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INTRODUCTION: Lung cancer is the most common cancer in China, with the highest mortality rate. Surgery is the primary treatment for early lung cancer. However, patients with lung cancer have a heavy burden of symptoms within 3 months after surgery, which seriously affects their quality of life (QOL). The symptom management model based on the patient-reported outcome (PRO) is considered the best caregiving model. The clinical evidence about the symptom management of lung cancer within 3 months after the operation is very limited. Herein, we propose a randomized controlled trial to evaluate the PRO score-based monitoring and alert system for follow-up on psychological and physiological symptoms of lung cancer patients within 3 months after surgery and further investigate the effect of intervention measures based on this PRO score-based system. METHODS AND ANALYSIS: This multicenter, open-label, randomized, parallel superiority trial will be conducted at four hospitals in China. A total of 440 lung cancer patients will be recruited in this study, who will be randomly assigned to the intervention group or the control group in a ratio of 1:1. Any of the target symptoms reaches the preset threshold (score ≥ 4), the patients will accept the symptom management advices based on the PRO. The patients in the control group will follow the current standard procedure of symptom management. The symptom management system is an electronic management system based on WeChat mini programs. All patients will be evaluated for symptoms through the lung cancer module of the MDASI lung cancer-specific scale on the day before surgery, days 1, 3, 5, and 7 after surgery, and once a week during the 12-week post-discharge period. Simultaneously, the EORTC QLQ-C30 scale will be used to evaluate patients' quality of life at baseline and the fourth and twelfth week after the surgery. The mean number of symptom threshold events of the intervention and the control groups were compared by t-test, and the changes of PRO were compared by a mixed effect model. The primary endpoint has been set as the 12-week post-discharge period. DISCUSSION: This study will test the feasibility of the symptom management system based on the mobile social media applet in postoperative caregiving and the efficacy of psychiatrist-assisted treatment and provide evidence in managing the symptoms of patients in the medium and long term. TRIALS REGISTRATION: Trials registration number: ChiCTR 2200058876, Registered 18 April 2022.
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COVID-19 , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/cirugía , SARS-CoV-2 , Calidad de Vida , Cuidados Posteriores , Alta del Paciente , Medición de Resultados Informados por el Paciente , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
Importance: The benefit of neoadjuvant camrelizumab plus chemotherapy for resectable stage IIIA or IIIB non-small cell lung cancer (NSCLC) remains unknown. Objective: To assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy vs chemotherapy alone for patients with resectable stage IIIA or IIIB NSCLC. Design, Setting, and Participants: In this randomized phase 2 clinical trial conducted at 2 hospitals in China, patients aged 18 to 70 years with resectable stage IIIA or IIIB (T3N2) NSCLC were enrolled between April 7, 2020, and January 12, 2022. Interventions: Patients were randomly assigned to receive 3 cycles of camrelizumab (200 mg) plus chemotherapy (nab-paclitaxel, 130 mg/m2, and platinum [cisplatin, 75 mg/m2; carboplatin, area under the curve, 5; or nedaplatin, 100 mg/m2]) or chemotherapy alone, followed by surgery after 4 to 6 weeks. Main Outcomes and Measures: The primary end point was the pathologic complete response (pCR) rate. Secondary end points included the major pathologic response (MPR) rate, objective response rate (ORR), event-free survival (EFS), and safety. Disease-free survival (DFS, defined as the time from surgery to disease recurrence or death from any cause) was analyzed post hoc. Efficacy was assessed on a modified intention-to-treat basis. Results: Ninety-four Chinese patients were randomized, and 88 (93.6%; median age, 61 years [IQR, 54-65 years]; 74 men [84.1%]) received allocated neoadjuvant treatment (43 received camrelizumab plus chemotherapy, and 45 received chemotherapy alone). Among these 88 patients, the pCR rate was 32.6% (14 of 43; 95% CI, 19.1%-48.5%) with camrelizumab plus chemotherapy vs 8.9% (4 of 45; 95% CI, 2.5%-21.2%) with chemotherapy alone (odds ratio, 4.95; 95% CI, 1.35-22.37; P = .008). The MPR rates were 65.1% (95% CI, 49.1%-79.0%) with camrelizumab plus chemotherapy and 15.6% (95% CI, 6.5%-29.5%) with chemotherapy alone. The radiographic ORRs were 72.1% (95% CI, 56.3%-84.7%) with camrelizumab plus chemotherapy and 53.3% (95% CI, 37.9%-68.3%) with chemotherapy alone. With a median follow-up of 14.1 months (IQR, 9.2-20.9 months), the median EFS and DFS were not reached in either group. The most common neoadjuvant treatment-related adverse events of grade 3 or higher were decreased white blood cell count (6 of 43 [14.0%] in the camrelizumab plus chemotherapy group vs 2 of 45 [4.4%] in the chemotherapy group) and decreased neutrophil count (3 of 43 [7.0%] in the camrelizumab plus chemotherapy group vs 5 of 45 [11.1%] in the chemotherapy group). No treatment-related deaths were reported. Conclusions and Relevance: This randomized clinical trial found that among patients with resectable stage IIIA or IIIB (T3N2) NSCLC, camrelizumab plus chemotherapy, compared with chemotherapy alone, significantly improved the pCR rate with manageable toxic effects. Trial Registration: ClinicalTrials.gov Identifier: NCT04338620.
