G, G/G) genotypes. These results demonstrated that thalidomide is effective in patients with TDT.

4.
Adv Exp Med Biol ; 1302: 71-90, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34286442

RESUMO

Chemokines have emerged as important players in tumorigenic process. An extensive body of literature generated over the last two or three decades strongly implicate abnormally activated or functionally disrupted chemokine signaling in liaising most-if not all-hallmark processes of cancer. It is well-known that chemokine signaling networks within the tumor microenvironment are highly versatile and context-dependent: exert both pro-tumoral and antitumoral activities. The C-X-C motif chemokine ligand 13 (CXCL13), and its cognate receptor CXCR5, represents an emerging example of chemokine signaling axes, which express the ability to modulate tumor growth and progression in either way. Collateral evidence indicate that CXCL13-CXCR5 axis may directly modulate tumor growth by inducing proliferation of cancer cells, as well as promoting invasive phenotypes and preventing their apoptosis. In addition, CXCL13-CXCR5 axis may also indirectly modulate tumor growth by regulating noncancerous cells, particularly the immune cells, within the tumor microenvironment. Here, we review the role of CXCL13, together with CXCR5, in the human tumor microenvironment. We first elaborate their patterns of expression, regulation, and biological functions in normal physiology. We then consider how their aberrant activity, as a result of differential overexpression or co-expression, may directly or indirectly modulate the growth of tumors through effects on both cancerous and noncancerous cells.


Assuntos
Neoplasias , Microambiente Tumoral , Apoptose , Quimiocina CXCL13/genética , Humanos , Neoplasias/genética , Receptores CXCR5 , Transdução de Sinais
5.
FEBS Open Bio ; 11(9): 2586-2599, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34293829

RESUMO

Butyrophilin 3A1 (BTN3A1), a major histocompatibility complex-associated gene that encodes a membrane protein with two extracellular immunoglobulin domains and an intracellular B30.2 domain, is critical in T-cell activation and adaptive immune response. Here, the expression of BTN3A1 in cancers was analyzed in eight databases comprising 86 733 patients of 33 cancers, and the findings were validated in patient samples and cell models. We showed that BTN3A1 was expressed in most cancers, and its expression level was strongly correlated with clinical outcome of 13 cancers. Mutations of BTN3A1 were detected, and the mutations were distributed throughout the entire gene. Gene set enrichment analysis showed that BTN3A1 co-expression genes and interacting proteins were enriched in immune regulation-related pathways. BTN3A1 was associated with tumor-infiltrating immune cells and was co-expressed with multiple immune checkpoints in patients with breast cancer (BRCA) and non-small cell lung cancer (NSCLC). We reported that BTN3A1 was downregulated in 46 of 65 (70.8%) NSCLCs, and its expression level was inversely associated with clinical outcome of the patients. BTN3A1 in tumor samples was lower than in counterpart normal tissues in 31 of 38 (81.6%) BRCAs. Bioinformatics analyses showed that BTN3A1 could be a target gene of transcription factor Spi-1 proto-oncogene (SPI1), and our 'wet' experiments showed that ectopic expression of SPI1 upregulated, whereas silencing of SPI1 downregulated, BTN3A1 expression in cells. These results suggest that BTN3A1 may function as a tumor suppressor and may serve as a potential prognostic biomarker in NSCLCs and BRCAs.

6.
Acta Pharmacol Sin ; 2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035487

RESUMO

The tumor suppressor p53 is usually inactivated by somatic mutations in malignant neoplasms, and its reactivation represents an attractive therapeutic strategy for cancers. Here, we reported that a new quinolone compound RYL-687 significantly inhibited non-small cell lung cancer (NSCLC) cells which express wild type (wt) p53, in contract to its much weaker cytotoxicity on cells with mutant p53. RYL-687 upregulated p53 in cells with wt but not mutant p53, and ectopic expression of wt p53 significantly enhanced the anti-NSCLC activity of this compound. RYL-687 induced production of reactive oxygen species (ROS) and upregulation of Nrf2, leading to an elevation of the NAD(P)H:quinoneoxidoreductase-1 (NQO1) that can protect p53 by inhibiting its degradation by 20S proteasome. RYL-687 bound NQO1, facilitating the physical interaction between NQO1 and p53. NQO1 was required for RYL-687-induced p53 accumulation, because silencing of NQO1 by specific siRNA or an NQO1 inhibitor uridine, drastically suppressed RYL-687-induced p53 upregulation. Moreover, a RYL-687-related prodrug significantly inhibited tumor growth in NOD-SCID mice inoculated with NSCLC cells and in a wt p53-NSCLC patient-derived xenograft mouse model. These data indicate that targeting NQO1 is a rational strategy to reactivate p53, and RYL-687 as a p53 stabilizer bears therapeutic potentials in NSCLCs with wt p53.

