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Circular RNAs (circRNAs) are a type of non-coding RNA that plays a vital role in biology. circRNAs appear to have a role in the development and progression of several malignancies, according to research. However, circRNAs that regulate prostate cancer (PCa) progression are still largely unknown and deserve further exploration. The aim of this study was to investigate the effect of hsa_circ_0070512 on the function and mechanism of PCa. hsa_circ_0070512 was increased in PCa tissues and cells and was mostly found in the cytoplasm of PCa cells. Overexpression of hsa_circ_0070512 considerably increased PCa cell proliferation and migration, whereas silencing of hsa_circ_0070512 greatly decreased PCa cell proliferation and migration. Mechanistically, we show that hsa_circ_0070512 acts as a "molecular sponge" for miR-338-3p and that the miR-338-3p mimics partially block the pro-tumor effects of hsa_circ_0070512. RNA sequencing analysis of PC3 cells stably overexpressing hsa_circ_0070512 revealed that hedgehog was downstream of the signaling pathways of hsa_circ_0070512 and miR-338-3p. Our results implied that hsa_circ_0070512 regulated the hedgehog signaling pathways through miR-338-3p to enhance PCa growth and migration, providing a new diagnostic and therapeutic target for PCa.
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MicroARNs , Neoplasias de la Próstata , Masculino , Humanos , MicroARNs/genética , MicroARNs/metabolismo , ARN Circular/genética , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Neoplasias de la Próstata/genética , Transducción de Señal/genética , Proliferación Celular/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión GénicaRESUMEN
BACKGROUND: Bladder cancer is one of the most common malignant tumors of the urinary system and is associated with a poor prognosis once invasion and distant metastases occur. Epithelial-mesenchymal transition (EMT) drives metastasis and invasion in bladder cancer. Transforming growth factor ß1 (TGF-ß1) and stromal fibroblasts, especially cancer-associated fibroblasts (CAFs), are positive regulators of EMT in bladder cancer. However, it remains unclear how TGF-ß1 mediates crosstalk between bladder cancer cells and CAFs and how it induces stromal fibroblast-mediated EMT in bladder cancer. We aimed to investigate the mechanism of TGF-ß1 regulation of stromal fibroblast-mediated EMT in bladder cancer cells. METHODS: Primary CAFs with high expression of fibroblast activation protein (FAP) were isolated from bladder cancer tissue samples. Subsequently, different conditioned media were used to stimulate the bladder cancer cell line T24 in a co-culture system. Gene set enrichment analysis, a human cytokine antibody array, and cytological assays were performed to investigate the mechanism of TGF-ß1 regulation of stromal fibroblast-mediated EMT in bladder cancer cells. RESULTS: Among the TGF-ß family, TGF-ß1 was the most highly expressed factor in bladder cancer tissue and primary stromal fibroblast supernatant. In the tumor microenvironment, TGF-ß1 was mainly derived from stromal fibroblasts, especially CAFs. In stimulated bladder cells, stromal fibroblast-derived TGF-ß1 promoted bladder cancer cell migration, invasion, and EMT. Furthermore, TGF-ß1 promoted the activation of stromal fibroblasts, inducing CAF-like features, by upregulating FAP in primary normal fibroblasts and a normal fibroblast cell line. Stromal fibroblast-mediated EMT was induced in bladder cancer cells by TGF-ß1/FAP. Versican (VCAN), a downstream molecule of FAP, plays an essential role in TGF-ß1/FAP axis-induced EMT in bladder cancer cells. VCAN may also function through the PI3K/AKT1 signaling pathway. CONCLUSIONS: TGF-ß1 is a critical mediator of crosstalk between stromal fibroblasts and bladder cancer cells. We revealed a new mechanism whereby TGF-ß1 dominated stromal fibroblast-mediated EMT of bladder cancer cells via the FAP/VCAN axis and identified potential biomarkers (FAP, VCAN, N-cadherin, and Vimentin) of bladder cancer. These results enhance our understanding of bladder cancer invasion and metastasis and provide potential strategies for diagnosis, treatment, and prognosis.
