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1.
Nat Commun ; 12(1): 4230, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244494

RESUMO

Extracellular matrix protein-1 (ECM1) promotes tumorigenesis in multiple organs but the mechanisms associated to ECM1 isoform subtypes have yet to be clarified. We report in this study that the secretory ECM1a isoform induces tumorigenesis through the GPR motif binding to integrin αXß2 and the activation of AKT/FAK/Rho/cytoskeleton signaling. The ATP binding cassette subfamily G member 1 (ABCG1) transduces the ECM1a-integrin αXß2 interactive signaling to facilitate the phosphorylation of AKT/FAK/Rho/cytoskeletal molecules and to confer cancer cell cisplatin resistance through up-regulation of the CD326-mediated cell stemness. On the contrary, the non-secretory ECM1b isoform binds myosin and blocks its phosphorylation, impairing cytoskeleton-mediated signaling and tumorigenesis. Moreover, ECM1a induces the expression of the heterogeneous nuclear ribonucleoprotein L like (hnRNPLL) protein to favor the alternative mRNA splicing generating ECM1a. ECM1a, αXß2, ABCG1 and hnRNPLL higher expression associates with poor survival, while ECM1b higher expression associates with good survival. These results highlight ECM1a, integrin αXß2, hnRNPLL and ABCG1 as potential targets for treating cancers associated with ECM1-activated signaling.


Assuntos
Processamento Alternativo , Carcinoma Epitelial do Ovário/genética , Proteínas da Matriz Extracelular/metabolismo , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Ovarianas/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/terapia , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas da Matriz Extracelular/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Integrina alfaXbeta2/genética , Integrina alfaXbeta2/metabolismo , Estimativa de Kaplan-Meier , Camundongos , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Ovário/patologia , Ovário/cirurgia , Fosforilação/genética , Prognóstico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA-Seq , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
J Cell Mol Med ; 25(12): 5443-5456, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33955688

RESUMO

Neutrophil extracellular DNA traps (NETs) are newly discovered forms of activated neutrophils. Increasing researches have shown that NETs play important roles in cancer progression. Our previous study has proved that tumour-infiltrating NETs could predict postsurgical survival in patients with pancreatic ductal adenocarcinoma (PDAC). However, the roles of NETs on the progression of pancreatic cancer are unknown. Here, we investigated the effects of NETs on pancreatic cancer cells. Results showed that both PDAC patients' and normal individuals' neutrophils-derived NETs could promote migration and invasion of pancreatic cancer cells with epithelial-mesenchymal transition. Further, study confirmed that EGFR/ERK pathway played an important role in this progression. The addition of neutralizing antibodies for IL-1ß could effectively block the activation of EGFR/ERK companied with reduction of EMT, migration and invasion. Taken together, NETs facilitated EMT, migration and invasion via IL-1ß/EGFR/ERK pathway in pancreatic cancer cells. Our study suggests that NETs may provide promising therapeutic targets for pancreatic cancer.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Armadilhas Extracelulares/metabolismo , Regulação Neoplásica da Expressão Gênica , Neutrófilos/patologia , Neoplasias Pancreáticas/patologia , Animais , Apoptose , Movimento Celular , Proliferação de Células , Receptores ErbB/genética , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/genética , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Neutrófilos/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Cancer Res ; 81(3): 552-566, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33229341

