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OBJECTIVE: This research was designed to probe into the regulatory mechanism of long non-coding RNA (LncRNA) differentiation antagonizing non-protein coding RNA (DANCR) in potential applications and molecular mechanisms of prostate carcinoma (PC). METHODS: The DANCR and miR-214-5p levels in PC tissues and cell lines were tested via real-time PCR, and those of transforming growth factor-ß (TGF-ß) signaling pathway related proteins were evaluated via Western Blot (WB). Cell proliferation, migration, apoptosis and the regulatory relationship between target genes were assessed via MTT method, scratch test, flow cytometry, dual-luciferase report, RNA co-immunoprecipitation and RNA pull-down test, respectively. RESULTS: DANCR was up-regulated in PC patients' serum and cell lines, while miR-214-5p was opposite, showing negative correlation. Besides, DANCR was significantly correlated with PSA, Gleason score and T stage in PC patients. The area under the curve (AUC) of DANCR and miR-214-5p for diagnosing PC was not less than 0.850, while the AUC for predicting poor prognosis was more than 0.800. Cox analysis results also revealed that the two might be prognostic indicators of PC patients. We found that DANCR high levels or miR-214-5p low levels were related to PC patients' poor prognosis. Up-regulating DANCR or down-regulating miR-214-5p could promote PC cells' malignant proliferation and migration, prevent apoptosis, and activate TGF-ß signaling pathway, while reverse treatment of DANCR or miR-214-5p can reverse the above results. DANCR regulates miR-214-5p in a targeted manner, and DANCR over-expression can reduce the cancer inhibitory effect of miR-214-5p on PC cells. CONCLUSION: DANCR-miR-214-5p-TGF-ß axis regulatory network plays a key regulatory part in PC progression. It may provide new strategies for the screening and treatment of patients.
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BACKGROUND: Long noncoding RNA (lncRNA) are critical regulators of tumor progression. OBJECTIVE: To determine how the lncRNA membrane associated guanylate kinase, WW and PDZ domain-containing 2 (MAG12) antisense RNA 3 (MAGI2-AS3) and the phosphatase and tensin homolog (PTEN) gene function in regulating bladder cancer (Bca) progression. METHODS: Total RNA from 80 Bca tissues and 30 paired para-cancerous tissues from patients was sequentially extracted, quantified, purified, and reverse transcribed using RT-PCR. A library was constructed and sequenced. Four Bca cell lines and a normal urothelial cell line were transfected with lentiviral plasmids, and cell migration and invasion were assayed in vitro. An orthotopic mouse model of Bca was created for in vivo studies. RESULTS: MAGI2-AS3 expression was significantly downregulated in Bca, compared with normal tissues, and negatively associated with tumor stage and a poor prognosis. MAGI2-AS3 and its sense RNA MAGI2 showed significant and positive correlation. The expression of MAGI2 and its downstream gene, PTEN, increased in Bca cells overexpressing MAGI2-AS3, and interference by MAGI2 expression reversed the migration and invasion inhibited by MAGI2-AS3 overexpression. CONCLUSION: MAGI2-AS3 overexpression inhibited Bca cell progression by regulating the MAGI2/PTEN/epithelial-mesenchymal transition, offering novel insights into the mechanism of Bca progression.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Guanilato-Quinasas/metabolismo , Fosfohidrolasa PTEN/metabolismo , ARN Largo no Codificante/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismo , Animales , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Femenino , Humanos , Ratones Endogámicos NOD , ARN sin Sentido/genética , ARN sin Sentido/metabolismo , ARN Largo no Codificante/genética , Transfección , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
OBJECTIVE: To analyz the correlation of the expression of ERp29 with the clinicopathological characteristics of PCa and investigate the effect of small interfering RNA (siRNA) silencing the ERp29 gene on the biological behavior of PCa LNCaP cells. METHODS: The expression of the ERp29 gene in the BPH and PCa tissues was detected by immunohistochemistry and that of the ERp29 protein in the PCa and adjacent normal tissues of 6 PCa patients determined by Western blot. Human LNCaP cells were transfected with siRNA using LipofectamineTM 2000, and the expressions of ERp29 mRNA and protein in the LNCaP cells detected by quantitative real-time PCR (qRT-PCR) and Western blot, respectively. The proliferation of the LNCaP cells was measured by MTT assay, their in vitro migration and invasiveness evaluated by the Transwell method, and the expressions of E-cadherin and Vimentin determined by qRT-PCR. RESULTS: The expression of ERp29 was significantly lower in the PCa than in the adjacent normal tissue (73.9% vs 91.9%ï¼ P < 0.05), with a significant correlation between the down-regulated ERp29 expression and metastasis (M) staging (P < 0.05). After transfection with siRNA, the LNCaP cells showed dramatically increased proliferation, migration and invasiveness (P < 0.05), and the expression of E-cadherin was markedly down-regulated while that of Vimentin up-regulated as compared with those in the normal control group (P < 0.05). CONCLUSIONS: The ERp29 gene may be a novel repressor of tumor metastasis. Silencing ERp29 can promote the invasiveness of human PCa cells in vitro by down-regulating the expression of E-cadherin and increasing epithelial-mesenchymal transition.
