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Osimertinib resistance is regarded as a major obstacle limiting survival beneï¬ts for patients undergoing treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). However, the underlying mechanisms of acquired resistance remain unclear. In this study, we report that estrogen receptor ß (ERß) is highly expressed in osimertinib-resistant NSCLC and plays a pivotal role in promoting osimertinib resistance. We further identified ubiquitin-specific protease 7 (USP7) as a critical binding partner that deubiquitinates and upregulates ERß in NSCLC. ERß promotes osimertinib resistance by mitigating reactive oxygen species (ROS) accumulation. We found that ERß mechanistically suppresses peroxiredoxin 3 (PRDX3) SUMOylation and thus confers osimertinib resistance onto NSCLC. Furthermore, we provide evidence showing that depletion of ERß induces ROS accumulation and reverses osimertinib resistance in NSCLC both in vitro and in vivo. Thus, our results demonstrate that USP7-mediated ERß stabilization suppresses PRDX3 SUMOylation to mitigate ROS accumulation and promote osimertinib resistance, suggesting that targeting ERß may be an effective therapeutic strategy to overcome osimertinib resistance in NSCLC.
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Acrilamidas , Carcinoma de Pulmón de Células no Pequeñas , Indoles , Neoplasias Pulmonares , Pirimidinas , Humanos , Compuestos de Anilina/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos , Receptor beta de Estrógeno , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Peroxiredoxina III/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Especies Reactivas de Oxígeno , Sumoilación , Peptidasa Específica de Ubiquitina 7RESUMEN
Esophageal cancer (ESCA) is a lethal malignancy and is associated with the alterations of various genes and epigenetic modifications. The protein dpy-30 homolog (DPY30) is a core member of histone H3K4 methylation catalase and its dysfunction is associated with the occurrence and development of cancer. Therefore, the present study investigated the role of DPY30 in ESCA and evaluated the association between the expression of DPY30, the clinicopathological characteristics of ESCA and the tumor immune microenvironment. It conducted a comprehensive analysis of DPY30 in patients with ESCA using The Cancer Genome Atlas (TCGA) database and clinical tissue microarray specimens of ESCA. Immunohistochemistry was performed to assess the expression levels of DPY30 in tissues. Receiver operating curve analysis, Kaplan-Meier survival analysis and Cox regression analysis were performed to identify the diagnostic and prognostic value of DPY30. Gene Set Enrichment Analysis, protein-protein interaction network and Estimation of Stromal and Immune cells in Malignant Tumor tissues using the Expression data were used to screen DPY30-associated genes and evaluate the immune score of the TCGA samples. The results demonstrated that the expression of mRNA and protein levels of DPY30 were significantly upregulated in tumor tissues compared with normal tissue samples. The expression of DPY30 was closely associated with the poor prognosis of patients with ESCA. The present study also found that DPY30 expression and the pathological characteristics of ESCA were significantly correlated. Additionally, the expression of DPY30 demonstrated a significant positive correlation with various immune cells infiltration. The results suggested that DPY30 might influence tumor immune infiltration. In conclusion, the findings suggested that DPY30 might be a potential prognostic biomarker and an immunotherapeutic target in ESCA.