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Hypoxia, a common feature of solid tumors, can promote chemoresistance in cancer cells. PRMT5 mediates various cellular processes involved in cancer development and progression. However, the role of PRMT5 in hypoxia-induced chemoresistance is unclear. In this study, hypoxia upregulated PRMT5 expression in lung cancer cells. Additionally, PRMT5 overexpression promoted cancer cell resistance to carboplatin. In carboplatin-resistant cancer cells, PRMT5 overexpression promoted the methylation of ULK1, a critical regulator of autophagy. ULK1 hypermethylation leads to the upregulation of autophagy, which can improve the survival of cancer cells under hypoxic conditions. Furthermore, this study demonstrated that the PRMT5 inhibitor C9 significantly enhanced the sensitivity of lung cancer cells to carboplatin. These findings suggest that targeting PRMT5-mediated autophagy with C9 can overcome hypoxia-induced carboplatin resistance and improve the efficacy of chemotherapy in patients with cancer.
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Neoplasias Pulmonares , Humanos , Carboplatino/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Pulmón/metabolismo , Hipoxia , Autofagia , Línea Celular Tumoral , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/metabolismoRESUMEN
BACKGROUND: In recent years, there have been breakthroughs in the preclinical research of respiratory diseases, such as organoids and organ tissue chip models, but they still cannot provide insight into human respiratory diseases well. Human lung slices model provides a promising in vitro model for the study of respiratory diseases because of its preservation of lung structure and major cell types. METHODS: Human lung slices were manually prepared from small pieces of lung tissues obtained from lung cancer patients subjected to lung surgery. To evaluate the suitability of this model for lung fibrosis research, lung slices were treated with CdCl2 (30 µM), TGF-ß1 (1 ng/ml) or CdCl2 plus TGF-ß1 for 3 days followed by toxicity assessment, gene expression analysis and histopathological observations. RESULTS: CdCl2 treatment resulted in a concentration-dependent toxicity profile evidenced by MTT assay as well as histopathological observations. In comparison with the untreated group, CdCl2 and TGF-ß1 significantly induces MMP2 and MMP9 gene expression but not MMP1. Interestingly, CdCl2 plus TGF-ß1 significantly induces the expression of MMP1 but not MMP2, MMP7 or MMP9. Microscopic observations reveal the pathogenesis of interstitial lung fibrosis in the lung slices of all groups; however, CdCl2 plus TGF-ß1 treatment leads to a greater alveolar septa thickness and the formation of fibroblast foci-like pathological features. The lung slice model is in short of blood supply and the inflammatory/immune-responses are considered minimal. CONCLUSIONS: The results are in favor of the hypothesis that idiopathic pulmonary fibrosis (IPF) is mediated by tissue damage and abnormal repair. Induction of MMP1 gene expression and fibroblast foci-like pathogenesis suggest that this model might represent an early stage of IPF.