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Factor de Crecimiento Transformador beta1 , Neoplasias de la Vejiga Urinaria , Humanos , Línea Celular Tumoral , Movimiento Celular/genética , Transición Epitelial-Mesenquimal/genética , Fibroblastos/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta1/metabolismo , Microambiente Tumoral , Vejiga Urinaria/metabolismo , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Versicanos/metabolismoRESUMEN
MicroRNA-9 upregulation was reported in several tumors. However, its function and mechanism in human bladder cancer remains obscure. The present study aims to identify the expression pattern, biological roles and potential mechanism of miR-9 in human bladder cancers. We found that expression level of miR-9 in bladder cancer tissues was higher than normal tissues. miR-9 mimic transfection was performed in T24 and 5637 cells with low miR-9 expression, and miR-9 inhibitor was employed in BIU-87 cell line with high endogenous expression. miR-9 increased cell proliferation, cell cycle progression, invasion and chemoresistance, with upregulation of cyclin D1, MMP9, Bcl-2, and survivin and downregulation of E-cadherin. Using luciferase reporter assay, we confirmed that LASS2 was a direct target of miR-9 in bladder cancer cells. Transfection of miR-9 mimic downregulated LASS2 expression. LASS2 transfection downregulated Bcl-2 and survivin expression, which were induced by miR-9 mimic in both cell lines. In conclusion, these results indicate that miR-9 upregulation might be associated with malignant phenotype of bladder cancer. miR-9 promotes chemoresistance of bladder cancer cells by target LASS2.
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Proliferación Celular/genética , Proteínas de la Membrana/biosíntesis , MicroARNs/biosíntesis , Esfingosina N-Aciltransferasa/biosíntesis , Proteínas Supresoras de Tumor/biosíntesis , Neoplasias de la Vejiga Urinaria/genética , Apoptosis , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de la Membrana/genética , MicroARNs/genética , Proteínas de Neoplasias/biosíntesis , Esfingosina N-Aciltransferasa/genética , Proteínas Supresoras de Tumor/genética , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: Both radical prostatectomy and radiation therapy are effective in controlling the condition of patients with hormone-resistant prostate cancer (HRPCa). However, there is limited research on the prognosis and quality of life of HRPCa patients after different treatment modalities. OBJECTIVE: To explore the efficacy of radical prostatectomy (RP) and radiotherapy (RT), when treating high-risk prostate cancer (HRPCa). METHODS: Overall 103 HRPCa patients were included and were divided into RP group and RT group according to different treatment methods. The propensity score matching method (PSM) was used to balance the baseline data of the two groups and match 34 patients in each group. The prognosis, quality of life, and basic efficacy of patients were compared. RESULTS: After intervention, the disease-free survival rate of the RT group was higher than that of the RP group (79.41% vs. 55.88%, p= 0.038). Quality of life scores between the two treatment methods had no difference before intervention (p> 0.05), but higher in RT group than that of the RP group after intervention (p< 0.05). After treatment, there was no statistically significant difference in total effective rate of treatment between two groups (44.12% vs. 58.82%, p> 0.05), but the disease control rate was significantly higher in RT group (94.12% vs. 76.47%, p= 0.040). CONCLUSION: Radical radiotherapy is effective in the clinical treatment of HRPCa patients, with a higher disease-free survival rate and improved quality of life after treatment, and is worth promoting.
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Bladder cancer (BC) is one of the most common human malignancies that account for major death in the world. Apoptin that is derived from chicken anemia virus (CAV) has displayed tumor-specific cytotoxic activity in a variety of human carcinomas. However, the magical function of apoptin in bladder carcinoma cell lines has not been identified yet. In our study, we delivered apoptin into bladder-originating T24, EJ, and HCV29 cell lines by adenovirus system. The selective cytotoxic effect of apoptin was determined by cell viability assay, active caspase-3 measurement, and annexin V/PI double staining. Importantly, we have examined the differential expression patterns of tumor-associated genes including Ki67, C-erbB-2, Rb, and nm23 by flow cytometry and western blot in vitro. In an animal study, apoptin was infused into animal models by AAV system, and immunohistochemistry and quantitative real-time PCR (qRT-PCR) were employed to validate results in vivo. The results indicated that apoptin could selectively induce apoptosis in bladder tumorigenic cells coupled with tumor-specific nucleus accumulation in vitro. Interestingly, apoptin could downregulate expression levels of Ki67 and C-erbB-2 and upregulate the expression of Rb both in vitro and in vivo. Moreover, the animal models treated with AAV-apoptin have shown smaller tumor volumes and displayed better prognosis than controls. In conclusion, apoptin could selectively induce apoptosis in bladder tumor cells through altering expression profiles of tumor-associated genes.