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Although the advent of osimertinib has brought revolutionary changes to the treatment landscape of non-small cell lung cancer (NSCLC) patients, acquired resistance remains a major obstacle limiting long-term survival beneï¬ts for the treatment of cancer. The purpose of this study was to examine the mechanisms involved in the ability of bazedoxifene to synergistically enhance osimertinib sensitivity, which will aid in delaying and overcoming osimertinib resistance to improve patient outcomes. Here, we found that osimertinib increased the production of reactive oxygen species (ROS), promoted mitochondrial fission, diminished mitochondrial membrane potential, and activated cell apoptosis. Moreover, the p-STAT3/suppressor of cytokine signaling 3 (SOCS3) and KEAP1/NRF2 signaling pathways were activated to scavenge ROS and promote osimertinib resistance. Mechanistically, SOCS3 can directly bind to KEAP1 to prevent the degradation of NRF2, resulting in the activation of an NRF2-dependent transcriptional program. Furthermore, the osimertinib-induced mitochondrial dysfunction and apoptosis were enhanced by bazedoxifene, thereby delaying and overcoming osimertinib resistance by inhibiting these pathways in vitro and in vivo. These findings identified a new critical link in the p-STAT3/SOCS3 pathway, KEAP1/NRF2 pathway, mitochondrial dysfunction, and osimertinib resistance. The present study demonstrated that bazedoxifene can be used for delaying or overcoming osimertinib resistance in NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Compuestos de Anilina/farmacología , Mitocondrias/metabolismo , Resistencia a Antineoplásicos , Línea Celular Tumoral , Proteína 3 Supresora de la Señalización de Citocinas/metabolismoRESUMEN
Background: Identification of the intersegmental plane (ISP) is the critical step in lung segmentectomy because of the complicated anatomic variations. Bronchial methylene blue staining was developed by our team in 2015 and is now commonly used at our center, it could rapidly and accurately identify the ISP. In this study, we aimed to compare bronchial methylene blue staining with the modified inflation-deflation method in terms of their perioperative characteristics and to present our experience of the methylene blue method. Methods: From June 2020 to September 2021, the data of 112 patients with pulmonary ground-glass nodules who underwent segmentectomy by video-assisted thoracoscopic surgery were retrospectively reviewed. Sixty-two patients underwent bronchial methylene blue staining, and 50 patients underwent the modified inflation-deflation method. Results: Both methods could accurately identify the ISP. The time taken to clearly display the ISP (82.94±28.08 vs. 868.20±145.89 seconds; P<0.001) and the surgical duration (131.69±32.05 vs. 146.08±28.11 minutes; P=0.014) were significantly shorter in the bronchial methylene blue staining group than in the modified inflation-deflation group. There were no significant differences between the two groups in the bleeding volume, drainage time, and length of postoperative hospital stay, as well as in most other perioperative characteristics. Conclusions: Compared with the modified inflation-deflation method, the bronchial methylene blue staining method can quickly display the ISP and shorten the surgical duration. This method is safe and feasible, can be widely applied during thoracoscopic anatomic segmentectomy.
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Background: A sleeve lobectomy is a routine operation in thoracic surgery. However, sleeve lobectomy is not only a complex operation, but also has the risk of anastomotic leakage and stenosis. We used bronchial flap to reconstruct the airway instead of sleeve lobectomy. The above disadvantages can be avoided because the bronchial flap reconstruction airway has no anastomosis. This technique has not previously been reported. This paper discusses the feasibility and safety of reconstructing the bronchus with the pedicle autogenous bronchus flap in lung cancer surgery. Methods: During the operation, when the tumor tissue had invaded ≤1/3 of the circumference of the lobar bronchus, the bronchus wall was removed at least 5 mm away from the tumor, but the contralateral healthy bronchus wall was preserved. The healthy bronchial wall was made into a "tongue-shaped" pedicled autogenous bronchial flap, approximately the size of the bronchial defect, and the flap was turned up or down to repair the root defect of the bronchus. The patients were examined every 3 months after surgery by chest computed tomography (CT) to observe the re-expansion of lung and reconstruction of the bronchus, and analyze the incidence of bronchus stenosis and local recurrence. Results: The lobar bronchus was successfully reconstructed with the pedicled autologous bronchial flap in 45 patients; 36 males and 9 females with an average age of 56.5 years. The diameters of the tumors ranged from 3-12 cm. The pathological examination results showed that the margin of bronchus was negative. There was no perioperative death or bronchopleural fistula. The bronchoscopy showed that the reconstructed bronchus healed well, and no atelectasis or bronchostenosis was found in the follow-up period. Conclusions: This is the first report on the application of the pedicled autogenous bronchial flap being used to reconstruct the airway instead of a sleeve lobectomy in lung cancer surgery. In the radical resection of lung cancer, the operation can simplify the operation process, and reduce the risk of anastomotic leakage or stenosis. The operation is safe and feasible, and should be more widely used.
