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The role of TELO2-interacting protein 1 (TTI1) in the progression of several types of cancer has been reported recently. The aim of this study was to estimate the expression and potential value of TTI1 in non-small-cell lung cancer (NSCLC) patients. The expression of TTI1 and its prognostic value in NSCLC from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database were analyzed. To verify the bioinformatics findings, a tissue microarray containing 160 NSCLC and paired peritumoral tissues from NSCLC patients was analyzed by immunohistochemistry for TTI1. Subsequently, the roles of TTI1 in NSCLC cells were investigated in vivo by establishing xenograft models in nude mice and in vitro by transwell, CCK-8, wound healing, and colony formation assays. In addition, quantitative real-time polymerase chain reaction and western blot were applied to explore the underlying mechanism by which TTI1 promotes tumor progression. Finally, the relationship between TTI1 and Ki67 expression level in NSCLC was probed, and Kaplan-Meier and Cox analyses were performed to assess the prognostic merit of TTI1 and Ki67 in NSCLC patients. We found that the expression of TTI1 was significantly upregulated in NSCLC tissues compared to paired peritumoral tissues, which coincides with the bioinformatics findings from the TCGA and GEO databases. TTI1 was highly expressed in NSCLC patients with large tumors, advanced tumor stage, and lymphatic metastasis. In addition, the prognostic analysis identified TTI1 as an independent indication for poor prognosis of NSCLC patients. In vitro, upregulation of TTI1 in NSCLC cells could facilitate cell invasion, metastasis, viability, and proliferation. Mechanistically, our study verified that TTI1 could regulate mTOR activity, which has a pivotal role in human cancer. Consistently, the expressions of TTI1 and Ki67 had a positive relationship in NSCLC cells and tissues. Notably, patients with overexpression of TTI1 or Ki67 had a shorter overall survival rate and a higher disease-free survival rate compared to patients with low expression of TTI1 or Ki67, and the combination of TTI1 and Ki67 was an independent parameter predicting the prognosis and recurrence of NSCLC patients. We conclude that TTI1 promotes NSCLC cell proliferation, metastasis, and invasion by regulating mTOR activity, and the combination of TTI1 and Ki67 is a valuable molecular biomarker for the survival and recurrence of NSCLC patients.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Humanos , Ratones , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Antígeno Ki-67/metabolismo , Neoplasias Pulmonares/patología , Ratones Desnudos , Pronóstico , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: There is an increasing demand for minimally invasive myxoma resection. This study aimed to investigate the safety and feasibility of minimally invasive myxoma resection. METHODS: In this retrospective study, we collected information from 95 patients who underwent myxoma resection between January 2016 and December 2020. Based on the operative approach, the patients were divided into the minimally invasive myxoma resection (Mini-MR) group (N = 30) and the sternotomy myxoma resection (SMR) group (N = 65). Intraoperative and postoperative data were compared between the two groups. RESULTS: The postoperative ventilator-assisted time, CSICU time, and postoperative hospital stay were shorter in the Mini-MR group than in the SMR (13.05 ± 4.98 vs. 17.07 ± 9.52 h; 1.73 ± 0.29 vs. 2.27 ± 1.53 d; 6.20 ± 1.50 vs. 9.48 ± 3.37 d, respectively), and the difference was statistically significant (P < 0.05). Mini-MR had lower postoperative drainage and blood transfusion rate in the first 24 h compared with SMR (38.93 ± 69.62 vs. 178.25 ± 153.06 ml; 26.6% vs. 63.1%), and the differences were statistically significant (P < 0.05). CONCLUSION: Mini-MR has the advantages of less CSICU stay time, less ventilator time, less postoperative drainage in the first 24h, less blood transfusion, fewer postoperative hospital stays, and faster recovery. Mini-MR is a safe and feasible surgical procedure for myxoma resection.