7.
Int J Oncol ; 56(5): 1274-1283, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32319553

RESUMO

RNA­binding protein Musashi­2 (MSI2) serves as a regulator of numerous pivotal biological processes associated with cancer initiation, development and resistance to treatment, and may represent a promising drug target. However, whether MSI2 inhibition is of value in antitumor treatment remains to be determined. The present study demonstrated that MSI2 was upregulated in non­small cell lung cancer (NSCLC) and was inversely associated with the clinical outcome of the patients. Molecular docking analysis demonstrated that the small compound largazole binds to and may be a potential inhibitor of MSI2. Largazole markedly decreased the protein and mRNA levels of MSI2 and suppressed its downstream mammalian target of rapamycin signaling pathway. Largazole also inhibited the proliferation and induced apoptosis of NSCLC and chronic myeloid leukemia (CML) cells (including bone marrow mononuclear cells harvested from CML patients). These results indicate that MSI2 is an emerging therapeutic target for NSCLC and CML, and the MSI2 inhibitor largazole may hold promise as a treatment for these malignancies.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Depsipeptídeos/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Neoplasias Pulmonares/genética , Proteínas de Ligação a RNA/genética , Tiazóis/farmacologia , Adulto , Idoso , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Depsipeptídeos/química , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Moleculares , Simulação de Acoplamento Molecular , Conformação Proteica , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/química , Tiazóis/química , Regulação para Cima/efeitos dos fármacos
8.
EBioMedicine ; 53: 102689, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32114396

RESUMO

BACKGROUND: How the oncoprotein epidermal growth factor receptor (EGFR) evades proteolytic degradation and accumulates in non-small cell lung cancer (NSCLC) remains unclear, and ubiquitin pathway genes (UPGs) that are critical to NSCLC needs to be systematically identified. METHODS: A total of 696 UPGs (including E1, E2, E3, and deubiquitinases) were silenced by small interfering RNA (siRNA) library in NSCLC cells, the candidates were verified, and their significance was evaluated in patients with NSCLC. The effects of a candidate gene on EGFR were investigated in vitro and in vivo. FINDINGS: We report 31 candidates that are required for cell proliferation, with the E2 ubiquitin conjugase CDC34 as the most significant one. CDC34 is elevated in tumor tissues in 76 of 114 (66.7%) NSCLCs and inversely associated with prognosis, is higher in smoker patients than nonsmoker patients, and is induced by tobacco carcinogens in normal human lung epithelial cells. Forced expression of CDC34 promotes, whereas knockdown of CDC34 inhibits, NSCLC cell proliferation in vitro and in vivo. CDC34 competes with c-Cbl to bind Y1045 to inhibit polyubiquitination and degradation of EGFR. In EGFR-L858R and EGFR-T790M/Del (exon 19)-driven lung tumor growth in mouse models, knockdown of CDC34 significantly inhibits tumor formation. INTERPRETATION: These results demonstrate that an E2 enzyme is capable of competing with E3 ligase to stabilize substrates, and CDC34 represents an attractive therapeutic target for NSCLCs. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China, and the CAMS Innovation Fund for Medical Sciences.