RESUMO

Cancer cells need to generate large amounts of glutathione (GSH) to buffer oxidative stress during tumor development. A rate-limiting step for GSH biosynthesis is cystine uptake via a cystine/glutamate antiporter Xc-. Xc- is a sodium-independent antiporter passively driven by concentration gradients from extracellular cystine and intracellular glutamate across the cell membrane. Increased uptake of cystine via Xc- in cancer cells increases the level of extracellular glutamate, which would subsequently restrain cystine uptake via Xc-. Cancer cells must therefore evolve a mechanism to overcome this negative feedback regulation. In this study, we report that glutamate transporters, in particular SLC1A1, are tightly intertwined with cystine uptake and GSH biosynthesis in lung cancer cells. Dysregulated SLC1A1, a sodium-dependent glutamate carrier, actively recycled extracellular glutamate into cells, which enhanced the efficiency of cystine uptake via Xc- and GSH biosynthesis as measured by stable isotope-assisted metabolomics. Conversely, depletion of glutamate transporter SLC1A1 increased extracellular glutamate, which inhibited cystine uptake, blocked GSH synthesis, and induced oxidative stress-mediated cell death or growth inhibition. Moreover, glutamate transporters were frequently upregulated in tissue samples of patients with non-small cell lung cancer. Taken together, active uptake of glutamate via SLC1A1 propels cystine uptake via Xc- for GSH biosynthesis in lung tumorigenesis. SIGNIFICANCE: Cellular GSH in cancer cells is not only determined by upregulated Xc- but also by dysregulated glutamate transporters, which provide additional targets for therapeutic intervention.


Assuntos
Cistina/metabolismo , Transportador 3 de Aminoácido Excitatório/metabolismo , Ácido Glutâmico/metabolismo , Glutationa/biossíntese , Neoplasias Pulmonares/metabolismo , Animais , Antiporters/metabolismo , Morte Celular , Linhagem Celular Tumoral , Glutamina/deficiência , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Estresse Oxidativo , Receptores Acoplados a Proteínas G , Estresse Fisiológico , Regulação para Cima
4.
Oncogene ; 39(18): 3754-3773, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32157214

RESUMO

The reason for the reduced efficacy of lung cancer therapy is the existence of lung cancer stem cells (CSCs). Targeting CSCs results in evolved phenotypes with increased malignancy, leading to therapy failure. Here, we propose a new therapeutic strategy: investigating the "transitional" cells that represent the stage between normal lung stem cells and lung CSCs. Identifying and targeting the key molecule that drives carcinogenesis to inhibit or reverse this process would thus provide new perspectives for early diagnosis and intervention in lung cancer. We used Gprc5a-knockout (KO) mice, the first animal model of spontaneous lung adenocarcinoma established by the deletion of a single lung tumor suppressor gene. We investigated the interaction of lung progenitor cells AT2 with Lgr5 cells in the generation of CSCs and related signaling mechanism. In the present study, using Gprc5a-KO mice, we found the initiator Sca-1+Abcg1+ subset with a CSC-like phenotype within the lung progenitor AT2 cell population in mice that had not yet developed tumors. We confirmed the self-renewal and tumor initiation capacities of this subset in vitro, in vivo, and clinical samples. Mechanistically, we found that the generation of Sca-1+Abcg1+ cells was associated with an interaction between AT2 and Lgr5 cells and the subsequent activation of the ECM1-α6ß4-ABCG1 axis. Importantly, Sca-1+Abcg1+ and SPA+ABCG1+ cells specifically existed in the small bronchioles of Gprc5a-KO mice and patients with pneumonia, respectively. Thus, the present study unveiled a new kind of lung cancer-initiating cells (LCICs) and provided potential markers for the early diagnosis of lung cancer.


Assuntos
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adenocarcinoma de Pulmão/genética , Antígenos Ly/genética , Proteínas de Membrana/genética , Pneumonia/genética , Receptores Acoplados a Proteínas G/genética , Adenocarcinoma de Pulmão/patologia , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Linhagem da Célula/genética , Técnicas de Cocultura , Modelos Animais de Doenças , Células Epiteliais/patologia , Humanos , Camundongos , Camundongos Knockout , Células-Tronco Neoplásicas/patologia , Pneumonia/patologia , Alvéolos Pulmonares/patologia
5.
Front Oncol ; 9: 1086, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31750234