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Mixoma , Humanos , Mixoma/diagnóstico , Mixoma/cirugía , Estudios Retrospectivos , Esternotomía/métodos , Toracotomía/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: Previous studies have confirmed the oncogenic role of HMGB2 in various cancers, but the biological functions of HMGB2-derived circRNAs remain unknown. Thus, we intended to investigate the potential role of HMGB2-derived circRNAs in lung adenocarcinomas (LUAD) and squamous cell carcinomas (LUSC). METHODS: The expression profiles of HMGB2-derived circRNAs in LUAD and LUSC tissues and matched normal tissues were assessed using qRT-PCR. The role of circHMGB2 in the progression of the LUAD and LUSC was determined in vitro by Transwell, CCK-8, flow cytometry and immunohistochemistry assays, as well as in vivo in an immunocompetent mouse model and a humanized mouse model. In addition, in vivo circRNA precipitation assays, luciferase reporter assays and RNA pulldown assays were performed to explore the underlying mechanism by which circHMGB2 promotes anti-PD-1 resistance in the LUAD and LUSC. RESULTS: The expression of circHMGB2 (hsa_circ_0071452) was significantly upregulated in NSCLC tissues, and survival analysis identified circHMGB2 as an independent indicator of poor prognosis in the LUAD and LUSC patients. We found that circHMGB2 exerted a mild effect on the proliferation of the LUAD and LUSC cells, but circHMGB2 substantially reshaped the tumor microenvironment by contributing to the exhaustion of antitumor immunity in an immunocompetent mouse model and a humanized mouse model. Mechanistically, circHMGB2 relieves the inhibition of downstream CARM1 by sponging miR-181a-5p, thus inactivating the type 1 interferon response in the LUAD and LUSC. Moreover, we found that the upregulation of circHMGB2 expression decreased the efficacy of anti-PD-1 therapy, and we revealed that the combination of the CARM1 inhibitor EZM2302 and an anti-PD-1 antibody exerted promising synergistic effects in a preclinical model. CONCLUSION: circHMGB2 overexpression promotes the LUAD and LUSC progression mainly by reshaping the tumor microenvironment and regulating anti-PD-1 resistance in the LUAD and LUSC patients. This study provides a new strategy for the LUAD and LUSC treatment.
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Adenocarcinoma del Pulmón , Carcinoma de Células Escamosas , Neoplasias Pulmonares , MicroARNs , Proteína-Arginina N-Metiltransferasas , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Animales , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Proteína HMGB2/genética , Humanos , Terapia de Inmunosupresión , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Ratones , MicroARNs/genética , Proteína-Arginina N-Metiltransferasas/genética , ARN Circular/genética , Microambiente TumoralRESUMEN
BACKGROUND: Lung cancer is one of the most lethal malignant tumors that endangers human health. Lung adenocarcinoma (LUAD) has increased dramatically in recent decades, accounting for nearly 40% of all lung cancer cases. Increasing evidence points to the importance of the competitive endogenous RNA (ceRNA) intrinsic mechanism in various human cancers. However, behavioral characteristics of the ceRNA network in lung adenocarcinoma need further study. METHODS: Groups based on SLC2A1 expression were used in this study to identify associated ceRNA networks and potential prognostic markers in lung adenocarcinoma. The Cancer Genome Atlas (TCGA) database was used to obtain the patients' lncRNA, miRNA, and mRNA expression profiles, as well as clinical data. Informatics techniques were used to investigate the effect of hub genes on prognosis. The Cox regression analyses were performed to evaluate the prognostic effect of hub genes. The methylation, GSEA, and immune infiltration analyses were utilized to explore the potential mechanisms of the hub gene. The CCK-8, transwell, and colony formation assays were performed to detect the proliferation and invasion of lung cancer cells. RESULTS: We eventually identified the ITGB1-DT/ARNTL2 axis as an independent fact may promote lung adenocarcinoma progression. Furthermore, methylation analysis revealed that hypo-methylation may cause the dysregulated ITGB1-DT/ARNTL2 axis, and immune infiltration analysis revealed that the ITGB1-DT/ARNTL2 axis may affect the immune microenvironment and the progression of lung adenocarcinoma. The CCK-8, transwell, and colonu formation assays suggested that ITGB1-DT/ARNTL2 promotes the progression of lung adenocarcinoma. And hsa-miR-30b-3p reversed the ITGB1/ARNTL2-mediated oncogenic processes. CONCLUSION: Our study identified the ITGB1-DT/ARNTL2 axis as a novel prognostic biomarker affects the prognosis of lung adenocarcinoma.