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BACKGROUND: Ovarian cancer (OC) progression is an unmet medical challenge. Since omental metastases were palpated harder than their primary counterparts during cytoreductive surgery of patients with epithelial ovarian cancer (EOC), we were inspired to investigate OC progression from the perspective of biomechanics. METHODS: Atomic Force Microscope (AFM) was used to measure the Young's modulus of tissues. The collagen-coated polyacrylamide hydrogel (PA gel) system was prepared to mimic the soft and stiff substrates in vitro. The effect of TAGLN was evaluated both in vitro and in vivo using transwell assay, immunofluorescence, western blot analysis and immunohistochemistry. RESULTS: We quantitatively confirmed that omental metastases were stiffer and more abundant in desmoplasia compared with paired primary tumors, and further demonstrated that matrix stiffness could notably regulate OC progression. Remarkably, TAGLN, encoding an actin cross-linking/gelling protein, was identified as a potent mechanosensitive gene that could form a regulation loop with Src activation reacting to environmental stiffness, thus mediating stiffness-regulated OC progression through regulating RhoA/ROCK pathway. CONCLUSIONS: These data demonstrate that targeting extra-cellular matrix (ECM) stiffness could probably hamper OC progression, and of note, targeting TAGLN might provide promising clinical therapeutic value for OC therapy.
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Proteínas de Microfilamentos/metabolismo , Proteínas Musculares/metabolismo , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Transducción de Señal , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Matriz Extracelular/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Ratones , Proteínas de Microfilamentos/genética , Modelos Biológicos , Proteínas Musculares/genética , Metástasis de la Neoplasia , Neoplasias Ováricas/etiología , Neoplasias Ováricas/mortalidad , Pronóstico , Microambiente Tumoral , Familia-src Quinasas/genética , Familia-src Quinasas/metabolismoRESUMEN
BACKGROUND: Advanced non-small cell lung cancer (NSCLC) accounts for a high proportion of lung cancer cases. Targeted therapy improve the survival in these patients, but acquired drug resistance will inevitably occur. If tumor downstaging is achieved after targeted therapy, could surgical resection before drug resistance improve clinical benefits for patients with advanced NSCLC? Here, we conducted a clinical trial showing that for patients with advanced driver gene mutant NSCLC who did not progress after targeted therapy, salvage surgery (SS) could improve progression-free survival (PFS). Herein, we retrospectively reviewed our former clinical trial and thoracic cancer database in our medical institutions. METHODS: We identified patients with advanced driver gene mutant NSCLC treated with targeted therapy plus SS or targeted therapy alone in our former clinical trial and our thoracic cancer database from July 2016 to July 2019. PFS was compared between the targeted therapy plus SS group and the targeted therapy only group using the log-rank test. RESULTS: We identified 73 patients with driver gene mutant NSCLC who were treated with targeted therapy and 18 treated with targeted therapy plus SS.Among the 18 patients treated with targeted therapy plus SS, there were no obvious perioperative complications and deaths. Targeted therapy followed by SS resulted in a significantly longer PFS compared with targeted therapy alone (23.4 months VS 12.9 months, p = 0.0004). CONCLUSIONS: Salvage surgery after tumor downstaging is a promising therapeutic strategy for some patients with advanced (stage IIIB-IV) NSCLC and may offer a new therapeutic option for multidisciplinary comprehensive treatment of lung cancer.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Quimioterapia/métodos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Terapia Recuperativa/métodos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Supervivencia sin Progresión , Estudios RetrospectivosRESUMEN
Situs inversus totalis (SIT) is a rare congenital condition, which is characterized by abnormal placement of the thoracic and abdominal organs. The incidence of this condition is estimated to be from 1/8000 to 1/25,000. There have been minimal reports on SIT patients with esophageal cancer. In this report, we discuss a patient with SIT complicated by middle and lower esophageal cancer who underwent laparoscopic and thoracoscopic esophagectomy with intrathoracic anastomosis, and provide useful information with regards to treatment of this rare condition.