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Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Proteínas de Choque Térmico/genética , Neoplasias de la Próstata/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Transición Epitelial-Mesenquimal , Humanos , Masculino , Invasividad Neoplásica/genética , Neoplasias de la Próstata/genética , ARN Interferente Pequeño/genéticaRESUMEN
Bladder cancer is one of the most commonly diagnosed and fatal malignancies of the urinary tract. Noncoding RNAs have been reported to be new biomarkers and effective treatment targets for bladder cancer. In the present study, we identified a novel bladder cancer-related circRNA-miRNA-mRNA network, the circ_0004463/miR-380-3p/FOXO1 axis. circ_0004463 is significantly downregulated, whereas miR-380-3p is upregulated in bladder carcinoma tissue samples and cells. circ_0004463 acts as a tumor suppressor by inhibiting bladder cancer cell proliferation. Genes that negatively correlated with miR-380-3p and genes that miR-380-3p might target are enriched in mitochondrial respiration chain-related pathways. miR-380-3p promotes the proliferation of bladder cancer cells and mitochondrial respiration by acting as an oncogenic miRNA. circ_0004463 competes with FOXO1 for miR-380-3p binding to counteract miR-380-3p-mediated repression of FOXO1. Circ_0004463 overexpression inhibits cancer cell proliferation and mitochondrial respiration in bladder cancer cell lines, while miR-380-3p overexpression dramatically reverses the roles of circ_0004463 overexpression. In conclusion, the circ_0004463/miR-380-3p/FOXO1 axis could regulate mitochondrial respiration and bladder cancer cell apoptosis via FOXO1 signaling.
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Apoptosis/genética , Proteína Forkhead Box O1/metabolismo , MicroARNs/metabolismo , Mitocondrias/metabolismo , ARN Circular/metabolismo , Transducción de Señal/genética , Neoplasias de la Vejiga Urinaria/metabolismo , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Respiración de la Célula/genética , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Humanos , MicroARNs/genética , Oncogenes , Fenotipo , ARN Circular/genética , Transfección , Regulación hacia Arriba/genética , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
OBJECTIVE: The model of acute renal injury (AKI) induced by sepsis in rats was established by abdominal resection through surgical suture. The activation mechanism of nod-like receptor with pyrin domain containing 3 (NLRP3) inflammatory corpuscle in AKI induced by sepsis was analyzed. METHODS: Here, 60 male rats were selected and divided into two groups, including sham-operated group (NO-OPs group, n = 15) and sepsis group (CELP group, n = 45). In order to examine each index of CELP group, four time points (10, 20, 30, and 40 h) were set as control. In NO-OPs group, only abdominal resection through surgical suture was carried out. The expression levels of NLRP3, apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), caspase-1, and the expression level of NLRP3-TXNIP signaling pathway were measured by immunohistochemistry, Western blotting, immunoprecipitation, and mito-TEMPO (a mitochondria-targeted antioxidant) 40 h after operation and 10, 20, 30, and 40 h post-operation in CELP group. Herein, 40 h post-operation in NO-OPs group and 10, 20, 30, and 40 h post-operation in CELP group, peripheral blood samples were collected. RESULTS: Compared with NO-OPs group, the levels of serum creatinine (Scr) and blood urea nitrogen (BUN) in CELP group were increased (P < 0.05). Compared with NO-OPs group, the expression levels of interleukin-1ß (IL-1ß), NLRP3, ASC, and caspase-1 in CELP group were increased (P < 0.05). The expression level of TXNIP in renal tubular epithelial cells in rats was up-regulated. There was a positive correlation between TXNIP and NLRP3. The binding of NLRP3-TXNIP signaling pathway could be inhibited by siRNA transfection or mito-TMPO, and the activity of NLRP3 inflammatory bodies could be inhibited as well. CONCLUSION: Activation of NLRP3 inflammatory corpuscles could promote AKI induced by sepsis. Simultaneously, renal injury may lead to the production of mitochondrial reactive oxygen species (mROS), which may induce the binding of TXNIP to NLRP3.