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Fibrosis Pulmonar Idiopática , Factor de Crecimiento Transformador beta1 , Humanos , Factor de Crecimiento Transformador beta1/genética , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Pulmón/patología , Fibroblastos/metabolismoRESUMEN
Lung cancer is the leading cause of cancer-related deaths worldwide, and insights into its underlying mechanisms as well as potential therapeutic strategies are urgently needed. The microbiome plays an important role in human health, and is also responsible for the initiation and progression of lung cancer through its induction of inflammatory responses and participation in immune regulation, as well as for its role in the generation of metabolic disorders and genotoxicity. Here, the distribution of human microflora along with its biological functions, the relationship between the microbiome and clinical characteristics, and the role of the microbiome in clinical treatment of lung cancer were comprehensively reviewed. This review provides a basis for the current understanding of lung cancer mechanisms with a focus on the microbiome, and contributes to future decisions on treatment management.
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Neoplasias Pulmonares , Microbiota , Humanos , Pulmón , Microbiota/fisiologíaRESUMEN
ABSTRACT: Neurogenic cervical spondylosis is the most common type of cervical spondylosis, accounting for approximately 60% percent of the incidence of cervical spondylosis. Cervical spine Long manipulation and sling exercise training (SET) have obtained good therapeutic results in clinical rehabilitation. The aim of this study was to evaluate the effect of Long manipulation combined with SET on neurogenic cervical spondylosis. In this assessor-blind, randomized controlled trial, 90 eligible patients will be randomized into a combination treatment group (Long manipulation combined with SET), a Long manipulation group and a conventional massage group. The visual analogue score, the Neck Disability Index score, and muscle fatigue in the bilateral upper oblique and Musculus sternocleidomastoideus, using mean power frequency and median frequency from the surface electromyography frequency domain index, will be assessed before and after the intervention at 0 and 4âweeks, respectively.Trial registration: Registered in the Chinese Clinical Trial Registration Center with the number ChiCTR2100054978. Registered December 30, 2021.
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Quiropráctica/métodos , Manipulación Espinal/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Espondilosis/terapia , Vértebras Cervicales , Humanos , Masaje/métodos , Fatiga Muscular , Espondilosis/complicaciones , Resultado del TratamientoRESUMEN
Background: Alterations in MET exon 14 (METex14) and its flanking intronic regions have been identified in a variety of cancers. Patients with METex14 alterations often benefit from MET inhibitors such as crizotinib. Given the unique mutation profiles of Chinese lung cancer patients, it is necessary to investigate the prevalence of METex14 alterations in a large cohort of cancer patients. Patients and methods: Cases carrying METex14 alterations were screened from 26,391 Chinese cancer patients by next-generation sequencing (NGS), and the clinicopathologic and molecular characteristics were reviewed. Results: Compared to Western population (~3%), the frequency of METex14 alterations is much lower in Chinese cancer patients (0.7%, n=184) and lung cancer patients (1.1%, n=175). Seventy-eight distinct METex14 alterations, including several novel alteration types were detected. Concurrent MET copy gain and non-exon14 MET mutations were also found. EGFR copy gain (11%) and mutations (8%), KRAS (5%) and PIK3CA (5%), appeared in a mutually exclusive pattern. Female patients contain much less TP53 mutations than male patients (65% vs. 24%, FDR = 0.01). Co-amplification of CDK4 and MDM2, CDK6 and EGFR were identified, which indicated cell cycle dysregulation and EGFR alteration are important co-occurring features in patients with METex 14 alteration. Of 9 tissue specimens having PD-L1 immunohistochemistry (IHC) results, 5 of them (55.5%) were found PD-L1 positive, which is comparable to other types of tumor. In 14 crizotinib-treated patients, the median progression free survival (mPFS) was 7 months. Upon resistance to crizotinib, two patients acquired secondary mutations in MET and one patient acquired BRAF p.K601E that can be a novel resistance mechanism. Conclusion: Chinese cancer patients have a relatively lower frequency of METex14 alterations compared to Western patients. Patients with METex14 alterations showed distinct molecular characteristics and the representative case study showed responses to MET tyrosine kinase inhibitor (TKI).