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Estrogen promotes nonsmall cell lung cancer (NSCLC) metastasis via estrogen receptor ß (ERß)mediated invasivenessassociated matrix metalloprotease 2 (MMP2) upregulation. However, how ERß increases the aggressiveness of NSCLC cells remains unclear. Recently, MMP2 was found to be upregulated by Tolllike receptor 4 (TLR4) signaling activation and to promote NSCLC metastasis. Our present study aimed to examine the role of ERß in the activation of TLR4 signaling and in tumor progression and metastasis, and to explore the synergistic metastatic effect of a combination of ERß and TLR4 activation on human NSCLC cells in vitro and in vivo. Here, we found that ERß is associated with TLR4 in metastatic lymph nodes. Western blot analysis and immunofluorescence revealed that ERß overexpression upregulated TLR4 protein expression and activated downstream targets, myeloid differentiation primary response 88 (myd88)/nuclear factor (NF)κB/MMP2, enhancing NSCLC cell migration and invasion in vitro. A novel ERßTLR4 interaction in cell plasma was identified by coimmunoprecipitation and confocal immunofluorescence. The combination of estradiol and specific TLR4 agonist lipopolysaccharide (LPS) synergistically promoted metastatic behaviors in NSCLC cells. In cell culture and murine lung metastasis models, exposure to estradiol and LPS induced increased matrix degradation and accelerated invadopodia and metastasis formation in NSCLC cells compared with that in cells treated with estradiol or LPS alone. Together, we showed that estrogen promoted NSCLC metastasis via ERß by upregulating TLR4 and activating its downstream signaling axis myd88/NFκB/MMP2. The combined targeting of ERß and TLR4 may be a novel therapeutic strategy against advanced metastatic lung cancer.
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Ovarian cancer (OC) is highly metastatic due to frequent peritoneal dissemination, and its treatment poses a major challenge in clinical practice. Yesassociated protein (YAP) is known to be associated with the development of multiple tumors. However, whether targeting YAP can restrain OC progression and the underlying mechanisms have yet to be fully elucidated. In the present study, YAP was found to be highly expressed in OC, and its expression was correlated with the prognosis of OC patients. Moreover, silencing of YAP markedly inhibited the malignant behavior of OC cells, possibly through regulation of the PI3K/Akt/mTOR pathway. Notably, peptide 17, a YAP inhibitor, exerted a significant attenuating effect on OC progression by diminishing the activation of the PI3K/Akt/mTOR pathway in vitro as well as in vivo. Taken together, these findings demonstrated that targeting YAP attenuated OC progression and suggested the potential application of peptide 17 in OC therapy, thus providing new insights into improving the treatment of OC.
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Proteínas Adaptadoras Transductoras de Señales/genética , Carcinogénesis/genética , Proliferación Celular/genética , Neoplasias Ováricas/genética , Factores de Transcripción/genética , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Xenoinjertos , Humanos , Estimación de Kaplan-Meier , Ratones , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Ovario/patología , Péptidos/farmacología , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/genética , Factores de Transcripción/antagonistas & inhibidores , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND: Non-small cell lung cancer (NSCLC) patients with sensitive epidermal growth factor receptor (EGFR) mutations are successfully treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs); however, resistance to treatment inevitably occurs. Given lipid metabolic reprogramming is widely known as a hallmark of cancer and intimately linked with EGFR-stimulated cancer growth. Activation of EGFR signal pathway increased monounsaturated fatty acids (MUFA) and lipid metabolism key enzyme Stearoyl-CoA Desaturase 1 (SCD1) expression. However the correlation between EGFR-TKI resistance and lipid metabolism remains to be determined. METHODS: In this study the differences in lipid synthesis between paired TKI-sensitive and TKI-resistant patient tissues and NSCLC cell lines were explored. Oleic acid (OA, a kind of MUFA, the SCD1 enzymatic product) was used to simulate a high lipid metabolic environment and detected the affection on the cytotoxic effect of TKIs (Gefitinib and osimertinib) in cell lines with EGFR-activating mutations. (20S)-Protopanaxatriol (g-PPT), an aglycone of ginsenosides, has been reported to be an effective lipid metabolism inhibitor, was used to inhibit lipid metabolism. Additionally, synergism in cytotoxic effects and signal pathway activation were evaluated using CCK-8 assays, Western blotting, flow cytometry, Edu assays, plate clone formation assays and immunofluorescence. Furthermore, two