RESUMO

Background: Chemotherapy is an essential component for comprehensive cancer treatment, while drug resistance usually fails therapy. DNA repair mechanism of cancer cells restrains the efficacy of therapeutics targeting DNA damage. Investigating target-inducing irreversible cell death of cancer cells may be promising. Methods: The present study used lung cancer cell lines, transplanted tumor model of lung cancers derived from patients with lung adenocarcinoma, and molecular experiments to investigate the effects and mechanism of Actinomycin D (Act D)-activated RNase L in lung canceers. Results: We report that RNase L, when activated by Act D, induces Caspase-3/PARP activation. The latter further enables ROCK-1 to initiate subsequent membrane blebbing and, meanwhile, result in DNA cleavage and cell cycle arrest mediated by H2A.X/H2B-p21 axis, leading to irreversible DNA damage, and apoptosis of lung cancer cells. The present study highlighted the crucial role of RNase L in triggering apoptosis mechanism through the Caspase-3/ROCK-1/PARP/H2A.X+H2B/p21 axis during Act D treatment. Moreover, activation of RNase L suppressed the tumor formation and the induction of lung cancer stem cells. Conclusion: This study unveiled the regulatory function and related mechanism of RNase L and implied the promising application of therapeutics targeting RNase L in lung cancer.

6.
Cell Death Dis ; 10(9): 642, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501431

RESUMO

RNase L is an essential component in interferon (IFN)-mediated antiviral signaling that showed antitumor effects in cancer. Cancer immunotherapy based on interferon has achieved encouraging results that indicate an applicable potential for cancer therapy. Here we showed that function of RNase L, though highly upregulated, was functionally impaired both in nuclear and cytoplasm in lung cancer cells. In normal lung epithelial cells, RNase L activation induced by 2-5A promoted nuclear condensation, DNA cleavage, and cell apoptosis, while in lung cancer cells, these processes were inhibited and RNase L-mediated downregulation of fibrillarin, Topo I and hnRNP A1 was also impaired in lung cancer cells. Moreover, the impairment of RNase L in lung cancer cells was due to the elevated expression of RLI. Application of IFN-γ to lung cancer cells led to enhanced expression of RNase L that compensated the RLI inhibition and restored the cytoplasmic and nuclear function of RNase L, leading to apoptosis of lung cancer cells. Thus, the present study discovered the impaired function and mechanism of RNase L in lung cancer cells and proved the efficacy of IFN-γ in restoring RNase L function and inducing apoptosis in the lung cancer cell. These results indicated the RNase L as a therapeutic target in lung cancer cells and immunotherapy of IFN-γ may serve as an adjuvant to enhance the efficacy.


Assuntos
Endorribonucleases/metabolismo , Interferon gama/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Apoptose , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Transdução de Sinais , Transfecção , Regulação para Cima
7.
Theranostics ; 9(4): 1096-1114, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30867818