Assuntos
Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pulmonares/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Animais , Carcinogênese/efeitos dos fármacos , Carcinógenos/toxicidade , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos SCID , Poluição por Fumaça de Tabaco/efeitos adversos , Transcriptoma , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
9.
J Abnorm Psychol ; 129(4): 331-342, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31928031

RESUMO

Failure in translating emotional salience into effortful behavior is thought to be a core feature of anhedonia and avolition in individuals with schizophrenia (SCZ), but little is known about emotion-behavior coupling in individuals with bipolar disorder (BD) and major depressive disorder (MDD). In this study, we compared emotion-behavior correspondence in participants with SCZ, BD, and MDD. Forty-two participants with SCZ, 44 participants with MDD, 43 participants with BD, and 43 healthy controls were recruited. A computerized anticipatory and consummatory pleasure task was used to evaluate emotion-behavior correspondence. Clinical ratings of negative symptoms and self-report anhedonia questionnaires were also administered. We found that participants with SCZ, MDD, and BD exhibited different levels of negative symptoms and self-reported anhedonia, as well as emotion-behavior decoupling. In SCZ participants, both desirable and undesirable images elicited lower correspondence between self-reported liking and behavior. In MDD and BD participants, undesirable images elicited lower emotion-behavior correspondence under both direct stimulus presentation and representation conditions, whereas deficits in emotion-behavior coupling under desirable conditions were only observed when stimuli were present. Taken together, emotion-behavior decoupling showed both common and unique patterns in participants with SCZ, MDD, and BD, and showed some associations with negative symptoms and anhedonia across the combined clinical sample. This finding may be helpful for early identification and the development of novel interventions for different psychiatric diagnoses. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Assuntos
Anedonia , Transtorno Bipolar/psicologia , Transtorno Depressivo Maior/psicologia , Emoções , Psicologia do Esquizofrênico , Adulto , Feminino , Humanos , Masculino , Autorrelato , Adulto Jovem
10.
Cancer Med ; 8(18): 7720-7727, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31643147

RESUMO

BACKGROUND: Many studies have documented the abnormal concentrations of major/trace elements in serum or malignant tissues of patients, but very few works systematically tested the concentrations of elements in tumor tissues in comparison with paired adjacent normal tissues from the same patients. METHODS: Tumor and adjacent normal lung tissues were obtained from 93 patients with previously untreated NSCLC, and 43 patients whose tumor and paired normal lung tissues reached 200 mg or more were selected for measurement of the elements' concentrations using an inductively coupled plasma-atomic emission spectrometer. RESULTS: We found that the concentrations of the 52 elements varied from 0.4 ng/g tissue (Lu, Pd, and Tm) to 1 658 000 ng/g (Na), 1 951 000 ng/g (P), and 2 495 000 ng/g (K). Thirty eight of the 52 (73.1%) elements showed approximately equal concentrations in tumor and adjacent normal lung tissues of the patients. The concentrations of nine elements (K, P, Mg, Zn, Rb, Cu, Se, Cs, and Tl) in tumor samples were significantly higher than their paired normal lung tissues, and five elements (Na, Fe, Cr, Cd, and Ge) exhibited decreased concentrations in cancer samples compared to counterpart normal lung tissues. Low Fe in tumor samples was associated with smoking history, whereas low Cr was associated with histology (squamous cell carcinoma) of the patients. CONCLUSIONS: Our results demonstrate that measurement of elements' concentrations in both cancer and paired normal tissues is important to get insights into the roles of these elements in carcinogenesis, and therapeutic approaches to normalize the elements are warranted to treat NSCLCs.


Assuntos
Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Pulmão/metabolismo , Oligoelementos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/etiologia , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Espectrofotometria Atômica , Análise Serial de Tecidos/métodos
11.
Nat Commun ; 10(1): 1125, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850589