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Reprogramming of the tumor immune microenvironment is a salient feature during metastasis in LUAD. miR-24-3p and KLF8, which are key regulators of the tumor immune microenvironment, had been proved to show metastasis-promoting property in LUAD. However, whether miR-24-3p could regulate LUAD metastasis by targeting KLF8 remains unclear. This study explored the functions and mechanisms of miR-24-3p/KLF8 signaling in advanced LUAD. The expression level of miR-24-3p and KLF8 were tested in LUAD patients, and the corelation of miR-24-3p and KLF8 was evaluated. The interaction of miR-24-3p and KLF8 was demonstrated by luciferase reporter activity assay, in vitro migration and invasion studies, and in vivo metastatic studies. miR-24-3p level was downregulated in LUAD and negatively associated with KLF8 mRNA expression. miR-24-3p controls LUAD metastasis by directly targeting KLF8 and inducing Snail and E-cadherin expressions. Targeting the miR-24-3p/KLF8/EMT axis might be of great therapeutic value to advanced LUAD patients.
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Adenocarcinoma del Pulmón/genética , Transición Epitelial-Mesenquimal/genética , Factores de Transcripción de Tipo Kruppel/genética , Neoplasias Pulmonares/genética , MicroARNs/metabolismo , Células A549 , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/secundario , Animales , Antígenos CD/metabolismo , Cadherinas/metabolismo , Proliferación Celular , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Pulmón/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Ratones , Transducción de Señal/genética , Factores de Transcripción de la Familia Snail/metabolismo , Microambiente Tumoral/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Our previous studies showed that Fibroblast growth factor receptor 3 (FGFR3) contributed to cell growth in lung cancer. However, the correlation between FGFR3 and tumor progression, coupled with the underlying mechanisms, are not fully understood. The clinical significance of FGFR3 was determined in two cohorts of clinical samples (n = 22, n = 78). A panel of biochemical assays and functional experiments was utilized to elucidate the underlying mechanisms and effects of FGFR3 and miR-24-3p on lung adenocarcinoma progression. Upregulated FGFR3 expression indicated an adverse prognosis for lung adenocarcinoma individuals and promoted metastatic potential of lung adenocarcinoma cells. Owing to the direct regulation towards FGFR3, miR-24-3p could interfere with the potential of proliferation, migration, and invasion in lung adenocarcinoma, following variations of EMT-related protein expression. As a significant marker of EMT, E-cadherin was negatively correlated with FGFR3, of which ectopic overexpression could neutralize the antitumour effects of miR-24-3p and reverse its regulatory effects on EMT markers. Taken together, these findings define a novel insight into the miR-24-3p/FGFR3 signaling axis in regulating lung adenocarcinoma progression and suggest that targeting the miR-24-3p/FGFR3 axis could be an effective and efficient way to prevent tumor progression.
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Adenocarcinoma/genética , Neoplasias Pulmonares/genética , MicroARNs/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Carcinogénesis , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Estudios de Cohortes , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Transducción de Señal , Regulación hacia ArribaRESUMEN
Metastasis is the major cause for the death of patients with colorectal cancer (CRC). Anoikis resistance enhances the survival of cancer cells during systemic circulation, thereby facilitating secondary tumor formation in distant organs. miR-124 is a pleiotropically tumor suppressive small non-coding molecule. However, its role and mechanism in the regulation of cancer cell anoikis are still unknown. Here, we found that overexpression of miR-124 promotes anoikis of CRC cells in vitro and in vivo. In silico analysis and the experimental evidence supported that ITGA3 is a bona fide target of miR-124. Moreover, we identifies that ITGA3 plays a critical role in the regulation of anoikis sensitivity in CRC cells. Finally, our analysis in TCGA datasets demonstrates that high levels of ITGA3 are closely associated with poor prognosis in CRC patients. Collectively, we establish a functional link between miR-124 and anoikis susceptibility and provide that a miR-124/ITGA3 axis could be a potential target for the treatment of metastatic CRC.