RESUMO

The interplay between p53 and RAS signaling regulates cancer chemoresistance, but the detailed mechanism is unclear. In this study, we investigated the interactive effects of p53 and RAS on ovarian cancer cisplatin resistance to explore the potential therapeutic targets. Methods: An inducible p53 and RAS mutants active in either MAPK/ERK (S35 and E38) or PI3K/AKT (C40) or both (V12) were sequentially introduced into a p53-null ovarian cancer cell line-SKOV3. Comparative microarray analysis was performed using Gene Chip Prime View Human Gene Expression arrays (Affymetrix). In vitro assays of autophagy and apoptosis and in vivo animal experiments were performed by p53 induction and/or cisplatin treatment using the established cell lines. The correlation between HDAC4 and HIF-1α or CREBZF and the association of HDAC4, HIF-1α, CREBZF, ERK, AKT, and p53 mRNA levels with patient survival in 523 serous ovarian cancer cases from TCGA was assessed. Results: We show that p53 and RAS mutants differentially control cellular apoptosis and autophagy to inhibit or to promote chemoresistance through dysregulation of Bax, Bcl2, ATG3, and ATG12. ERK and AKT active RAS mutants are mutually suppressive to confer or to deprive cisplatin resistance. Further studies demonstrate that p53 induces HIF-1α degradation and HDAC4 cytoplasmic translocation and phosphorylation. S35, E38, and V12 but not C40 promote HDAC4 phosphorylation and its cytoplasmic translocation along with HIF-1α. Wild-type p53 expression in RAS mutant cells enhances HIF-1α turnover in ovarian and lung cancer cells. Autophagy and anti-apoptotic processes can be promoted by the overexpression and cytoplasmic translocation of HDAC4 and HIF1-α. Moreover, the phosphorylation and cytoplasmic translocation of HDAC4 activate the transcription factor CREBZF to promote ATG3 transcription. High HDAC4 or CREBZF expression predicted poor overall survival (OS) and/or progression-free survival (PFS) in ovarian cancer patients, whereas high HIF-1α expression was statistically correlated with poor or good OS depending on p53 status. Conclusion: HIF-1α and HDAC4 may mediate the interaction between p53 and RAS signaling to actively control ovarian cancer cisplatin resistance through dysregulation of apoptosis and autophagy. Targeting HDAC4, HIF-1α and CREBZF may be considered in treatment of ovarian cancer with p53 and RAS mutations.


Assuntos
Antineoplásicos/farmacologia , Apoptose , Autofagia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Histona Desacetilases/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Repressoras/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Análise em Microsséries , Transplante de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Transdução de Sinais , Transplante Heterólogo , Proteína Supressora de Tumor p53/metabolismo , Proteínas ras/metabolismo
8.
Int J Oncol ; 51(1): 18-24, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28560457

RESUMO

Cellular autophagy and epithelial-mesenchymal transition (EMT) are key events mostly resulted from the interplay of tumor suppressors and oncogenes during cancer progression. The master tumor suppressor p53 may control tumor cell autophagy and EMT through the transcriptional induction of multiple target genes, while the activated oncogene RAS may also play a critical role in regulating mitogenic signaling to tumor cell autophagy and EMT. Although the fundamental functions of p53 and RAS are well understood, the interactive effects of p53 and RAS on autophagy and EMT are still unclear. In this review, we highlight the recent advances in the regulation of autophagy and EMT by p53 and RAS, aiming to explore novel therapeutic targets and biomarkers in cancer treatment and prevention.


Assuntos
Autofagia , Transição Epitelial-Mesenquimal , Neoplasias/metabolismo , Neoplasias/patologia , Proteína Supressora de Tumor p53/metabolismo , Proteínas ras/metabolismo , Animais , Progressão da Doença , Humanos , Transdução de Sinais
9.
Oncotarget ; 7(18): 25251-63, 2016 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-26958807

RESUMO

Salivary adenoid cystic carcinoma (SACC) is characterized by invasive local growth and a high incidence of lung metastasis. Patients with lung metastasis have a poor prognosis. Treatment of metastatic SACC has been unsuccessful, largely due to a lack of specific targets for the metastatic cells. In this study, we showed that epidermal growth factor receptors (EGFR) were constitutively activated in metastatic lung subtypes of SACC cells, and that this activation was induced by autocrine expression of epiregulin (EREG), a ligand of EGFR. Autocrine EREG expression was increased in metastatic SACC-LM cells compared to that in non-metastatic parental SACC cells. Importantly, EREG-neutralizing antibody, but not normal IgG, blocked the autocrine EREG-induced EGFR phosphorylation and the migration of SACC cells, suggesting that EREG-induced EGFR activation is essential for induction of cell migration and invasion by SACC cells. Moreover, EREG-activated EGFR stabilized Snail and Slug, which promoted EMT and metastatic features in SACC cells. Of note, targeting EGFR with inhibitors significantly suppressed both the motility of SACC cells in vitro and lung metastasis in vivo. Finally, elevated EREG expression showed a strong correlation with poor prognosis in head and neck cancer. Thus, targeting the EREG-EGFR-Snail/Slug axis represents a novel strategy for the treatment of metastatic SACC even no genetic EGFR mutation.