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Apoptosis , Biomarcadores de Tumor/metabolismo , Proteínas de la Cápside/metabolismo , Proliferación Celular , Transcriptoma , Neoplasias de la Vejiga Urinaria/patología , Animales , Biomarcadores de Tumor/genética , Western Blotting , Proteínas de la Cápside/genética , Virus de la Anemia del Pollo , Dependovirus/genética , Ensayo de Inmunoadsorción Enzimática , Técnica del Anticuerpo Fluorescente , Genes erbB-2/genética , Vectores Genéticos , Humanos , Técnicas para Inmunoenzimas , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nucleósido Difosfato Quinasas NM23/genética , Nucleósido Difosfato Quinasas NM23/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteína de Retinoblastoma/genética , Proteína de Retinoblastoma/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Trasplante Homólogo , Células Tumorales Cultivadas , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/prevención & controlRESUMEN
Bladder cancer (BC) is one of the most common malignancies involving the urinary system. Our previous study demonstrated that cobra venom membrane toxin 12 (MT-12) could effectively inhibit BC cell growth and metastasis and induce apoptosis. However, the specific molecular mechanism remains unknown. In this study, we explored whether MT-12 inhibits BC cell proliferation by inducing autophagy cell death through mitochondrial dysfunction. As a result, MT-12 inhibited proliferation and colony formation in RT4 and T24 cells. In the BC xenograft mouse model, autophagy inhibitor 3-MA alleviated the inhibitory effect of MT-12 on tumor growth. In addition, immunostaining revealed downregulated autophagy in MT-12-treated RT4 and T24 cells. We also found that MT-12 led to dysfunctional mitochondria with decreased mitochondrial membrane potential, mtDNA abundance, and increased ROS production, ultimately inducing autophagic apoptosis via the ROS/JNK/P53 pathway. MT-12 inhibits BC proliferation in vitro and in vivo by enhancing autophagy. MT-12 induces mitochondrial dysfunction and decreases autophagy, leading to increased ROS production, which in turn activates the JNK/p53 pathway, leading to BC apoptosis.
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Prostate cancer (PCa) is one of the most prevalent cancers of the urinary system. In previous research, Kinesin family member 2C (KIF2C), as an oncogene, has been demonstrated to have a key role in the incidence and progression of different cancers. However, KIF2C has not been reported in PCa. We combined data from different databases, including The Cancer Genome Atlas, the Cancer Cell Line Encyclopedia, Genotype Tissue-Expression, cBioPortal, and the Genomics of Drug Sensitivity in Cancer database, to explore the potential oncogenic role of KIF2C in PCa through a series of bioinformatics approaches, including analysis of the association between KIF2C and prognosis, clinicopathological features, gene mutations, DNA methylation, immune cell infiltration, and drug resistance. The results showed that KIF2C was significantly up-regulated in PCa. High KIF2C expression was associated with age, pathological stage, lymph node metastases, prostate-specific antigen (PSA), and Gleason score and significantly predicted an unfavorable prognosis in PCa patients. Results from Gene Set Enrichment Analysis (GSEA) suggested that KIF2C was involved in the cell cycle and immune response. KIF2C DNA methylation was reduced in PCa and was inversely linked with KIF2C expression. KIF2C was shown to have a strong relationship with the tumor microenvironment (TME), infiltrating cells, and immune checkpoint genes. Furthermore, high KIF2C expression was significantly resistant to a variety of MAPK signaling pathway-related inhibitors. Our study reveals that KIF2C may be a possible predictive biomarker for assessing prognosis in PCa patients with immune infiltration.