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Anoicis , Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica , Integrina alfa3/genética , MicroARNs/genética , Metástasis de la Neoplasia/genética , Línea Celular , Línea Celular Tumoral , Movimiento Celular , Neoplasias Colorrectales/patología , Humanos , Metástasis de la Neoplasia/patologíaRESUMEN
Protein arginine methyltransferase 5 (PRMT5) functions as a tumor initiator to regulate several cancer progressions, such as proliferation and apoptosis, by catalyzing the symmetrical dimethylation (me2s) of arginine residues within targeted molecules. However, the exact role of PRMT5-mediated metastasis in lung cancer is not fully understood. Here, we illustrated its potential effects in lung cancer metastasis in vivo and vitro. PRMT5 was frequently overexpressed in lung tumors, and its expression was positively related to tumor stages, lymphatic metastasis and poor outcome. In this model, PRMT5 repressed the transcription of the miR-99 family by symmetrical dimethylation of histone H4R3, which increased FGFR3 expression and in turn activated Erk1/2 and Akt, leading to cell growth and metastasis in lung cancer. Furthermore, loss of PRMT5 exerted anti-metastasis effects on lung cancer progression by blocking histone-modification of miR-99 family. Overall, this study provides new insights into the PRMT5/miR-99 family/FGFR3 axis in regulating lung cancer progression and identifies PRMT5 as a promising prognostic biomarker and therapeutic target.
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Epigénesis Genética , Neoplasias Pulmonares/genética , MicroARNs/genética , Proteína-Arginina N-Metiltransferasas/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Células A549 , Animales , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , MicroARNs/metabolismo , Persona de Mediana Edad , Metástasis de la Neoplasia , Proteína-Arginina N-Metiltransferasas/metabolismo , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal/genética , Trasplante HeterólogoRESUMEN
Arginine methylation as a common pattern of post-translational modification is involved in many cellular biological processes. Protein arginine methyltransferase 5 (PRMT5) is a primary enzyme in charge of symmetric dimethylation (me2s) of arginine residues. Increasing literatures lead to the belief that PRMT5, as a potential oncogene, plays crucial roles in the tumorigenesis and progression of cancers. First of all, PRMT5 is overexpressed in several cancer cells, with various sub-cellular localization in different type of cells and different phases. Besides, PRMT5 participates in controlling cellular proliferation, differentiation, invasion, migration as well apoptosis through histone and other protein methylation. Moreover, PRMT5 is essential for growth and metastasis of lung cancer cells, and its overexpression indicates a poor clinical outcome of lung cancer. Therefore, in this review, we reviewed the substantial new literatures on PRMT5 and its functions, in order to highlight the significance of understanding this essential enzyme in lung cancer tumorigenesis and progression.
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Protein arginine methyltransferase 5 (PRMT5) plays critical roles in a wide variety of biological processes, including tumorigenesis. By screening a library of small chemical compounds, we identified eight compounds that selectively inhibit the PRMT5 enzymatic activity, with IC50 values ranging from 0.1 to 6 µM. Molecular docking simulation and site-directed mutagenesis indicated that identified compounds target the substrate-binding site in PRMT5. Treatment of lung cancer cells with identified inhibitors led to inhibition of the symmetrical arginine methylation of SmD3 and histones and the cellular proliferation. Oral administration of the inhibitor demonstrated antitumor activity in a lung tumor xenograft model. Thus, identified PRMT5-specific small-molecule inhibitors would help elucidate the biological roles of PRMT5 and serve as lead compounds for future drug development.
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Antineoplásicos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Proteína-Arginina N-Metiltransferasas/metabolismo , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Administración Oral , Animales , Antineoplásicos/análisis , Antineoplásicos/química , Antineoplásicos/farmacología , Unión Competitiva/efectos de los fármacos , Disponibilidad Biológica , Línea Celular Tumoral , Permeabilidad de la Membrana Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Cinética , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Ratones Desnudos , Fenilalanina/metabolismo , Bibliotecas de Moléculas Pequeñas/análisis , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Especificidad por Sustrato/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: As acute lung injury (ALI) caused high mortality rate, it is important to explore the protection and treatment of ALI. The aim of the current study is to evaluate the effect of low molecular weight heparin (LMWH) nebulization on attenuating acute lung injury and the associated mechanism. METHODS: The arterial blood gas, total protein content in bronchoalveolar lavage fluid, lung wet/dry weight ratio, malondialdehyde (MDA) content, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, and Akt phosphorylation were evaluated after the ALI rabbits were treated with or without LMWH nebulization. RESULTS: PaO2 was increased and lung wet/dry weight ratio as well as total protein content in BALF was decreased after LMWH nebulization. After the application of LMWH nebulization therapy, the SOD and GSH-Px activity was rebounded and the increase of MDA content was significantly inhibited. The Akt protein phosphorylation level was decreased after LMWH nebulization therapy. CONCLUSIONS: LMWH nebulization treatment can relieve the traumatic ALI in rabbits and inhibit oxidative stress possibly by suppressing the Akt phosphorylation.