Assuntos
Carcinoma Adenoide Cístico/secundário , Epirregulina/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Receptores ErbB/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias das Glândulas Salivares/patologia , Animais , Carcinoma Adenoide Cístico/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/fisiologia , Xenoenxertos , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias das Glândulas Salivares/metabolismo , Transdução de Sinais/fisiologia
10.
Zhongguo Fei Ai Za Zhi ; 18(10): 633-9, 2015 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-26483336

RESUMO

Cancer stem cells (CSCs) are emerging as a hot topic for cancer research. Lung CSCs share many characteristics with normal lung stem cells (SCs), including self-renewal and multi-potency for differentiation. Many molecular markers expressed in various types of CSCs were also found in lung CSCs, such as CD133, CD44, aldehyde dehydrogenase (ALDH) and ATP-binding cassette sub-family G member 2 (ABCG2). Similarly, proliferation and expansion of lung CSCs are regulated not only by signal transduction pathways functioning in normal lung SCs, such as Notch, Hedgehog and Wnt pathways, but also by those acting in tumor cells, such as epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3) and phosphatidylinositol 3 kinase (PI3K) pathways. As CSC plays an critical role in tumor recurrence, metastasis and drug-resistance, understanding the difference between lung CSCs and normal lung SCs, identifying and targeting CSC markers or related signaling pathways may increase the efficacy of therapy on lung cancer and improved survival of lung cancer patients.


Assuntos
Neoplasias Pulmonares/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Antineoplásicos/farmacologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Transdução de Sinais
11.
Cancer Res ; 75(9): 1801-14, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25744720

RESUMO

GPRC5A is a G-protein-coupled receptor expressed in lung tissue but repressed in most human lung cancers. Studies in Gprc5a(-/-) mice have established its role as a tumor-suppressor function in this setting, but the basis for its role has been obscure. Here, we report that GPRC5A functions as a negative modulator of EGFR signaling. Mouse tracheal epithelial cells (MTEC) from Gprc5a(-/-) mice exhibited a relative increase in EGFR and downstream STAT3 signaling, whereas GPRC5A expression inhibited EGFR and STAT3 signaling. GPRC5A physically interacted with EGFR through its transmembrane domain, which was required for its EGFR inhibitory activity. Gprc5a(-/-) MTEC were much more susceptible to EGFR inhibitors than wild-type MTEC, suggesting their dependence on EGFR signaling for proliferation and survival. Dysregulated EGFR and STAT3 were identified in the normal epithelia of small and terminal bronchioles as well as tumors of Gprc5a(-/-) mouse lungs. Moreover, in these lungs EGFR inhibitor treatment inhibited EGFR and STAT3 activation along with cell proliferation. Finally, overexpression of ectopic GPRC5A in human non-small cell lung carcinoma cells inhibited both EGF-induced and constitutively activated EGFR signaling. Taken together, our results show how GPRC5A deficiency leads to dysregulated EGFR and STAT3 signaling and lung tumorigenesis. Cancer Res; 75(9); 1801-14. ©2015 AACR.


Assuntos
Receptores ErbB/metabolismo , Neoplasias Pulmonares/genética , Receptores Acoplados a Proteínas G/metabolismo , Animais , Bronquíolos/metabolismo , Carcinogênese/genética , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Células Epiteliais/metabolismo , Receptores ErbB/genética , Células HEK293 , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores Acoplados a Proteínas G/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
12.
Oncotarget ; 6(9): 6887-901, 2015 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-25749385