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BACKGROUND: CD8+ T cells play a critical role in the innate antitumour immune response. Recently, CD8+ T cell dysfunction has been verified in various malignant cancers, including non-small cell lung cancer (NSCLC). However, the molecular biological mechanisms of CD8+ T cell dysfunction in human NSCLC are still unclear. METHODS: The expression of circular ubiquitin-specific protease-7 (circUSP7) in NSCLC tissues, exosomes, and cell lines was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Exosomes were isolated from the culture medium of NSCLC cells and the plasma of NSCLC patients using an ultracentrifugation method and the ExoQuick Exosome Precipitation Solution kit. The exosomes were then characterized by transmission electronic microscopy (TEM), NanoSight and western blotting. The role of circUSP7 in CD8+ T cell dysfunction was assessed by enzyme-linked immunosorbent assay (ELISA). In vivo circular RNA (circRNA) precipitation (circRIP), RNA immunoprecipitation (RIP), and luciferase reporter assays were performed to explore the molecular mechanisms of circUSP7 in CD8+ T cells. In a retrospective study, the clinical characteristics and prognostic significance of circUSP7 in NSCLC tissues were determined. RESULTS: The expression levels of circUSP7 were higher in human NSCLC tissues than in matched adjacent nontumour tissues. Increased levels of circUSP7 indicate poor clinical prognosis and CD8+ T cell dysfunction in patients with NSCLC. The circUSP7 found in NSCLC patient plasma is predominantly secreted by NSCLC cells in an exosomal manner, and circUSP7 inhibits IFN-γ, TNF-α, Granzyme-B and Perforin secretion by CD8+ T cells. Furthermore, circUSP7 inhibits CD8+ T cell function by upregulating the expression of Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) via sponging miR-934. Finally, we show that circUSP7 may promote resistance to anti-PD1 immunotherapy in NSCLC patients. CONCLUSIONS: Exosomal circUSP7 is predominantly secreted by NSCLC cells and contributes to immunosuppression by promoting CD8+ T cell dysfunction in NSCLC. CircUSP7 induces resistance to anti-PD1 immunotherapy, providing a potential therapeutic strategy for NSCLC patients.
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Linfocitos T CD8-positivos/metabolismo , Resistencia a Antineoplásicos/genética , MicroARNs/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , ARN Circular/genética , Peptidasa Específica de Ubiquitina 7/genética , Adulto , Anciano , Animales , Linfocitos T CD8-positivos/inmunología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Exosomas/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Recuento de Linfocitos , Masculino , Ratones , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Interferencia de ARNRESUMEN
BACKGROUND: There is an increasing demand for minimally invasive aortic valve replacement. This study aimed to investigate the safety and feasibility of minimally invasive aortic valve replacement through a right parasternal second intercostal transverse incision. METHODS: This was a retrospective study, and we collected information from 111 patients who underwent isolated aortic valve replacement surgery performed by the same surgeon from January 2018 to December 2019. According to the operative approach, the patients were divided into a sternotomy aortic valve replacement (SAVR) group (n = 62) and a minimally invasive aortic valve replacement (Mini-AVR) group (n = 49). We compared the intraoperative and postoperative data between the two groups. RESULT: There was no difference in preoperative data between the Mini-AVR and SAVR. The postoperative ventilator-assisted time, CSICU time and postoperative hospital stay of the Mini-AVR were shorter than those of the SAVR [(15.45 ± 5.75) VS (18.51 ± 6.71) h; (1.77 ± 0.31) VS (2.04 ± 0.63) d; (8.69 ± 2.75) VS (10.77 ± 2.94) d], and the difference was statistically significant (P < 0.05). Mini-AVR had lower postoperative drainage and blood transfusion rates in the first 24 h than SAVR [(109.86 ± 125.98) VS (508.84 ± 311.70) ml; 22.4% VS 46.8%], and the differences were statistically significant (P < 0.05). The incidence of postoperative AF in the Mini-AVR group was also lower than that in the SAVR group (10.2% VS 30.6%), and the differences were statistically significant (P < 0.05). CONCLUSION: Mini-AVR has the advantages of less ventilator time, a reduced need for blood transfusion, less AF and a faster recovery. Mini-AVR is a safe and feasible surgical technique that is worthy of clinical application.