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Lesión Pulmonar Aguda/tratamiento farmacológico , Heparina de Bajo-Peso-Molecular/farmacología , Lesión Pulmonar Aguda/sangre , Administración por Inhalación , Animales , Modelos Animales de Enfermedad , Glutatión Peroxidasa/sangre , Malondialdehído/sangre , Nebulizadores y Vaporizadores , Conejos , Superóxido Dismutasa/sangreRESUMEN
We previously reported that a novel WD-40 domain-containing protein, p44/WDR77, drives quiescent epithelial cells to re-enter the cell cycle and plays an essential role for growth of lung and prostate cancer cells. Transforming growth factor beta (TGFß) signaling is important in the maintenance of non-transformed cells in the quiescent or slowly cycling stage. However, both non-transformed proliferating cells and human cancer cells are non-responsive to endogenous TGFß signaling. The mechanism by which proliferating cells become refractory to TGFß inhibition is not well established. Here, we found that silencing p44/WDR77 increased cellular sensitivity to TGFß signaling and that this was inversely correlated with decreased cell proliferation. Smad2 or 3 phosphorylation, TGFß-mediated transcription, and TGFß2 and TGFß receptor type II (TßRII) expression were dramatically induced by silencing of p44/WDR77. These data support the hypothesis that p44/WDR77 down-regulates the expression of the TGFß ligand and its receptor, thereby leading to a cellular non-response to TGFß signaling. Finally, we found that p44/WDR77 expression was correlated with cell proliferation and decreased TGFß signaling during lung tumorigenesis. Together, these results suggest that p44/WDR77 expression causes the non-sensitivity of proliferating cells to TGFß signaling, thereby contributing to cellular proliferation during lung tumorigenesis.
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Proliferación Celular , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador beta2/metabolismo , Carcinogénesis , Línea Celular Tumoral , Humanos , Receptor Tipo II de Factor de Crecimiento Transformador betaRESUMEN
The androgen receptor (AR) pathway plays critical roles in controlling differentiation and proliferation of prostate epithelial cells. We previously identified a novel AR cofactor, p44/WDR77, which specifically enhances AR transcriptional activity in the prostate gland and prostate cancer. To further elucidate p44/WDR77's role in the AR signaling pathway, we conducted a yeast two-hybrid screening and identified cGMP-dependent protein kinase (PKG) as a p44/WDR77-interacting protein. Further investigation by lusiferase assay and kinase assay demonstrated that PKG-Iß physically interacted with and phosphorylated both p44 and AR and enhanced AR transactivity in synergy with p44 in an androgen- and cGMP-dependent manner. Furthermore, PKG1ß expression promoted p44/WDR77 nuclear translocation and inhibited prostate cancer cell growth via G1 cell cycle arrest. Our findings characterize PKG as a novel regulator of AR-mediated transcription by enhancing AR cofactor p44/WDR77's function, which provide a novel mechanism for the growth regulation of prostate cancer cells by the androgen signaling.