RESUMO

Whether tobacco carcinogens enable exposed cells immune escape resulting in carcinogenesis, and why patients who smoke respond better to immunotherapies than non-smokers, remains poorly understood. Here we report that cigarette smoke and the carcinogen benzo(a)pyrene (BaP) induce PD-L1 expression on lung epithelial cells in vitro and in vivo, which is mediated by aryl hydrocarbon receptor (AhR). Anti-PD-L1 antibody or deficiency in AhR significantly suppresses BaP-induced lung cancer. In 37 patients treated with anti-PD-1 antibody pembrolizumab, 13/16 (81.3%) patients who achieve partial response or stable disease express high levels of AhR, whereas 12/16 (75%) patients with progression disease exhibit low levels of AhR in tumor tissues. AhR inhibitors exert significant antitumor activity and synergize with anti-PD-L1 antibody in lung cancer mouse models. These results demonstrate that tobacco smoke enables lung epithelial cells to escape from adaptive immunity to promote tumorigenesis, and AhR predicts the response to immunotherapy and represents an attractive therapeutic target.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígeno B7-H1/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Receptores de Hidrocarboneto Arílico/genética , Carcinoma de Pequenas Células do Pulmão/genética , Tabaco/toxicidade , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Benzo(a)pireno/toxicidade , Benzoflavonas/farmacologia , Carcinógenos/toxicidade , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Imunoterapia/métodos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/imunologia , Transdução de Sinais , Carcinoma de Pequenas Células do Pulmão/etiologia , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/terapia , Fumar/efeitos adversos , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Cell Mol Med ; 23(1): 143-154, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30353639

RESUMO

Red wine consists of a large amount of compounds such as resveratrol, which exhibits chemopreventive and therapeutic effects against several types of cancers by targeting cancer driver molecules. In this study, we tested the anti-lung cancer activity of 11 red wine components and reported that a natural polyphenol compound ellagic acid (EA) inhibited lung cancer cell proliferation at an efficacy approximately equal to that of resveratrol. EA markedly increased the expression of the autophagosomal marker LC3-II as well as inactivation of the mechanistic target of rapamycin signalling pathway. EA elevated autophagy-associated cell death by down-regulating the expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), and CIP2A overexpression attenuated EA-induced autophagy of lung cancer cells. Treating tumour-bearing mice with EA resulted in significant inhibition of tumour growth with suppression of CIP2A levels and increased autophagy. In addition, EA potentiated the inhibitory effects of the natural compound celastrol on lung cancer cells in vitro and in vivo by enhancing autophagy and down-regulating CIP2A. These findings indicate that EA may be a promising chemotherapeutic agent for lung cancer, and that the combination of EA and celastrol may have applicability for the treatment of this disease.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Ácido Elágico/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Autoantígenos/genética , Proliferação de Células/efeitos dos fármacos , Ácido Elágico/administração & dosagem , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Membrana/genética , Camundongos Endogâmicos BALB C , Triterpenos Pentacíclicos , Polifenóis/farmacologia , Triterpenos/administração & dosagem , Vinho , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Zhongguo Zhong Yao Za Zhi ; 43(14): 2964-2972, 2018 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-30111056

RESUMO

The polysaccharides of different germplasm resources of Astragalus membranaceus var. mongholicus〓(cultured Astragalus Radix (RA) and natural RA) and A. membranaceus (MJ) (cultured RA and natural RA) were studied by using the optimal enzymatic conditions of endo-1,4-ß-mannanase. Saccharide fingerprints were obtained for the identification and evaluation of the germplasm resources of RA by Fluorophore-assisted Carbohydrate Electrophoresis (FACE). The data were analyzed by principal component analysis to obtain the difference between RA of different germplasm resources. The results showed that trisaccharide, tetrasaccharide and pentasaccharide of endo-1,4-ß-mannanase hydrolyzate could be used as the differential fragments to distinguish MG (cultured RA and natural RA); the pentasaccharide and hexasaccharide can be used as differentially expressed carbohydrate fragments that distinguish MJ (cultured RA and natural RA); the trisaccharide and tetrasaccharide can be used as the differential fragments to distinguish the cultured MG and cultured MJ. Studies have shown that polysaccharide products degraded by endo-1,4-ß-mannanase can well distinguish RA species (MG and MJ), growth mode (cultured RA and natural RA). This study laid the foundation for the quality evaluation of Astragalus medicinal herbs and screening of active oligosaccharides.


