RESUMEN
Encouraging insight into novel underlying mechanisms targeting abnormal biological pathways in colorectal cancer (CRC) are currently under investigation, edging closer and closer to clinical use. Of note, basic leucine zipper ATF-like transcription factor 3 (BATF3) has been implicated with the tumorigenicity of CRC. The current study aimed to elucidate the oncogenic BATF3-mediated S1PR1/p-STAT3/miR-155-3p/WDR82 axis in CRC. Initially, clinical samples of CRC tissues as well as CRC cell lines were collected to evaluate the expression patterns of BATF3/S1PR1/p-STAT3/miR-155-3p/WDR82. Dual luciferase assay was employed to assess the binding affinity between miR-155-3p and WDR82. Artificial modulation of BATF3 (down- and overexpression) was conducted to measure the malignant phenotypes of CRC cells, while tumor-bearing mice were examined to determine the in vivo effects. BATF3 facilitated the proliferative, migratory, and invasive potential of CRC cells by upregulating S1PR1. Besides, the stimulatory effect of S1PR1 was realized via restored p-STAT3 expression. Furthermore, p-STAT3 was evidenced to heighten the expression of miR-155-3p and subsequently restrict the expression of its target gene WDR82. The in vivo assays provided data further substantiating the in vitro findings that inactivation of the BATF3/S1PR1/p-STAT3/miR-155-3p/WDR82 axis suppresses CRC tumor growth. Collectively, the results of the present study emphasize the oncogenic function of BATF3 illustrated by the reinforcement the biological processes of proliferation, invasion, as well as the metastatic capacity of CRC cells through activating the S1PR1/p-STAT3/miR-155-3p/WDR82 axis.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Proteínas Represoras/metabolismo , Factor de Transcripción STAT3/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Apoptosis , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Proliferación Celular , Proteínas Cromosómicas no Histona/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Pronóstico , Proteínas Represoras/genética , Factor de Transcripción STAT3/genética , Receptores de Esfingosina-1-Fosfato/genética , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Gastric cancer (GC) is a common cancer and a leading cause of cancer-related deaths worldwide. Recent studies have supported the important role of long non-coding RNAs (lncRNAs) in GC progression. This study identified functional significance of X inactive specific transcript (XIST) in GC. The expression of XIST and EPHA1 in GC tissues and cells was measured. Then, dual luciferase reporter gene assay, RNA immunoprecipitation (RIP) assay and Chromatin Immunoprecipitation (ChIP) assay were performed to explore the interaction among XIST, EPHA1 and HNF4A. The effects of XIST on GG progression were evaluated by determining expression of proliferation- and invasion-related proteins (Ki67, PCNA, MMP-2, and MMP-9). Further, the functional role of XIST in GC with the involvement of NFκB pathway was also analyzed. Subsequently, the tumor growth in nude mice was evaluated. High expression of XIST and EPHA1 was observed in GC. XIST elevated EPHA1 expression by recruiting HNF4A. In addition, silencing of XIST inhibited GC progression in vitro and in vivo. Overexpressed XIST and EPHA1 yielded a reversed effect on cell proliferation and invasion. SN50 treatment (inhibitor of NFκB pathway) counteracted the promotive effect on GC cell proliferation and invasion mediated by XIST. The present study unveils that XIST increases the enrichment of HNF4A in the promoter region of EPHA1, thus promoting the deterioration of GC.
Asunto(s)
Factor Nuclear 4 del Hepatocito/antagonistas & inhibidores , Factor Nuclear 4 del Hepatocito/metabolismo , FN-kappa B/metabolismo , ARN Largo no Codificante/genética , Receptor EphA1/metabolismo , Neoplasias Gástricas/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular/fisiología , Progresión de la Enfermedad , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , ARN Largo no Codificante/antagonistas & inhibidores , ARN Largo no Codificante/biosíntesis , ARN Largo no Codificante/metabolismo , Receptor EphA1/genética , Transducción de Señal , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Transcripción GenéticaRESUMEN
MicroRNAs (miRNAs) delivered by gastric cancer (GC)-secreted extracellular vesicles (GC-EVs) are associated with the immune escape in GC. Microarray analysis based on the GEO: GSE112369 dataset identified the presence of poorly expressed CXXC finger protein 4 (CXXC4) in GC, which was validated in clinical samples of GC patients. Moreover, prediction based on TargetScan analysis demonstrated the putative miR-675-3p binding site in the 3' UTR region of CXXC4. Thereby, our study aims to determine the role of GC-EV-encapsulated miR-675-3p in GC. First, CXXC4 was found to be negatively correlated with programmed cell death 1 ligand 1 (PD-L1). The effects of mitogen-activated protein kinase (MAPK) signaling on GC were evaluated using activator of the MAPK pathway. The overexpression of CXXC4 led to a downregulated MAPK signaling pathway, thus decreasing PD-L1 expression to augment the proliferation and activation of T cells co-cultured with GC HGC-27 cells. GC-EV-encapsulated miR-675-3p negatively regulated the expression of its target gene CXXC4. GC-EV-encapsulated miR-675-3p increased PD-L1 expression to stimulate the immune escape in vitro and EV-encapsulated miR-675-3p accelerated cisplatin resistance in vivo. Collectively, the aforementioned findings present a mechanism in which EV-mediated miR-675-3p upregulates PD-L1 expression, promoting immune escape in GC.