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Proteína Quinasa Dependiente de GMP Cíclico Tipo I/metabolismo , Regulación Neoplásica de la Expresión Génica , Fragmentos de Péptidos/metabolismo , Receptores Androgénicos/metabolismo , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Ciclo Celular , Línea Celular Tumoral , Núcleo Celular/metabolismo , Proliferación Celular , Proteína Quinasa Dependiente de GMP Cíclico Tipo I/química , Humanos , Masculino , Ratones Endogámicos C57BL , Fosforilación , Regiones Promotoras Genéticas/genética , Próstata/crecimiento & desarrollo , Próstata/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Transporte de Proteínas , Receptores de Glucocorticoides/metabolismo , Receptores de Progesterona/metabolismo , Transcripción Genética , Técnicas del Sistema de Dos HíbridosRESUMEN
OBJECTIVE: To verify the clinical efficacy on intractable hiccup treated by acupuncture at the lower He-sea points mainly. METHODS: Fifty-two cases were randomized into an acupuncture-moxibustion group and a western medication group, 26 cases in each one. In the acupuncture-moxibustion group, acupuncture was applied to Zusanli (ST 36), Shangjuxu (ST 37) and Xiajuxu (ST 39). The mild moxibustion was applied to Zhongwan (CV 12) and Xiawan (CV 10). In the western medication group, the intravenous drop with lidocaine was administered. The efficacy and the score changes of the main associated symptoms were compared in the two groups. RESULTS: The total effective rate was 96.1% (25/26) in the acupuncture-moxibustion group, which was better than 69.3% (18/26) in the western medication group (P.<0.01). After treatment, for the patients in both groups, the scores of the main associated symptoms such as anxiety, tension, insomnia, respiratory symptoms and the restlessness in conversation were all improved (all P<0.05). The improvements in the acupuncture-moxibustion group were much obvious than those in the western medication group (all P<0.05). CONCLUSION: Acupuncture at the lower He-sea points mainly relieves effectively the symptoms of hiccup and the efficacy is better than that with lidocaine.
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Puntos de Acupuntura , Terapia por Acupuntura , Hipo/terapia , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Protein arginine methyltransferase 5 (PRMT5) plays multiple roles in a large number of cellular processes, and its subcellular localization is dynamically regulated during mouse development and cellular differentiation. However, little is known of the functional differences between PRMT5 in the cytoplasm and PRMT5 in the nucleus. Here, we demonstrated that PRMT5 predominantly localized in the cytoplasm of prostate cancer cells. Subcellular localization assays designed to span the entire open-reading frame of the PRMT5 protein revealed the presence of three nuclear exclusion signals (NESs) in the PRMT5 protein. PRMT5 and p44/MED50/WD45/WDR77 co-localize in the cytoplasm, and both are required for the growth of prostate cancer cells in an PRMT5 methyltransferase activity-dependent manner. In contrast, PRMT5 in the nucleus inhibited cell growth in a methyltransferase activity-independent manner. Consistent with these observations, PRMT5 localized in the nucleus in benign prostate epithelium, whereas it localized in the cytoplasm in prostate premalignant and cancer tissues. We further found that PRMT5 alone methylated both histone H4 and SmD3 proteins but PRMT5 complexed with p44 and pICln methylated SmD3 but not histone H4. These results imply a novel mechanism by which PRMT5 controls cell growth and contributes to prostate tumorigenesis.
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Núcleo Celular/enzimología , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/patología , Proteína-Arginina N-Metiltransferasas/metabolismo , Secuencia de Aminoácidos , Animales , Células COS , Línea Celular Tumoral , Proliferación Celular , Chlorocebus aethiops , Silenciador del Gen , Humanos , Masculino , Ratones , Datos de Secuencia Molecular , Señales de Localización Nuclear , Unión Proteica , Transporte de Proteínas , Proteína-Arginina N-Metiltransferasas/química , Fracciones Subcelulares/enzimología , Especificidad por Sustrato , Factores de Transcripción/metabolismoRESUMEN
PRMT5 (protein arginine methyltransferase 5) is an enzyme that catalyses transfer of methyl groups from S-adenosyl methionine to the arginine residues of histones or non-histone proteins and is involved in a variety of cellular processes. Although it is highly expressed in some tumours, its direct role in cancer growth has not been fully investigated. In the present study, in human lung tissue samples we found that PRMT5 was highly expressed in lung cancer cells, whereas its expression was not detectable in benign lung tissues. Silencing PRMT5 expression strongly inhibited proliferation of lung adenocarcinoma A549 cells in tissue culture, and silencing PRMT5 expression in A549 cells also abolished growth of lung A549 xenografts in mice. In vitro and in vivo studies showed that the cell growth arrest induced by loss of PRMT5 expression was partially attributable to down-regulation of fibroblast growth factor receptor signalling. These results suggest that PRMT5 and its methyltransferase activity is essential for proliferation of lung cancer cells and may serve as a novel target for the treatment of lung cancer.