Assuntos
Astrágalo (Planta) , Medicamentos de Ervas Chinesas , Hidrólise , Polissacarídeos , beta-Manosidase
14.
Cancer Lett ; 434: 132-143, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30031117

RESUMO

To systematically unveil transcription factors (TFs) that are critical to lung carcinogenesis, here we conducted a genome-wide lethality screening in non-small cell lung cancer (NSCLC) cells and reported that among the 1530 TFs tested, 21 genes were required for NSCLC cell proliferation and were negatively or positively associated with overall survival (OS) of patients with NSCLC. These included 11 potential tumor suppressing genes (AFF3, AhR, AR, CBFA2T3, CHD4, KANK2, NR3C2, PTEN, PRDM16, RB1, and STK11) and 10 potential oncogenic TFs (BARX1, DLX6, ELF3, EN1, ETV1, FOXE1, HOXB7, IRX4, IRX5, and SALL1). The expression levels of IRX5 were positively associated with OS of smoker and inversely associated with OS of non-smoker patients with lung adenocarcinoma. We showed that tobacco carcinogen benzo(a)pyrene (BaP) induced upregulation of IRX5 in lung epithelial cells, and Cyclin D1 was a downstream target of IRX5. Furthermore, silencing of IRX5 by lentivirus mediated transfection of short hairpin RNA significantly inhibited tumor growth in nude mice. These results indicate that tobacco smoke can modulate TFs to facilitate lung carcinogenesis, and inhibition of IRX5 may have therapeutic potentials in NSCLCs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Estudo de Associação Genômica Ampla/métodos , Neoplasias Pulmonares/genética , Fatores de Transcrição/genética , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/terapia , Linhagem Celular , Linhagem Celular Tumoral , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Camundongos Endogâmicos NOD , Camundongos SCID , Interferência de RNA , Terapêutica com RNAi/métodos , Fatores de Transcrição/metabolismo , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
15.
J Natl Cancer Inst ; 110(2)2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29087503

RESUMO

Background: Overexpression of focal adhesion kinase (FAK) has been reported in lung cancer, but the somatic mutations and alternative splicing variants of this nonreceptor tyrosine kinase remain to be investigated. Methods: FAK in 91 lung cancer patients was sequenced using genomic DNA and cDNA samples of tumor and paired normal lung tissues as templates, and the RNA-seq data of The Cancer Genome Atlas (TCGA) data set were assessed. The biological functions of abnormal FAK transcripts and their response to FAK inhibitors were analyzed in eight cell lines using tyrosine kinase activity assay, trypan blue exclusion assay, MTT (3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-di-phenytetrazoliumromide) assay, and transwell assay. Results: We identified an internal tandem duplication (ITD), an A1004S point mutation, an exon 5-27 deletion (ΔE5-27) truncation variant, and four FAK6,7 splicing variants (containing exons for Boxes 6 and 7) in seven (7.7%) patients. Smokers had more FAK abnormalities than nonsmokers. In FAK-ITD, the sequence encoding the C-terminal of the FERM domain and kinase domain was duplicated in-frame and produced a protein product with elevated autophosphorylation and sensitivity to FAK inhibitors. FAK6,7 was detected in the tumor but not counterpart normal lung tissues of four (4.4%) patients. In TCGA RNA-seq data, Box 6 and/or Box 7 (Box 6/7)-containing FAK variants were positive in 42 (8.3%) of 508 lung adenocarcinomas (LUADs) and 37 (7.4%) of 501 lung squamous cell carcinomas, and smokers had higher expression of Box 6/7 (+) FAK than reformed or nonsmokers with LUAD. FAK6,7 promoted cell proliferation and migration, exhibited increased autophosphorylation, and was more sensitive to FAK inhibitor compared with wild-type FAK. Conclusions: Somatic mutations and splicing variants of FAK may have a role in lung carcinogenesis and represent potential biomarkers for FAK-targeted therapies.