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The expression pattern and detailed roles of long noncoding RNA LINC00511 in clear cell renal cell carcinoma (ccRCC) remain unknown. We measured LINC00511 expression in ccRCC. We clarified the clinical characteristics associated with LINC00511 in ccRCC. We examined the biological roles of LINC00511 in the progression of ccRCC, and we identified the potential mechanisms involved. LINC00511 was upregulated in ccRCC tissues and cell lines. High LINC00511 expression significantly correlated with TNM classification, lymph node metastasis, and short overall survival among patients with ccRCC. Additionally, LINC00511 knockdown restricted ccRCC cell proliferation, colony formation, and metastasis in vitro; accelerated cell cycle arrest at G0-G1 and apoptosis in vitro; and decreased tumor growth in vivo. Investigation of the mechanism revealed that LINC00511 directly interacted with microRNA-625 (miR-625), and the inhibitory effects of the LINC00511 knockdown on malignant characteristics were neutralized by miR-625 silencing. Furthermore, cyclin D1 (CCND1) was identified as a direct target of miR-625 in ccRCC cells. The tumor-suppressive activity of miR-625 upregulation on ccRCC cells was reversed by CCND1 reintroduction. In conclusion, LINC00511 serves as a competing endogenous RNA that regulates CCND1 expression by sponging miR-625 in ccRCC. Hence, the LINC00511/miR-625/CCND1 pathway might be a promising therapeutic target in ccRCC.
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Carcinoma de Células Renales/genética , Ciclina D1/genética , Neoplasias Renales/genética , Metástasis Linfática/genética , MicroARNs/genética , Anciano , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Proliferación Celular/genética , Ciclina D1/metabolismo , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/metabolismo , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Metástasis Linfática/patología , Masculino , MicroARNs/metabolismo , Persona de Mediana Edad , Fenotipo , ARN Largo no Codificante , Tasa de SupervivenciaRESUMEN
In recent years, circular RNAs (circRNAs) have been identified to be essential regulators of various human cancers. However, knowledge of the functions of circRNAs in prostate cancer remains very limited. The correlation between circABCC4 and human cancer is largely unknown. This study aims to investigate the biological functions of circABCC4 in prostate cancer progression and illustrate the underlying mechanism. We found that circABCC4 was remarkably up-regulated in prostate cancer tissues and cell lines and promoted FOXP4 expression by sponging miR-1182 in prostate cancer cells. CircABCC4 knockdown markedly suppressed prostate cancer cell proliferation, cell-cycle progression, migration and invasion in vitro. Furthermore, silencing of the circRNA also delayed tumor growth in vivo. Taken together, our findings indicated that circABCC4 facilitates the malignant behaviour of prostate cancer by promoting FOXP4 expression through sponging of miR-1182. The circABCC4-miR-1182-FOXP4 regulatory loop may be a promising therapeutic target for prostate cancer intervention.
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Factores de Transcripción Forkhead/genética , MicroARNs/genética , Neoplasias de la Próstata/genética , ARN Circular/genética , Anciano , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/genética , Xenoinjertos , Humanos , Masculino , Ratones , Persona de Mediana Edad , Neoplasias de la Próstata/patologíaRESUMEN
Tumor cells utilize the overexpression of the programmed death-1 ligand 1(PD-L1) to escape T-cell controlled immune-surveillance. The clinical therapy that dilapidates PD1 or PD-L1-mediated cancer tolerance has pushed out the need to uncover the molecular regulation of PD-L1 overexpression in the tumor cell. In this study, we identify histone methyltransferase mixed-lineage leukemia protein 3 (MLL3) as a critical regulator of PD-L1 in prostate cancer cells. MLL3 and PD-L1 were highly expressed in the metastatic cancer tissues, compared to the primary cancer tissues. Furthermore, their expressions were highly correlated in the cancer tissues in the databases of TCGA and Xiangya Hospital. We found that MLL3 bound to the enhancer of PD-L1. Depletion of MLL3 decreased the binding level of H3K4me1 in the enhancer of PD-L1 and Pol II Ser-5p in the promoter of PD-L1. Importantly, MLL3 depletion impaired the mouse xenograft growth and decreased the response to PD-L1 antibody treatment in mice. The findings extend the understanding of the biology regulation of PD-L1 transcription and identify the histone writer MLL3 in an important immune checkpoint, and give prominence to a hidden therapeutic target to conquer immune evasion by tumor cells.
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Antígeno B7-H1/genética , Proteínas de Unión al ADN/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Inmunidad , Neoplasias de la Próstata/inmunología , Transcripción Genética , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Elementos de Facilitación Genéticos/genética , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Evasión Inmune , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patologíaRESUMEN
Steroid receptor co-activator3 (SRC3) has been known to severe as an androgen receptor (AR) coactivator and is involved in the prostate cancer progression. Non-coding RNA (ncRNA) plays an important role in the cancer progression. However, the mechanism underlying the relationship between ncRNA and AR coactivators is still unclear. Here, we found a ncRNA, Nuclear Enriched Abundant Transcript 1 (NEAT1), was able to interact with SRC3 in the prostate cancer cell lines. NEAT1 can upregulate the AKT phosphorylation via a SRC3/IGF1R pathway. In function, NEAT1 promoted the prostate cancer cell growth through IGF1R/AKT signaling pathway. The NEAT1, SRC3, and IGF1R were highly expressed in the patients' samples of prostate cancer. Therefore, we found a novel SRC3 binding ncRNA that can promote the prostate cancer cell growth through SRC3/IGF1R/AKT pathway.