xenograft mouse models were used to verify the in vitro results. RESULTS: Gefitinib-resistant cells have higher lipid droplet content and SCD1 expression than Gefitinib-sensitive cells in both NSCLC cell lines and patient tissues. Additionally oleic acid (OA, a kind of MUFA, the SCD1 enzymatic product) abrogates the cytotoxic effect of both Gefitinib and osimertinib in cell lines with EGFR-activating mutations. As a reported effective lipid metabolism inhibitor, g-PPT significantly inhibited the expression of SCD1 in lung adenocarcinoma cells, and then down-regulated the content of intracellular lipid droplets. Combined treatment with Gefitinib and g-PPT reverses the resistance to Gefitinib and inhibits the activation of p-EGFR and the downstream signaling pathways. CONCLUSIONS: Our findings uncover a link between lipid metabolic reprogramming and EGFR-TKI resistance, confirmed that combination target both EGFR and abnormal lipid metabolism maybe a promising therapy for EGFR-TKI resistance and highlighting the possibility of monitoring lipid accumulation in tumors for predicting drug resistance.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Receptores ErbB/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Panax/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Sapogeninas/uso terapéutico , Estearoil-CoA Desaturasa/efectos de los fármacos , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular , Modelos Animales de Enfermedad , Receptores ErbB/farmacología , Femenino , Humanos , Lípidos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Sapogeninas/farmacologíaRESUMEN
AIM: To investigate the influence of tissue mechanics on the cellular uptake efficiency of nanoparticles (NPs) in cancer. MATERIALS & METHODS: Collagen-coated polyacrylamide gels were prepared as model substrates. Coumarin 6-loaded poly(lactic-co-glycolic) acid micelles (C6-NPs) were prepared to investigate the cellular uptake of NPs. RESULTS: We demonstrated that substrate stiffness modulated the cellular uptake of NPs of cancer. Mechanistically, mechanical cues exerted influence on the clathrin-mediated endocytosis and caveolae-mediated endocytosis pathways, which mediated stiffness-regulated cellular uptake of NPs. CONCLUSION: Our findings shed light on the regulatory role of the mechanical cues on the cellular uptake of NPs and will facilitate the selection of clinical patients who might benefit from a given nanotherapy.
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Caveolas/metabolismo , Clatrina/metabolismo , Células A549 , Resinas Acrílicas/química , Animales , Western Blotting , Línea Celular Tumoral , Endocitosis/fisiología , Femenino , Células HeLa , Humanos , Ratones , Nanopartículas/químicaRESUMEN
BACKGROUND: The primary focus of video-assisted thoracoscopic surgery (VATS) sleeve lobectomy is bronchial anastomosis. Both interrupted suture and continuous suture cannot overcome entanglement of the suture threads. The present study used the "continuous suture dividing and equal suture tightening" method in VATS sleeve lobectomy for bronchial anastomosis and discussed the feasibility of this approach. METHODS: A total of 17 patients underwent VATS sleeve lobectomy with bronchial anastomosis using the "continuous suture dividing and equal suture tightening" method. Four incisions were utilized in the operation as follows: (I) the pulmonary arteries and veins were cut-off using an endoscopic linear stapler. Systematic hilar and mediastinal lymph node dissection was performed; (II) the surgeon used a surgical knife for incision into the thoracic cavity and to cut the lung lobe and main bronchi. Intraoperative pathological analysis revealed negative bronchial margins; (III) the "continuous suture dividing and equal suture tightening" method was performed for anastomosis; (IV) the integrity of the anastomosis was assessed by intraoperative bronchoscopy. Computed tomography (CT), three-dimensional (3D) reconstruction and bronchoscopy assessed the anastomosis 1-week postoperatively. A follow-up was conducted using a 3-month bronchoscopy, and CT scans monitored the recurrence and stenosis of the anastomosis. RESULTS: The method was successfully completed for VATS sleeve lobectomy with bronchial anastomosis in 17 cases. Although various histological profiles were observed, the 1-week postoperative CT and bronchoscopy showed adequate healing of the anastomotic stoma as well as the absence of postoperative mortality and bronchial pleural fistula. All patients were alive and followed up for 31-49 months postoperatively; local recurrence and anastomotic stenosis were not detected. CONCLUSIONS: The continuous suture dividing and equal suture tightening method is convenient, feasible, and safe for bronchial anastomosis in VATS sleeve lobectomy. It can effectively avoid the entanglement of the suture threads, thereby enabling the widespread adoption of VATS sleeve lobectomy.