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Válvula Aórtica , Implantación de Prótesis de Válvulas Cardíacas , Válvula Aórtica/cirugía , China , Humanos , Procedimientos Quirúrgicos Mínimamente Invasivos , Estudios Retrospectivos , Esternotomía , Toracotomía , Resultado del TratamientoRESUMEN
In recent years, circular RNAs (circRNAs) have been increasingly reported to play a crucial role in the proliferation, migration, and invasion of non-small-cell lung cancer (NSCLC) cells. However, the circRNA MET (circMET) oncogenic mechanism that drives NSCLC development and progression remains largely unknown. In this study, the present results demonstrated that circMET expression was significantly higher in NSCLC tissues than in peritumoral tissues using quantitative real-time polymerase chain reaction. Notably, NSCLC patients with a large tumor diameter, poor differentiation and lymphatic metastasis had high RNA levels of circMET. Moreover, high circMET expression served as an independent risk factor for short overall survival (OS) and progression-free survival (PFS) in NSCLC patients. Next, we validated that circMET overexpression can enhance NSCLC cell proliferation, metastasis, and immune evasion in vitro. Mechanistically, our study uncovers that circMET acts as a miR-145-5p sponge to upregulate CXCL3 expression. Collectively, circMET regulates the miR-145-5p/CXCL3 axis and serves as a novel, promising diagnostic and prognostic biomarker in patients with NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Quimiocinas CXC/genética , MicroARNs/genética , Proteínas Proto-Oncogénicas c-met/genética , ARN Circular/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/genética , Quimiocinas CXC/metabolismo , Femenino , Humanos , Evasión Inmune/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , MicroARNs/metabolismo , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-met/metabolismo , ARN Circular/metabolismoRESUMEN
BACKGROUND: Circulatory arrest has been identified as an independent risk factor related to postoperative mortality in patients with Stanford type A aortic dissection. This study described a modified technique for distal aortic arch occlusion that markedly shortened the circulatory arrest time. The early results are encouraging. METHODS: From May 2016 to September 2018, 51 patients with Stanford type A aortic dissection underwent the modified procedure for aortic arch replacement. All operations were performed via transitory circulatory arrest by clamping the distal aorta between the left common carotid artery and the left subclavian artery. The in-hospital and follow-up data of the treated patients were investigated. RESULTS: Successful repair of the involved vasculature was achieved in all patients. One (1) patient died due to postoperative aspiration and infection, and three patients required continuous renal replacement therapy due to poor preoperative renal function. The remaining patients were successfully discharged. The median average circulatory arrest time was 5.0 (3.0-6.0) minutes. No cases of tracheotomy, delayed closure, secondary thoracotomy, or other complications occurred. During the follow-up period of 2.4-18.6 months, the implanted grafts and stented elephant trunks were all fully open and not kinked. CONCLUSIONS: A modified distal aortic arch occlusion can considerably shorten the duration of circulatory arrest. Current experience suggests that this approach can serve as a feasible alternative for patients during aortic arch replacement because of its simplicity and satisfactory clinical effects.
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Aorta Torácica/cirugía , Aneurisma de la Aorta Torácica/cirugía , Disección Aórtica/cirugía , Procedimientos Quirúrgicos Vasculares/métodos , Anciano , Disección Aórtica/diagnóstico , Aorta Torácica/diagnóstico por imagen , Aneurisma de la Aorta Torácica/diagnóstico , Angiografía por Tomografía Computarizada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Objectives: An increase in the trimethylation of lysine 4 of histone 3 (H3K4me3) has been reported to be involved in the development of several types of tumors. However, the level and role of H3K4me3 in human esophageal cancer (HEC) remain unknown. Here, we assessed the role and clinical significance of H3K4me3 in HEC. Methods: The level of H3K4me3 was determined in 15 pairs of HEC and paracancerous tissues by Western blotting. A tissue microarray including samples from 100 HEC patients was analyzed by immunohistochemistry to determine the relationship between the level of H3K4me3 and the clinicopathological features of HEC patients. Then, the levels of H3K4me3 in HEC cells were elevated via knockdown of inhibitor of growth family member 4(Ing4) expression. Finally, the prognostic significance of H3K4me3 levels in HEC patients was further analyzed. Results: We found that H3K4me3 levels were frequently elevated in HEC tissues compared with adjacent esophageal tissues, and elevated H3K4me3 was significantly associated with poor tumor differentiation (p =1.39×10-5) and advanced tumor stage (p=8.5×10-5). After Ing4 knockdown in HEC cells, we found that the cell proliferation, metastasis, invasion and colony formation abilities were enhanced compared to those in the control cells. Notably, we found that HEC patients with a high level of H3K4me3 exhibited an unfavorable 5-year survival rate compared to those with a low level of H3K4me3 (p=6.8×10-5). The univariate analysis showed that the tumor differentiation, TNM stage, and H3K4me3 level were predictors of the overall survival rate of HEC patients. In the multivariate analysis, tumor stage (p=0.015) and H3K4me3 level (p=0.034) were revealed to be independent parameters for predicting the prognosis of HEC patients. Conclusions: Thus, high levels of H3K4me3 may be used as a meaningful biomarker for HEC prognosis evaluation.