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Neoplasias de la Próstata , Transcriptoma , Análisis de Datos , Perfilación de la Expresión Génica/métodos , Humanos , Cinesinas/genética , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Microambiente Tumoral/genéticaRESUMEN
[This corrects the article DOI: 10.3892/ol.2016.5514.].
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BACKGROUND: Multiomics data analysis based on high-throughput sequencing technology has become a hotspot in tumor investigation. The present study aimed to explore prognostic biomarkers via investigating DNA copy number variation (CNV) and methylation variation (MET) data in prostate cancer. METHODS: We obtained the messenger RNA (mRNA) expression, CNV, and methylated data of prostate adenocarcinoma (PRAD) samples via The Cancer Genome Atlas (TCGA)-PRAD cohort. We calculated and assessed the associations between CNV and RNA sequencing (RNA-seq), and between MET and RNA-seq via Pearson correlation coefficients. We then used the "iCluster" package to perform multigroup cluster analysis with CNVcor gene CNV data, METcor gene methylation data, and CNVcor and METcor gene mRNA data. The univariate Cox analysis was used to screen significant hub genes, and multivariate Cox analysis was used to construct risk a model. The nomogram was constructed based on "rms" package, and the immune infiltrating patterns were compared between high- and low-risk groups. RESULTS: A total of 477 PRAD samples with complete CNV, methylation, mRNA, and matched clinical information were included in our study. A list of 10,073 CNVcor genes and 9841 METcor genes were confirmed with a significance level of P<0.01. We found that CNVcor is more likely to appear on chromosome (chr)8, chr17, and chr10, while METcor is more likely to appear on chr1, chr19, and chr17. Based on the core genes, we finally classified the samples into 4 subtypes, incorporating iC1 (iCluster) (92 samples), iC2 (79 samples), iC3 (165 samples), and iC4 (141 samples). Furthermore, we constructed the prognostic model for PRAD based on the 5 genes (IER3, AOX1, PRKCDBP, UBD, and FBLN5). Nomograms incorporating risk score and other clinical variables were further constructed, and these nomograms exhibited superior predictive ability. We further compared the differential immune infiltrating patterns in 2 risk groups and found significantly low levels of infiltrating cluster of differentiation (CD)8+ T cells in high-risk samples. CONCLUSIONS: Our study integrated the multi-omics data to elucidate the molecular features of PRAD and pivotal genes for predicting prognosis.
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Tumors are one of the main causes of death in humans. The development of safe and effective methods for early diagnosis and treatment of tumors is a difficult problem that needs to be solved urgently. It is well established that the occurrence of tumors involves complex biological mechanisms, and the tumor microenvironment (TME) plays an important role in regulating the biological behavior of tumors. Cancer-associated fibroblasts (CAFs) are a group of activated fibroblasts with significant heterogeneity and plasticity in the tumor microenvironment. They secrete a variety of active factors to regulate tumor occurrence, development, metastasis, and therapeutic resistance. Although most studies suggest that CAFs have significant tumor-promoting functions, some evidence indicates that they may have certain tumor-suppressive functions in the early stage of tumors. Current research on CAFs continues to face many challenges, and the heterogeneity of their origin, phenotype, and function is a major difficulty and hot spot. To provide new perspectives for the research on CAFs and tumor diagnosis and treatment, this review summarizes the definition, origin, biomarkers, generation mechanism, functions, heterogeneity, plasticity, subpopulations, pre-metastasis niches (PMN), immune microenvironment, and targeted therapy of CAFs, describes the research progress and challenges, and proposes possible future research directions based on existing reports.
