RESUMEN
Pulmonary fibrosis is a progressive and debilitating lung disease characterized by the excessive accumulation of extracellular matrix (ECM) components within the lung parenchyma. However, the underlying mechanism remains largely elusive, and the treatment options available for pulmonary fibrosis are limited. Interleukin 5 receptor, alpha (IL5RA) is a well-established regulator of eosinophil activation, involved in eosinophil-mediated anti-parasitic activities and allergic reactions. Recent studies have indicated additional roles of IL5RA in lung epithelium and fibroblasts. Nevertheless, its involvement in pulmonary fibrosis remains unclear. In present study, we employed single-cell analyses alongside molecular and cellular assays to unveil the expression of IL5RA in lung epithelial cells. Moreover, using both in vitro and in vivo models, we demonstrated a notable upregulation of epithelial IL5RA during the progression of pulmonary fibrosis. This upregulated IL5RA expression subsequently promotes epithelial-mesenchymal transition (EMT), leading to the generation of mesenchymal phenotype with augmented capability for ECM production. Importantly, our findings uncovered that the pro-fibrotic function of IL5RA is mediated by Jak2/STAT3 signaling cascades. Inhibiting IL5RA has the potential to deactivate Jak2/STAT3 and suppress the downstream EMT process and ECM production, thereby offering a promising therapeutic strategy for pulmonary fibrosis.
Asunto(s)
Fibrosis Pulmonar , Humanos , Transición Epitelial-Mesenquimal/fisiología , Fibrosis , Subunidad alfa del Receptor de Interleucina-5/metabolismo , Pulmón/metabolismo , Fibrosis Pulmonar/metabolismo , Receptores de Interleucina-5/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
Lung squamous cell carcinoma (LSCC) is a prevalent and progressive subtype of lung cancer. This study aimed to substantiate the regulatory effect of the PAK2/SOX2/DEK axis on the LSCC development. LSCC tissues (n = 83) and adjacent normal tissues were collected and SOX2 expression was determined by qRT-PCR and Western blotting. Correlation between SOX2 expression and the prognosis of LSCC patients was then explored utilizing Kaplan-Meier analysis. Co-immunoprecipitation and glutathione-S-transferase pull-down assays were conducted to validate the binding of SOX2 to DEK. Gain- and loss- of function assays were then performed on LSCC cells, with CCK-8 and Transwell assays applied to detect the malignant behaviors of cells. A mouse xenograft model of LSCC was further established for in vivo validation. The expression levels of SOX2, PAK2 and DEK were up-regulated in LSCC tissues and cells. SOX2 overexpression was correlated with poor prognosis of LSCC patients. Knockdown of SOX2 weakened the viability and the migratory and invasive potential of LSCC cells. Further, PAK2 directly interacted with SOX2. PAK2 overexpression accelerated the malignant phenotypes of LSCC cells through interplay with SOX2. Moreover, SOX2 activated the expression of DEK, and silencing DEK attenuated the malignant behaviors of LSCC cells. In conclusion, PAK2 could bind to the transcription factor SOX2 and thus activate the expression of DEK, thereby driving the malignant phenotypes of LSCC cells both in vivo and in vitro.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Laríngeas , Neoplasias Pulmonares , MicroARNs , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Células Escamosas/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Regulación Neoplásica de la Expresión Génica , Glutatión/metabolismo , Humanos , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patología , Pulmón/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones , MicroARNs/genética , Proteínas Oncogénicas , Proteínas de Unión a Poli-ADP-Ribosa/genética , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Factores de Transcripción SOXB1 , Sincalida/genética , Sincalida/metabolismo , Quinasas p21 Activadas/genética , Quinasas p21 Activadas/metabolismoRESUMEN
Idiopathic pulmonary fibrosis (IPF), a progressive and fatal lung disease, usually leads to an irreversible distortion of the pulmonary structure. The functional roles of bone marrow-derived mesenchymal stem cells (BMSC)-secreted extracellular vesicles (EVs) in fibroblasts have been implicated, yet their actions in the treatment of IPF are not fully understood. This study investigated the roles of BMSC-derived EVs expressing miR-29b-3p in fibroblasts in IPF treatment. EVs derived from BMSCs were successfully isolated and could be internalized by pulmonary fibroblasts, and Cell Counting Kit-8 (CCK-8) and Transwell assay results identified that EVs inhibited the activation of fibroblast in IPF. miR-29b-3p, frizzled 6 (FZD6), α-skeletal muscle actin (α-SMA), and Collagen I expressions were examined, which revealed that miR-29b-3p was poorly expressed and FZD6, α-SMA, and Collagen I were overexpressed in pulmonary tissues. Dual-luciferase reporter assay results demonstrated that miR-29b-3p could inversely target FZD6 expression. The gain- and loss-of-function assays were conducted to determine regulatory effects of FZD6 and miR-29b-3p on IPF. CCK-8 and Transwell assays results displayed that BMSCs-derived EVs overexpressing miR-29b-3p contributed to inhibited pulmonary interstitial fibroblast proliferation, migration, invasion, and differentiation. Furthermore, the effects of BMSCs-derived EVs overexpressing miR-29b-3p on IPF progression were assessed in vivo, which confirmed the repressive effects of BMSCs-derived EVs overexpressing miR-29b-3p on IPF progression. Collectively, BMSCs-derived EVs overexpressing miR-29b-3p relieve IPF through FZD6.