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BACKGROUNDS: Emerging evidences has demonstrated that dysregulation of long non-coding RNAs (lncRNAs) is critically involved in esophageal squamous cell carcinoma (ESCC) progression. However, the function of lncRNA PSMA3-AS1 in ESCC is unclear. Therefore, we aimed to explore the functions and potential mechanisms of PSMA3-AS1 in ESCC cells progression. RESULTS: Here, we found that PSMA3-AS1 expression was significantly up-regulated in ESCC tissues. Forced PSMA3-AS1 expression was correlated with tumor size, distant metastasis, and poor prognosis in ESCC patients. Functionally, PSMA3-AS1-overexpression promoted ESCC cells proliferation, invasion, and migration in vitro. Mechanistically, PSMA3-AS1 up-regulated EZH2 expression by competitively binding to miR-101. CONCLUSION: PSMA3-AS1 is significantly up-regulated in ESCC tissues, and the PSMA3-AS1/miR-101/EZH2 axis plays a critical role in ESCC progression. Taken together, our results may provide promising targets for ESCC therapy. METHODS: PSMA3-AS1 and miR-101 expression were explored using qRT-PCR in ESCC tissues and cell lines. Immunohistochemistry assays were carried out to analyze EZH2 (enhancer of zeste homolog) protein expression. RIP, dual-luciferase reporter, fluorescence in situ hybridization, and biotin pull-down assays were used to detect the interactions of PSMA3-AS1, miR-101 and EZH2. The biological functions of PSMA3-AS1 in PSMA3-AS1-altered cells were explored using CCK-8, colony formation, wound healing, and transwell assays in vitro.
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Proteína Potenciadora del Homólogo Zeste 2/genética , Neoplasias Esofágicas/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Interferencia de ARN , ARN Largo no Codificante/genética , Regiones no Traducidas 3' , Adulto , Anciano , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias Esofágicas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Complejo de la Endopetidasa Proteasomal/genéticaRESUMEN
The dysregulation of circular RNA (circRNA) expression is involved in the progression of several cancers, including non-small cell lung cancer (NSCLC). However, the role and underlying molecular mechanisms of circRNA FGFR3 (circFGFR3) in NSCLC progression remains unknown. Here, we used quantitative real-time polymerase chain reaction to validate that circFGFR3 expression was higher in NSCLC tissues than in the paratumor tissues. Furthermore, our study indicated that the forced circFGFR3 expression promoted NSCLC cell invasion and proliferation. Mechanistically, we found that circFGFR3 promoted NSCLC cell invasion and proliferation via competitively combining with miR-22-3p to facilitate the galectin-1 (Gal-1), p-AKT, and p-ERK1/2 expressions. Clinically, we revealed that the high circFGFR3 expression correlates with the poor clinical outcomes in patients with NSCLC. Together, these data provide mechanistic insights into the circFGFR3-mediated regulation of both the AKT and ERK1/2 signaling pathways by sponging miR-22-3p and increasing Gal-1 expression.