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is a particularly aggressive cancer with poor prognosis, largely due to lymph node metastasis and local recurrence. Emerging evidence suggests that epithelial-to-mesenchymal transition (EMT) is important for cancer metastasis, and correlated with increased cancer stem cells (CSCs) characteristics. However, the mechanisms underlying metastasis to lymph nodes in HNSCC is poorly defined. In this study, we show that E-cadherin repression correlates with cancer metastasis and poor prognosis in HNSCC. We found that G9a, a histone methyltransferase, interacts with Snail and mediates Snail-induced transcriptional repression of E-cadherin and EMT, through methylation of histone H3 lysine-9 (H3K9). Moreover, G9a is required for both lymph node-related metastasis and TGF-ß-induced EMT in HNSCC cells since knockdown of G9a reversed EMT, inhibited cell migration and tumorsphere formation, and suppressed the expression of CSC markers. Our study demonstrates that the G9a protein is essential for the induction of EMT and CSC-like properties in HNSCC. Thus, targeting the G9a-Snail axis may represent a novel strategy for treatment of metastatic HNSCC.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/metabolismo , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Células-Tronco Neoplásicas/citologia , Antígenos CD , Caderinas/metabolismo , Carcinoma de Células Escamosas/patologia , Movimento Celular , Citometria de Fluxo , Neoplasias de Cabeça e Pescoço/patologia , Histonas/química , Humanos , Metástase Linfática , Metilação , Metástase Neoplásica , Recidiva Local de Neoplasia/metabolismo , Transplante de Neoplasias , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Células-Tronco/citologia , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento , Cicatrização
13.
Cell Cycle ; 14(9): 1403-12, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25714996

RESUMO

Susceptibility to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) varies greatly among patients in sepsis/septic shock. The genetic and biochemical reasons for the difference are not fully understood. G protein coupled receptor family C group 5 member A (GPRC5A), a retinoic acid target gene, is predominately expressed in the bronchioalveolar epithelium of lung. We hypothesized that Gprc5a is important in controlling the susceptibility to ALI or ARDS. In this study, we examined the susceptibility of wild-type and Gprc5a-knockout (ko) mice to induced ALI. Administration of endotoxin LPS induced an increased pulmonary edema and injury in Gprc5a-ko mice, compared to wild-type counterparts. Consistently, LPS administration induced higher levels of inflammatory cytokines (IL-1ß and TNFα) and chemokine (KC) in Gprc5a-ko mouse lungs than in wild-type. The enhanced pulmonary inflammatory responses were associated with dysregulated NF-κB signaling in the bronchioalveolar epithelium of Gprc5a-ko mouse lungs. Importantly, selective inhibition of NF-κB through expression of the super-repressor IκBα in the bronchioalveolar epithelium of Gprc5a-ko mouse lungs alleviated the LPS-induced pulmonary injury, and inflammatory response. Thus, Gprc5a is critical for lung homeostasis, and Gprc5a deficiency confers the susceptibility to endotoxin-induced pulmonary edema and injury, mainly through NF-κB signaling in bronchioalveolar epithelium of lung.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Endotoxinas , Pulmão/metabolismo , NF-kappa B/metabolismo , Receptores Acoplados a Proteínas G/deficiência , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Mediadores da Inflamação/metabolismo , Pulmão/patologia , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/genética , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Pneumonia/patologia , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Receptores Acoplados a Proteínas G/genética , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Transdução de Sinais , Fatores de Tempo , Regulação para Cima
14.
Lung Cancer ; 78(1): 30-8, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22925698

RESUMO

RNase L mediates critical cellular functions including antiviral, proapoptotic, antiproliferative and tumor suppressive activities. In this study, the expression and function of RNase L in lung cancer cells were examined. Interestingly we have found that the expression of RNase L in lung cancer cells was 3- and 9-fold higher in its mRNA and protein levels, but a significant decrease of its enzymatic activity when compared to that in corresponding normal lung cells. Further investigation revealed that 2-5A-induced dimerization of the RNase L protein, a necessary prerequisite for activation of RNase L, was inhibited, as a result of that RLI, a specific inhibitor of RNase L, was remarkably up-regulated in the cancer cells. Our findings provide new insight into how cancer cells escape normal growth-regulating mechanisms to form a tumor and the information may be useful for the design of novel strategies for treating lung cancer through regulating RNase L activity.