Assuntos
Adenocarcinoma/genética , Processamento Alternativo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Quinase 1 de Adesão Focal/genética , Neoplasias Pulmonares/genética , Mutação , Adenocarcinoma/enzimologia , Adenocarcinoma/patologia , Idoso , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Fosforilação , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas
16.
Oncotarget ; 8(61): 104113-104122, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29262625

RESUMO

Somatic genomic mutations in lung adenocarcinomas (LUADs) have been extensively dissected, but whether the counterpart normal lung tissues that are exposed to ambient air or tobacco smoke as the tumor tissues do, harbor genomic variations, remains unclear. Here, the genome of normal lung tissues and paired tumors of 11 patients with LUAD were sequenced, the genome sequences of counterpart normal controls (CNCs) and tumor tissues of 513 patients were downloaded from TCGA database and analyzed. In the initial screening, genomic alterations were identified in the "normal" lung tissues and verified by Sanger capillary sequencing. In CNCs of TCGA datasets, a mean of 0.2721 exonic variations/Mb and 5.2885 altered genes per sample were uncovered. The C:G→T:A transitions, a signature of tobacco carcinogen N-methyl-N-nitro-N-nitrosoguanidine, were the predominant nucleotide changes in CNCs. 16 genes had a variant rate of more than 2%, and CNC variations in MUC5B, ZXDB, PLIN4, CCDC144NL, CNTNAP3B, and CCDC180 were associated with poor prognosis whereas alterations in CHD3 and KRTAP5-5 were associated with favorable clinical outcome of the patients. This study identified the genomic alterations in CNC samples of LUADs, and further highlighted the DNA damage effect of tobacco on lung epithelial cells.

17.
Sci Rep ; 7: 41373, 2017 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28120897

RESUMO

This paper reports on a numerical study of the six-band metamaterial absorber composed of two alternating stack of metallic-dielectric layers on top of a continuous metallic plane. Six obvious resonance peaks with high absorption performance (average larger than 99.37%) are realized. The first, third, fifth, and the second, fourth, sixth resonance absorption bands are attributed to the multiple-order responses (i.e., the 1-, 3- and 5-order responses) of the bottom- and top-layer of the structure, respectively, and thus the absorption mechanism of six-band absorber is due to the combination of two sets of the multiple-order resonances of these two layers. Besides, the size changes of the metallic layers have the ability to tune the frequencies of the six-band absorber. Employing the results, we also present a six-band polarization tunable absorber through varying the sizes of the structure in two orthogonal polarization directions. Moreover, nine-band terahertz absorber can be achieved by using a three-layer stacked structure. Simulation results indicate that the absorber possesses nine distinct resonance bands, and average absorptivities of them are larger than 94.03%. The six-band or nine-band absorbers obtained here have potential applications in many optoelectronic and engineering technology areas.

18.
CNS Neurosci Ther ; 23(4): 291-300, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28130864

RESUMO

INTRODUCTION: Fungal transversal across the brain microvascular endothelial cells (BMECs) is the essential step for the development of cryptococcal meningoencephalitis. Annexin A2 (AnxA2) is an important signaling protein involved in several intracellular processes such as membrane trafficking, endocytosis, and exocytosis. AIM: To investigate the roles and mechanism of AnxA2 during cryptococcal transversal of BMECs. RESULTS: Cryptococcus neoformans infection initiated upregulation of AnxA2 in mouse BMECs. Blockade with anti-AnxA2 antibody led to a reduction in fungal transcytosis activity but no change in its adhesion efficiency. Intriguingly, AnxA2 depletion caused a significant increase in fungal association activity but had no effect on their transcytosis. AnxA2 suppression resulted in marked reduction in its partner protein S100A10, and S100A10 suppression in BMECs significantly reduced the cryptococcal transcytosis efficiency. Furthermore, AnxA2 dephosphorylation at Tyr23 and dephosphorylation of downstream cofilin were required for cryptococcal transversal of BMECs, both of which might be primarily involved in the association of C. neoformans with host cells. CONCLUSIONS: Our work indicated that AnxA2 played complex roles in traversal of C. neoformans across host BMECs, which might be dependent on downstream cofilin to inhibit fungal adhesion but rely on its partner S100A10 to promote cryptococcal transcytosis.