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Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , MicroARNs/genética , ARN Circular/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Células A549 , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Proliferación Celular/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Galectina 1/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Persona de Mediana Edad , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Invasividad Neoplásica/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , Resultado del TratamientoRESUMEN
Fused in sarcoma/translocated in liposarcoma (FUS/TLS), a ubiquitous and multifunctional DNA and RNA-binding protein, contributes an important function in cancer and neurodegenerative disease; however, its role in lung cancer remains unclear. In the present study, the expression of FUS/TLS in non-small cell lung cancer (NSCLC) and the significance of FUS/TLS for predicting the clinical outcome of patients with NSCLC, was examined. FUS/TLS expression was investigated in NSCLC tissues and their matched adjacent non-tumorous tissues by reverse transcription-quantitative polymerase chain reaction, western blotting, and immunohistochemistry. Tissue microarrays representing 208 patients with NSCLC were used to determine the expression pattern and associations with FUS/TLS using immunohistochemistry. Prognostic significance was assessed by Kaplan-Meier survival estimates and log-rank tests. Data revealed that FUS/TLS expression was elevated in NSCLC tissues compared with corresponding normal tissue mRNA (9.27±0.73 vs. 6.15±0.60) and protein (3.32±0.75 vs. 0.30±0.07) levels. In tissue microarrays, FUS/TLS was highly expressed in 103 (49.5%, 103/208) NSCLC tissues compared with adjacent normal lung tissues (28.4%, 59/208). Overexpression of FUS/TLS was associated with higher tumor node metastasis stage (P=0.016), poorer differentiation (P=0.008), large tumor size (P=0.019) and predicted poor prognosis (P=0.005) in patients with NSCLC. Notably, correlation analysis revealed a significant inverse association between the expression of FUS/TLS and E-cadherin (r2=0.51; P=0.036). Furthermore, patients with NSCLC with high FUS/TLS and impaired E-cadherin expression had a notably poor prognosis (P=4.01×10-4). Thus, the results from the present study indicate that elevated FUS/TLS expression promotes NSCLC progression. FUS/TLS, alone or in combination with E-cadherin, is a novel prognostic predictor for patients with NSCLC.
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Objectives: Ring finger protein 38 (RNF38), as an E3 ubiquitin ligase, plays an essential role in multiple biological processes by controlling cell apoptosis, cell cycle and DNA repair, and resides in chromosome 9 (9p13) which is involvement in cancer pathogenesis including lung cancer. However, its function in tumorigenesis remains unclear. Hence, this study set out to investigate the biological function and clinical implications of RNF38 in non-small cell lung cancer (NSCLC). Materials and Methods: Immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to detect RNF38 protein and mRNA levels in NSCLC and corresponding paratumor tissues. Tissue microarrays (TMA) analysis of 208 NSCLC cases were used to evaluate the relationship between RNF38 expression and clinical implications. Prognostic value was assessed by Kaplan-Meier analysis and log-rank tests. Wound-healing assays, trans-well assays, colony formation assays and CCK8 were used to assess cell migration, invasion and proliferative ability respectively. The analysis of epithelial-to-mesenchymal transition (EMT) phenotype was carried out by immunofluorescence and western blot. Results: Our data revealed that elevated RNF38 expression were more common in NSCLC tissues than paired normal tissues in both mRNA (2.82 ± 0.29 vs. 1.23 ± 0.13) and protein (2.75 ± 0.09 vs. 1.24 ± 0.02) level. High levels of RNF38 expression were significantly associated with lymph node metastases, higher TNM stages (p=0.011), larger tumor size (p=2.09E-04) and predicted poor prognosis. RNF38 expression was inversely correlated with E-cadherin expression (P= 0.025). Moreover, downregulation of RNF38 impaired the proliferation, metastatic and invasive abilities in NSCLC cells. In addition, aberrant RNF38 expression could modulate the key molecules of EMT. Conclusions: Our results indicate that elevated expression of RNF38 is significantly associated with the proliferation and metastatic capacity of NSCLC cells, and RNF38 overexpression can serve as a biomarker of NSCLC poor prognosis.
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Bromodomain containing protein 4 (BRD4), a member of the bromodomain and extra terminal domain (BET) protein family, has been shown to play important roles in tumor progression. However, its role in non-small cell lung cancer (NSCLC) is still largely unknown. Here, we found that BRD4 expression was significantly upregulated in NSCLC tissues and NSCLC cell lines with higher invasion and metastasis potentials. Suppression of BRD4 expression in NSCLC cell lines impaired cell invasion, inhibited cell proliferation, and accelerated cell apoptosis. Clinically, we observed that the BRD4 level was significantly related to histological type, lymph node metastasis, tumor stage and differentiation. More importantly, high level of BRD4 was closely correlated with the poor prognosis of NSCLC patients. Therefore, our study suggests that BRD4 is one of the major contributors to the invasion-prone phenotype of NSCLC, and a potential therapeutic target of NSCLC.