RESUMEN
The present study aims to elucidate the potential therapeutic role of lncRNA XIST in gastric cancer through regulation of microRNA-132 (miR-132) and paxillin (PXN) expression. The study employed 65 gastric cancer tissue specimens and SGC7901 cell lines. Our results demonstrated that expression of lncRNA XIST and PXN was significantly elevated while the expression of miR-132 was significantly reduced in gastric cancer tissues. Dual-luciferase, RNA pull-down and RIP assays demonstrated that lncRNA XIST up-regulated the PXN expression by competitively binding to miR-132. Moreover, silencing of lncRNA XIST and up-regulation of miR-132 could suppress tumor formation ability, cell proliferation and migration, but enhanced apoptosis in gastric cancer. However, the overexpression of PXN achieved the opposite tumor-promotive effect. Meanwhile, rescue experiments suggested that silencing of lncRNA XIST could reverse the tumor-promotive effect exerted by either miR-132 inhibitor or PXN. Taken together, the present study demonstrates lncRNA XIST as a novel oncogenic lncRNA in gastric cancer, highlighting its therapeutic role in this disease.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , MicroARNs/metabolismo , Paxillin/genética , ARN Largo no Codificante/metabolismo , Neoplasias Gástricas/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Regulación hacia Abajo , Femenino , Gastrectomía , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones , Persona de Mediana Edad , ARN Largo no Codificante/genética , Estómago/patología , Estómago/cirugía , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Gastric cancer, is the fourth most common tumour type yet, ranks second in terms of the prevalence of cancer-related deaths worldwide. CXXC finger protein 4 (CXXC4) has been considered as a novel cancer suppressive factor, including gastric cancer. This study attempted to investigate the possible function of CXXC4 in gastric cancer and the underlying mechanism. The binding of the ETS domain-containing protein-1 (ELK1) to the long non-coding RNA MIR100HG promoter region was identified. Then, their expression patterns in gastric cancer tissues and cells (SGC7901) were detected. A CCK-8 assay was used to detect SGC7901 cell proliferation. Subsequently, SGC7901 cells were co-cultured with CD3+ T cells, followed by measurement of CD3+ T cell proliferation, magnitude of IFN-γ+ T cell population and IFN-γ secretion. A nude mouse model was subsequently developed for in vivo validation of the in vitro results. Low CXXC4 expression was found in SGC7901 cells. Nuclear entry of ELK1 can be inhibited by suppression of the extent of ELK1 phosphorylation. Furthermore, ELK1 is able to bind the MIR100HG promoter. Overexpression of CXXC4 resulted in weakened binding of ELK1 to the MIR100HG promoter, leading to a reduced proliferative potential of SGC7901 cells, and an increase in IFN-γ secretion from CD3+ T cells. Moreover, in vivo experiments revealed that CXXC4 inhibited immune escape of gastric cancer cells through the ERK1/2 axis. Inhibition of the CXXC4/ELK1/MIR100HG pathway suppressed the immune escape of gastric cancer cells, highlighting a possible therapeutic target for the treatment of gastric cancer.