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BACKGROUND: In non-small cell lung cancer (NSCLC), estrogen (E2) significantly promotes NSCLC cell growth via estrogen receptor beta (ERß). Discovery and elucidation of the mechanism underlying estrogen-promoted NSCLC progression is critical for effective preventive interventions. IL6 has been demonstrated to be involved in the development, progression and metastasis in several cancers and IL6 overexpression is associated with poor prognosis in NSCLC. However, the exact role played by IL6 in estrogen-promoted NSCLC progress remain unknown. Here, we evaluated the expression and biological effects of IL6 in NSCLC cells when treated with E2 and explored the underlying mechanism of IL6 in E2-promoted NSCLC progression. METHODS: Expression of ERß/IL6 in 289 lung cancer samples was assessed by immunohistochemistry. Matched samples of metastatic lymph node and primary tumor tissues were used to quantify the expression of ERß/IL6 by western blot. Expression levels of IL6 in NSCLC cells were quantified by western blotting, ELISA, and immunofluorescence staining. The effects of IL6 stimulated by E2 on cell malignancy were evaluated using CCK8, colony formation, wound healing and transwell. Furthermore, overexpression and knockdown ERß constructs were constructed to measure the expression of IL6. The effects of IL6 stimulated by E2 on tumor growth were evaluated using a urethane-induced adenocarcinoma model. In addition, a xenograft mouse model was used to observe differences in ERß subtype tumor growth with respect to IL6 expression. RESULTS: IL6/ERß expression were significantly increased in lung cancer. Higher IL6/ERß expression was associated with decreased differentiation or increased metastasis. IL6 was an independent prognostic factor for overall survival (OS), higher IL6 expression was associated with decreased OS. Furthermore, ERß regulates IL6 expression via MAPK/ERK and PI3K/AKT pathways when stimulated by E2 and promotes cell malignancy in vitro and induced tumor growth in vivo. Finally we confirm that ERß isolation 1/5 is essential for E2 promotion of IL6 expression, while ERß2 not. CONCLUSIONS: Our findings demonstrate that E2 stimulates IL6 expression to promote lung adenocarcinoma progression through the ERß pathway. We also clarify the difference in each ERß subtype for E2 promoting IL6 expression, suggesting that ERß/IL6 might be potential targets for prognostic assessment and therapeutic intervention in lung cancer.