Assuntos
Anexina A2/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/microbiologia , Encéfalo/citologia , Cryptococcus neoformans , Células Endoteliais/metabolismo , Fatores de Despolimerização de Actina/metabolismo , Animais , Anexina A2/genética , Anexina A2/imunologia , Anticorpos/farmacologia , Barreira Hematoencefálica/patologia , Quelantes/farmacologia , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/microbiologia , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Regulação Fúngica da Expressão Gênica/genética , Camundongos , Mutação/genética , Fosforilação , Pirimidinas/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas S100/metabolismo , Fatores de Tempo , Transcitose/efeitos dos fármacos , Transcitose/genética , Tirosina/metabolismo
19.
Ying Yong Sheng Tai Xue Bao ; 28(12): 3891-3898, 2017 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-29696884

RESUMO

The research selected the alpine meadow located in the northeastern margin of the Qinghai-Tibet Plateau to study the changes of vegetation community and soil properties under different grazing intensities, as well as the quantitative relation between the distribution patterns of plant species and the physical and chemical properties of soil. The results showed that the grazing caused the differentiation of the initial vegetation community with the dominant plants, Elymus nutans and Stipa grandis. In the plots with high and low grazing intensities, the dominant plants had changed to Kobresia humilis and Melissitus ruthenica, and E. nutans and Poa crymophila, respectively. With the increase of grazing intensity, the plant richness, importance value and biomass were significantly decreased. The sequence of plant species importance value in each plot against grazing intensity could be fitted by a logarithmic model. The number of required plant species was reduced while the importance value of the remaining plant species accounted for 50% of the importance value in the whole vegetation community. The available P, available K, soil compaction, soil water content, stable infiltration rate and large aggregate index were significantly changed with grazing intensity, however, the changes were different. The CCA ordination showed that the soil compaction was the key factor affecting the distribution pattern of the plant species under grazing. The variance decomposition indicated that the soil factors together explained 30.5% of the distribution of the plant species, in particular the soil physical properties alone explained 22.8% of the distribution of the plant species, which had the highest rate of contribution to the plant species distribution. The soil physical properties affected the distribution pattern of plant species on grazed alpine meadow.


Assuntos
Pradaria , Solo , Biomassa , Ecossistema , Poaceae , Tibet
20.
Ying Yong Sheng Tai Xue Bao ; 28(6): 1824-1832, 2017 Jun 18.
Artigo em Chinês | MEDLINE | ID: mdl-29745144

RESUMO

The research selected the plots of six grazing intensities in an alpine meadow in north-eastern Tibet Plateau in four years (2012-2015) and studied the relation between ten species diversity indexes, including two measured indexes (Richness and Abundance) in field and two indexes of each dominance, evenness, richness, integrated indexes, and grazing intensity as well as grazing time aiming at scientific selection of biodiversity index under grazing disturbance. The results indicated that the abundance was a better index than importance value to calculate biodiversity level because it was more sensitive to grazing disturbance. Dominance indexes, including Berger-Parker and Dominance, were not sensitive to grazing intensity and grazing time because they could not clarify the effect of grazing disturbance on dominant species in plant community. Evenness indexes, including Equitability and Evenness, had not relation with grazing intensity, however, the evenness index had a negative correlation with grazing time and it was not influenced by occasional species as well as the variation coefficient of species abundance. Hereby, the evenness index could be chosen for studying evenness change at temporal scale. Richness indexes, including Menhinick and Margalef, had no relation with grazing time, however, the Margalef index had a positive correlation with grazing intensity and the index was not influenced by occasional species. Integrated index, including Shannon and Simpson indexes, had no relation with grazing intensity, however, the Shannon index had a significant positive correlation with species richness and abundance and the index was not influenced by occasional species, and it significantly increased along grazing time. Hereby, Shannon index could be used as an index of studying plant species diversity in long-term. In ten diversity indexes, only the measured indexes in field, including richness and abundance, were signifi-cantly negatively correlated with grazing intensity, and positively correlated with grazing time, and the two indexes were not influenced by occasional species. Hereby, the combination of species richness and abundance mea-sured in field could be considered as the most important indexes for studying plant species diversity under grazing disturbance. Besides, the selection of biodiversity indexes must consider the spatial-temporal feature of grazing, diversity components and research purpose.


Assuntos
Biodiversidade , Plantas , Tibet
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