Asunto(s)
Fibroblastos/metabolismo , Receptores Frizzled/genética , Células Madre Mesenquimatosas/metabolismo , MicroARNs/genética , Anciano , Animales , Diferenciación Celular/fisiología , Proliferación Celular/fisiología , Colágeno Tipo I/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Fibrosis Pulmonar Idiopática/metabolismo , Pulmón/metabolismo , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Persona de Mediana EdadRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a condition that results in the progressive deterioration of lung function with poor prognosis. The current study is aimed at exploring how microRNA-448 (miR-448) targeting ABCC3 affects fibroblast proliferation, apoptosis, and collagen synthesis of mice with IPF via the Jun N-terminal kinase (JNK) signaling pathway. Bioinformatics and dual-luciferase polymerase chain reaction were used to predict the relationship of miR-448 and ABCC3. The expression of miR-448 and ABCC3 was detected in IPF tissues. Using IPF mouse models, lung fibroblasts for the experiments were treated with miR-448 mimic, miR-448 inhibitor, si-ABCC3, or SP600125 (inhibitor of JNK) to evaluate the cell proliferation and apoptosis in response to miR-448. Reverse transcription quantitative polymerase chain reaction and western blot analysis were used to identify the expression of miR-448, ABCC3, and the activation of the JNK signaling pathway. ABCC3 was targeted and downregulated by miR-448 based on bioinformatics prediction and dual-luciferase reporter gene assay. Additionally, miR-448 was found to be highly expressed in IPF lung tissues with low expression levels of ABCC3. In response to the treatment of miR-448 mimic or si-ABCC3, lung fibroblasts exhibited decreased cell proliferation and increased apoptotic rates, whereas the miR-448 inhibitor reversed the conditions. Notably, we also found that miR-448 mimic inhibited the JNK signaling pathway. In conclusion, by using miR-448 to target and downregulate ABCC3 to block the JNK signaling pathway in mice with IPF, we found an increase in fibroblast apoptosis, inhibited cell proliferation, and decreased collagen synthesis of fibroblasts.
Asunto(s)
Colágeno/biosíntesis , Fibroblastos/patología , Fibrosis Pulmonar Idiopática/patología , Sistema de Señalización de MAP Quinasas/fisiología , MicroARNs/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Animales , Apoptosis/genética , Proliferación Celular/genética , Colágeno/genética , Fibroblastos/metabolismo , Regulación de la Expresión Génica/genética , Fibrosis Pulmonar Idiopática/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genéticaRESUMEN
Pulmonary fibrosis is a fatal lung disease characterized by progressive fibroblast proliferation and extensive extracellular matrix (ECM) deposition. Although great efforts have been placed to understand the pathogenesis and explore therapeutic strategies, the treatment options for pulmonary fibrosis are very limited and the prognosis of pulmonary fibrosis patients remains poor. Sinensetin is a polymethoxylated flavone derived from citrus fruits, and has been characterized with anti-fibrotic property. However, the underlying mechanism is still unclear. In present study, combining in vitro and in vivo models, we revealed for the first time that sinensetin can protect against pulmonary fibrosis via inhibiting glycogen synthase kinase-3ß (GSK-3ß)-mediated Wnt/ß-Catenin signaling pathway. According to our results, the activation of Wnt/ß-Catenin signaling pathway in pulmonary fibrosis is responsible for fibroblast proliferation and differentiation to form ECM-producing myofibroblasts. Sinensetin treatment dephosphorylates and activates GSK-3ß, a component of ß-Catenin destruction complex, which induces ß-Catenin degradation and deactivates Wnt/ß-Catenin-mediated fibroblast proliferation and differentiation. As a result, myofibroblasts formation and ECM production are reduced and the progression of pulmonary fibrosis is suppressed. These results not only advance our knowledge on the pharmacological activities of sinensetin, but also provide novel insights on pulmonary fibrosis treatment.