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Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Estradiol/farmacología , Receptor beta de Estrógeno/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Interleucina-6/genética , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/patología , Adulto , Anciano , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Interleucina-6/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Fosfatidilinositol 3-Quinasas/metabolismo , Pronóstico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFRTKIs) have revolutionized the treatment of patients with advanced EGFR-mutant NSCLC. However, drug resistance eventually develops in the majority of patients despite an excellent initial response. The present study aimed to investigate the mechanism of acquired resistance to EGFR-TKIs and to explore strategies to overcome the resistance to EGFR-TKIs from a gender perspective. PC9 and Hcc827 cell lines, sensitized to EGFR-TKI, and secondary TKI-resistant PC9-ER (erlotinib resistant) and Hcc827-ER cell lines were evaluated for the expression of ERß1. The proliferative ability of both cell lines was analyzed after transfection of siRNA-ERß1 using Cell Counting Kit-8 and colony formation assays. Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and Akt activation were detected. The co-inhibition efficiency of erlotinib and fulvestrant was analyzed in PC9-ER xenografts. The expression of ERß1 was investigated in tumor tissues of EGFR-TKI-treated patients, and its correlation with clinicopathological factors and progression-free survival (PFS) was assessed. The expression of ERß1 was upregulated secondary to EGFR-TKIs in PC9 and Hcc827 cell lines, with ß-estradiol dependence. Both PC9-ER and Hcc827-ER cell lines were re-sensitized to erlotinib after downregulation of the expression of ERß1. ERK1/2 and Akt pathways were activated following the silencing of the expression of ERß1 in PC9-ER and Hcc827 cell lines. The co-treatment of erlotinib and fulvestrant exhibited better growth inhibitory efficiency compared with the treatment of each agent alone in PC9-ER-derived xenografts. Primary NSCLC samples of 53 patients treated with EGFR-TKIs were analyzed. ERß1 was highly expressed, and the strong expression of cytoplasmic ERß1 was related to a shorter PFS. In conclusion, ERß1 was activated in EGFR-TKI secondary resistance. The downregulation of ERß1 sensitized the cells to EGFR-TKIs. ERß1 may be a key molecule in EGFR-TKI therapy. In addition, anti-ERß1 treatment may reverse TKI resistance.
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Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos , Receptores ErbB/antagonistas & inhibidores , Receptor beta de Estrógeno/metabolismo , Neoplasias Pulmonares/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Proliferación Celular , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Ratones , Ratones Endogámicos NOD , Ratones SCID , Transducción de Señal , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
@#Objective To develop a novel methylene blue staining technique to localize small esophageal leiomyomas ( small esophageal leiomyomas ( and 4 females with an average age of 51 years. We preoperatively injected 0.5–1.0 ml methylene blue in the submucosa adjacent to the tumors under the guidance of gastroscope. Then, we transferred the patients to the operating room. Results Staining was successful in 9 patients. The unstained tumor was exposed after the blue-stained mediastinal pleura and overlying muscle were incised longitudinally during ideo-assisted thoracoscopic surgery via one utility port. No abnormalities were detected in the esophageal mucosa. No major complications, such as esophageal leakage or esophageal diverticulum occurred. Conclusion Endoscopic methylene blue staining is safe and feasible for localizing small esophageal leiomyomas during video-assisted thoracoscopic surgery via one utility port. This method will enable enucleation precise and easy.
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In non-small cell lung cancer (NSCLC), estrogen significantly promotes NSCLC cell growth via estrogen receptor beta (ERß). However, the effects by which ERß contributes to metastasis in NSCLC have not been previously reported. This study aims at defining whether the stimulation of ERß promotes NSCLC metastasis in vitro and in vivo. Here, Our results showed that estrogen and ERß agonist enhanced aggressiveness of two lung cancer cell lines (A549 and H1793) and promoted murine lung metastasis formation. ER-inhibitor Fulvestrant treatment or ERß-knockdown significantly suppressed the migration, invasion and nodule formation of NSCLC cells. The expression level of ERß protein was analyzed in matched samples of metastatic lymph node and primary tumor tissues from the same individuals, and we found significantly higher levels of ERß were expressed in lymph node compared to primary tumor tissues. Moreover, Studies on both surgical biopsies and on lung cancer cells revealed that the expression level of ERß and matrix-metalloproteinase-2 (MMP-2) were associated. Furthermore, inhibition of ERß resulted in down-regulation of MMP-2 expression. Taken together, our results demonstrate that activation of ERß in lung cancer cells promotes tumor metastasis through increasing expression of invasiveness-associated MMP-2. These results also highlight the therapeutic potential of inhibition of ERßin the treatment of advanced NSCLC.