Asunto(s)
Quinasas Ciclina-Dependientes/genética , Proteínas de Unión al ADN/genética , Sistema de Señalización de MAP Quinasas/genética , MicroARNs/genética , Transducción de Señal/inmunología , Neoplasias Gástricas/genética , Factores de Transcripción/genética , Proteína Elk-1 con Dominio ets/genética , Adulto , Anciano , Animales , Complejo CD3/genética , Línea Celular , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Humanos , Interferón gamma/genética , Masculino , Ratones , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Persona de Mediana Edad , Regiones Promotoras Genéticas/genética , Transducción de Señal/genética , Estómago/patología , Neoplasias Gástricas/patologíaRESUMEN
PURPOSE: To improve the surface bio-properties of polyetheretherketone (PEEK)/nano magnesium silicate (n-MS) composite (PC). MATERIALS AND METHODS: The surface of PC was firstly treated by particle impact (PCP) and subsequently modified by concentrated sulfuric acid (PCPS). RESULTS: PCPS surface exhibited not only macropores with sizes of about 150 µm (fabricated by particle impact) but also micropores with sizes of about 2 µm (created by sulfonation of PEEK) on the macroporous walls, and sulfonic acid (-SO3H) groups were introduced on PCPS surface. In addition, many n-MS nanoparticles were exposed on the microporous walls, which formed micro-nano structures. Moreover, the surface roughness and hydrophilicity of PCPS were obviously enhanced as compared with PC and PCP. Moreover, the apatite mineralization of PCPS in simulated body fluid (SBF) was obviously improved as compared with PC. Furthermore, compared with PC and PCP, PCPS exhibited antibacterial performances due to the presence of -SO3H groups. In addition, the responses (eg, adhesion and proliferation as well as differentiation) of bone marrow mesenchymal stem cell of rat to PCPS were significantly promoted as compared with PC and PCP. CONCLUSION: PCPS with macro-microporous surface containing -SO3H groups and micro-nano structures exhibited antibacterial activity and induced cell responses, which might possess large potential for bone substitute and repair.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Cetonas/química , Silicatos de Magnesio/química , Nanopartículas/química , Polietilenglicoles/química , Animales , Apatitas/química , Benzofenonas , Líquidos Corporales/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Interacciones Hidrofóbicas e Hidrofílicas , Células Madre Mesenquimatosas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Polímeros , Ratas , Ácidos Sulfónicos/química , Propiedades de SuperficieRESUMEN
Long noncoding RNAs (lncRNAs) play crucial roles in tumor development of osteosarcoma (OS). LncRNA PCAT6 was involved in the progression of multiple human cancers. However, the biological function of PCAT6 in OS remains largely unknown. We found that PCAT6 was elevated in OS tissues relative to that in their adjacent normal tissues. The upregulation of PCAT6 was positively associated with metastasis status and advanced stages and predicted poor overall and progression-free survivals in patients with OS. Functionally, silencing PCAT6 inhibited the proliferation, migration and invasion abilities of OS cells. Mechanistically, PCAT6, acting as a competitive endogenous RNA, upregulated expression of TGFBR1 and TGFBR2 to activate TGF-ß pathway via sponging miR-185-5p. This study uncovers a novel underlying molecular mechanism of PCAT6-miR-185-5p-TGFBR1/2-TGF-ß signaling axis in promoting tumor progression in OS, which indicates that PCAT6 may serve as a promising prognostic factor and therapeutic target again OS.
Asunto(s)
MicroARNs/metabolismo , Osteosarcoma/patología , ARN Largo no Codificante/fisiología , Factor de Crecimiento Transformador beta/metabolismo , Progresión de la Enfermedad , Humanos , Osteosarcoma/metabolismo , Pronóstico , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Receptor Tipo II de Factor de Crecimiento Transformador beta/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: Currently, there remains a lack of consensus regarding factors predictive of complication such as re-nonunion after primary revision in femoral shaft nonunion subsequent to failed intramedullary nailing (IMN). A better understanding of prognostic factors could potentially reduce the risk of re-nonunion happening and allow patients to maximize their recovery in the most expeditious manner. Our study aims to identify risk factors in the development of re-nonunion after primary revision inclusive of exchanging reamed nailing (ERN) and augmentative compression plating (ACP) with IMN in situ for femoral shaft nonunion subsequent to failed IMN. METHODS: A retrospective study was performed for 63 cases (61 patients) of femoral shaft nonunion subsequent to failed IMN, who were made primary revision with either ERN or ACP from June 2007 to June 2015. The following set of variables was selected based on the speculation that they would contribute to the outcome: sex (male or female), age, body mass index(BMI), smoking, alcohol abuse, cause of injury, fracture type, type of IMN (antegrade or retrograde), use of IMN locking screws(dynamic or static), site of nonunion, primary nonunion time, pathological type of nonunion, bone defect (mm), primary revision method (ERN or ACP), and adjuvant autogenous bone grafting (ABG) (yes or no). Univariate analysis and multiple regression were used to identify risk factors in the development of re-nonunion after primary revision with either ERN or ACP for femoral shaft nonunion subsequent to failed IMN. The minimum follow-up time was 1.5 years (standard deviation [SD] = 1.2, range 1.5-8 years). RESULTS: Of 63 cases (61 patients) of femoral shaft nonunion subsequent to failed IMN, primary revision with ERN was performed in 33 (52.4%) cases and primary revision with ACP was performed in 30 (47.6%) cases. Adjuvant ABG procedure was undertaken in 39 (61.9%) cases during primary revisions. Re-nonunion was diagnosed as in 18 (28.6%) cases after primary revision with either ERN or ACP. There was a significant difference in time to union between patients treated with primary ERN and those with primary ACP (log-rank, p = 0.006). Furthermore, the difference was also statistically significant between patients with adjuvant ABG procedure and those without it (log-rank, p = 0.009). The relative risk factors included smoking, BMI, site of nonunion, bone defect, primary revision method, and adjuvant ABG procedure. However, primary revision method and adjuvant ABG procedure were shown to be two independent risk factors in multiple logistic regression analysis. CONCLUSIONS: Patients with excessive tobacco use, BMI ≥ 30 kg/m2, bone defect ≥ 5 mm, primary revision with ERN, and no adjuvant ABG procedure had a higher likelihood of developing re-nonunion. Of these risk factors, primary revision with ERN and no adjuvant ABG procedure were two strongest risk factors.