Assuntos
Endorribonucleases/química , Endorribonucleases/metabolismo , Neoplasias Pulmonares/enzimologia , Nucleotídeos de Adenina/farmacologia , Linhagem Celular Tumoral , Endorribonucleases/genética , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Humanos , Neoplasias Pulmonares/genética , Oligorribonucleotídeos/farmacologia , Multimerização Proteica/efeitos dos fármacos , Multimerização Proteica/genética , Inibidores da Síntese de Proteínas/farmacologia
15.
Zhong Yao Cai ; 30(4): 464-6, 2007 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-17674804

RESUMO

OBJECTIVE: To study the optimum parameters of the supercritical CO, fluid extraction of lotus leaves and chemical constituents of extractive matters. METHODS: Supercritical CO2 fluid extraction condition was selected by uniform design. The extraction pressure, extraction temperature, extraction time were three factors in the experiment. GC-MS was applied for analyzing the extraction. RESULTS: The optimum condition were obtained: the extraction pressure was 26 Mpa, the extraction temperature was 40 degrees C, the extracion time was 90 minutes. The major constituent was 1H-Pyrrole-2-carboxaldehyde, 1-ethyl-in extractive matters. CONCLUSION: Uniform design can optimize the CO2 Supercritical Fluid Extraction process quickly and accuratly with satisfactory results.


Assuntos
Cromatografia com Fluido Supercrítico/métodos , Medicamentos de Ervas Chinesas/análise , Cromatografia Gasosa-Espectrometria de Massas/métodos , Lotus/química , Folhas de Planta/química , Dióxido de Carbono , Medicamentos de Ervas Chinesas/isolamento & purificação , Ácidos Graxos/análise , Ácidos Graxos/isolamento & purificação , Monoterpenos/análise , Monoterpenos/isolamento & purificação , Plantas Medicinais/química , Pressão , Reprodutibilidade dos Testes , Tecnologia Farmacêutica/métodos , Temperatura , Fatores de Tempo
16.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 23(3): 260-3, 2007 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-17343796

RESUMO

AIM: To explore the apoptotic effect of the combined treatment of anti-p185(c-erbB-2/neu) engineered antibody with paclitaxel on p185-overexpressing human malignant breast cancer cell lines BT474 and to study its emerging mechanism. METHODS: The prohibitory effect of engineeded antibody plus paclitaxel on BT474 cells was assessed by MTS assay. The number of apoptotic cells was detected by Annexin V-FITC/PI. DNA content and cell cycle distribution were determined by FCM; DNA-binding activity of NF-kappaB was demonstrated by EMSA. RESULTS: Anti-p185(c-erbB-2/neu) engineered antibody plus paclitaxel resulted in synergistic effect on proliferative inhibiton of BT474 cells, which was mediated via apoptotic induction and caused cell cycle to arrest at G1 phase remarkably. Furthermore, the combined treatment of the engineered antibody with paclitaxel effectively suppressed the activation of NF-kappaB in BT474 cells. CONCLUSION: The combined treatment of anti-p185(c-erbB-2/neu) engineered antibody with paclitaxel rendered p185-overexpressing human malignant breast cancer cells BT474 more susceptible to paclitaxel-induced apoptosis by the effective suppression of NF-kappaB activation.


Assuntos
Anticorpos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Paclitaxel/farmacologia , Anticorpos/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Ensaio de Desvio de Mobilidade Eletroforética , Citometria de Fluxo , Fase G1/efeitos dos fármacos , Humanos , NF-kappa B/metabolismo , Receptor ErbB-2/imunologia
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