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Apoptosis/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/genética , Neoplasias Pulmonares/patología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Células A549 , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Proteínas de Ciclo Celular , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/genética , Pronóstico , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
PURPOSE: We investigated expression of TM4SF5 and its involvement in human esophageal cancer (HEC). METHODS: We analyzed TM4SF5 expression in normal esophageal epithelial cells (HEEC), in four HEC cell lines, and in 20 HEC clinical tissue samples and matched nontumor samples. The effect of TM4SF5 on HEC cell proliferation and metastasis and invasion was assessed, and the relationship between TM4SF5 and integrin ß1 was determined. Finally, TM4SF5 and integrin ß1 expression were further examined by use of immunohistochemistry (IHC) and tissue microarray analysis, and the prognostic use of TM4SF5 and integrin ß1 in HEC was evaluated. RESULTS: TM4SF5 was more highly expressed in HEC cells and in HEC tissues than in HEEC and matched nontumor tissues. Down-regulation of TM4SF5 in KYSE150 cells reduced cell proliferation and metastasis and invasion whereas metastasis and invasion by KYSE510 increased after TM4SF5 cDNA transfection. In HEC cells, TM4SF5 formed a complex with integrin ß1, and interference with integrin ß1 in KYSE510-TM4SF5 cells markedly inhibited cell invasion on laminin 5. Our findings also showed that TM4SF5 and integrin ß1 overexpression correlated with low differentiation and high stage (p<0.05, respectively). Postoperative 5-year overall survival of patients with TM4SF5low and/or integrin ß1low was higher than for patients with TM4SF5high and/or integrin ß1high. Multivariate analysis demonstrated that TM4SF5 and integrin ß1 co-overexpression was an independent prognostic marker for HEC. CONCLUSION: TM4SF5 is positively associated with HEC invasiveness. The combination of TM4SF5 with integrin ß1 could potentially serve as a novel marker for predicting HEC prognosis.
Asunto(s)
Carcinoma/metabolismo , Neoplasias Esofágicas/metabolismo , Proteínas de la Membrana/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma/mortalidad , Carcinoma/patología , Estudios de Casos y Controles , Línea Celular Tumoral , Proliferación Celular , China/epidemiología , Progresión de la Enfermedad , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Femenino , Humanos , Cadenas beta de Integrinas/metabolismo , Masculino , Proteínas de la Membrana/biosíntesis , Persona de Mediana Edad , Invasividad Neoplásica , Metástasis de la Neoplasia , Fenotipo , PronósticoRESUMEN
BACKGROUND: Individuals with implanted mechanical valve prostheses require lifelong anticoagulation therapy with warfarin. The narrow therapeutic index of warfarin makes it difficult to dose and maintain proper anticoagulation. A number of single nucleotide polymorphisms (SNPs) affecting vitamin K or warfarin metabolism have been shown to affect warfarin dosing. Our aim was to study the effect of the CYP4F2 rs2108622-1347 (C > T) variant on warfarin dosing in Chinese patients. METHODS: We studied 352 patients after heart valve replacement surgery. Warfarin dosing for patients was adjusted to achieve 1.8 ≤ INR ≤ 2.5. We determined the presence of SNPs in CYP4F2 in these patients and investigated their association with warfarin dosing. RESULTS: We found the frequency of the CYP4F2 rs2108622 C allele was 79.5% and T-allele frequency was 20.5%. The warfarin dose requirement for CC individuals was significantly lower than that for CT or TT individuals (P < 0.05). TT-homozygous individuals required a 0.56 mg/day higher dose of warfarin than their CC counterparts. CONCLUSIONS: This study demonstrates that CYP4F2 rs2108622 significantly affects the warfarin dose requirement to achieve adequate anticoagulant activity in Chinese individuals. Genotyping of this SNP may allow clinicians to determine the initiation dose for patients following valve-replacement surgery in China.