Asunto(s)
Flavonas , Fibrosis Pulmonar , Fibrosis , Flavonoides , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Fibrosis Pulmonar/tratamiento farmacológico , Vía de Señalización Wnt , beta Catenina/metabolismoRESUMEN
After the publication of the article, the authors have realized that the affiliation presented for the joint coauthor listed on the paper (JianRen Tu) was incorrect. The correct author list (and affiliations) should therefore have been published as follows: YuHua Xu1*, JianRen Tu2*, TianTian Zhao3, ShiGuang Xie3 and ShengBo Tang4. 1Department of Cardiovascular Medicine, Jiangxi Chest Hospital, Nanchang, Jiangxi 330006; 2Department of Oncology, Jiangxi Cancer Hospital, Nanchang, Jiangxi 330029; Departments of 3Respiratory Medicine and 4Medical Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China. *Contributed equally. The authors apologize for their oversight, and for any inconvenience that this has caused. [the original article was published in International Journal of Oncology 54: 295305, 2019; DOI: 10.3892/ijo.2018.4629].
RESUMEN
Chemoresistance is one of the most important biological elements affecting the progression and prognosis of cancer. Long noncoding RNAs (lncRNAs) are important regulators and are aberrantly expressed in various types of cancer in humans, including nonsmall cell lung cancer (NSCLC). The present study aimed to investigate the effect of lncRNAs on NSCLC resistance to chemotherapy. The relative expression level of epidermal growth factor receptor antisense RNA 1 (EGFRAS1) was quantified by reverse transcription-quantitative polymerase chain reaction analysis in NSCLC tissues, paired adjacent normal tissues, patient plasma and NSCLC cell lines, and its association with prognosis was assessed by multivariate analysis. The biological functions of EGFRAS1 in NSCLC cells were determined in vitro. It was found that EGFRAS1 was abnormally upregulated in NSCLC tissues compared with adjacent normal lung tissues. Furthermore, patients with NSCLC with increased expression of EGFRAS1 had a poor prognosis. EGFRAS1 knockdown significantly inhibited NSCLC malignancy in vitro, including cell proliferation and chemoresistance. Furthermore, the expression levels of EGFRAS1 were increased in plasma samples from patients with cisplatin-based chemotherapy resistance. Bioinformatics analysis and a luciferase reporter assay confirmed that EGFRAS1 mediated cell proliferation and chemoresistance through directly binding to microRNA223. Therefore, EGFRAS1 overexpression-induced chemoresistance can contribute to poor prognosis in NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Resistencia a Antineoplásicos , Neoplasias Pulmonares/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Receptores de Somatomedina/genética , Células A549 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular , Cisplatino/farmacología , Cisplatino/uso terapéutico , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Receptor IGF Tipo 1 , Análisis de SupervivenciaRESUMEN
OBJECTIVE: To study the safety and effectiveness of bilateral sequential whole lung lavage in the same treatment session for pulmonary alveolar proteinosis. METHODS: Twelve times bilateral sequential whole lung lavage in the same treatment session were performed under general anaesthesia using a double lumen endotracheal tube for 10 cases of pulmonary alveolar proteinosis. The volume of lavage, return volume and the return rate were calculated. The efficacy was evaluated according to the improvement of symptoms, pulmonary function and arterial blood gas analysis data. RESULTS: Twelve times bilateral sequential whole lung lavage in the same treatment session were performed successfully for the 10 cases of pulmonary alveolar proteinosis. The total volume of lavage was (26,417+/-7,064) ml, the return volume was (25,962+/-7,023) ml, the time of lavage was (192+/-26) minutes. The symptoms and chest radiograph were improved immediately after the procedure for all patients. The alveolar to arterial oxygen tension difference was decreased significantly. Arterial oxygen tensions were increased but no significant difference was reached. There was no significant immediate improvement for the pulmonary function. No complications were noted but pulmonary edema in one patient. CONCLUSION: Bilateral sequential whole lung lavage in the same treatment session is a safe and effective procedure for treatment of pulmonary alveolar proteinosis.