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Fibroblastos Asociados al Cáncer/patología , Neoplasias/inmunología , HumanosRESUMEN
Paris forrestii is a unique plant found in Tibet and Yunnan, China, and total saponins from Paris forrestii (PCT3) contain anticancer steroid glycosides. RNA expression plays an important role in various biological processes. However, the cytotoxicity effects and mechanisms of PCT3 in relation to prostate cancer (PCa) cells have not yet been reported. In the present study, the antitumor activity of PCT3 on PCa cells was evaluated. PCT3 displayed potent anticancer effects toward PCa cells that were similar to the effects of pure saponins from P. forrestii, but PCT3 had less activity in suppressing the prostate epithelial cell line RWPE. Furthermore, using CCK-8 assays, Edu incorporation, colony formation assays, Annexin V/PI assays and western blotting, we found that treatment with 4⯵g/mL PCT3 significantly decreased proliferation and induced apoptosis in PCa cells. Using wound healing and transwell assays, we demonstrated that treatment with 2⯵g/mL PCT3 significantly suppressed the migration and invasion of PCa cells. To explore the molecular mechanisms behind the anticancer effect of PCT3, PCT3 (5⯵g/mL) treated and untreated PCa cells (LNCAP and PC3 cell lines) were analyzed using transcriptomics. Taking the commonly differentially expressed genes (log2FCâ¯>â¯0.585) in both cell lines, 41 mRNAs and 5 lncRNAs were eventually identified. Bioinformatics analysis (GO and KEGG analyses) revealed that some genes involved in classical cell proliferation and apoptosis pathways were aberrantly expressed after PCT3 treatment of PCa cells. By using q-PCR, the expression levels of NEAT1, MALAT1, TIPIN, LYAR, IQGAP3, GINS2, and ZGRF1 were validated as consistent with microarray data, suggesting that these genes might participate in the PCT3 anticancer effect. The present study suggests that PCT3 exhibits an anticancer effect on PCa and reveals some crucial lncRNAs and mRNAs that are involved in the anticancer mechanisms of PCT3 on Pca.
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Antineoplásicos/farmacología , Regulación Neoplásica de la Expresión Génica , Melanthiaceae/química , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Saponinas/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ontología de Genes , Humanos , Concentración 50 Inhibidora , Masculino , Invasividad Neoplásica , Neoplasias de la Próstata/tratamiento farmacológico , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Saponinas/química , Saponinas/uso terapéuticoAsunto(s)
Neoplasias Renales , Neoplasias Complejas y Mixtas , Neoplasias de los Tejidos Blandos , Humanos , Riñón/patología , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/cirugía , Neoplasias Renales/patología , Neoplasias Complejas y Mixtas/diagnóstico , Neoplasias Complejas y Mixtas/cirugíaRESUMEN
BACKGROUND: Cobra venom membrane toxin (MT) has been defined as a major subset of cobra venom having cardiac toxicity and anticancer activity properties. In our previous study, cobra venom membrane toxin 12 (MT-12), isolated from the snake venom of Chinese Naja naja atra, was confirmed to selectively suppress the proliferation and invasion of the bladder cancer (BC) cell line EJ. However, the results have never been confirmed in other bladder cell lines, and the underlying mechanism by which MT-12 inhibits BC is still unknown. Thus, in this study, the effect of MT-12 on the proliferation, adhesion, and invasion of BC cells was explored in vitro and in vivo. As tumor angiogenesis is a prerequisite for tumor growth and metastasis, the factors involved, such as matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), were tested in our study. METHODS: Using RT4 and T24 cells for experiments, CCK-8 assays were used to determine cell proliferation. Annexin V-FITC/PI was used to determine cell apoptosis status. Wound-healing assays were used to determine cell invasion. Cell adhesion experiments were used to determine cell adhesion. Gelatin zymography was used to determine the enzymatic activity of MMP-9 and MMP-2. RT-PCR, ELISA, and immunohistochemistry were used to determine the expression of VEGF, ICAM-1, and VCAM-1. RESULTS: MT-12 inhibited proliferation, invasion, and adhesion and promoted cell apoptosis in RT4 and T24 cells; this anticancer effect was concentration-dependent. In the BC xenograft mouse model, the results revealed that MT-12 might decrease tumor growth and weight. MT-12 was shown to have an inhibitory effect on MMP-9 activation and the expression of VEGF and ICAM-1 in BC cells in vitro and in vivo. CONCLUSIONS: The results of the present study, suggest that MT-12 could effectively inhibit BC cell growth and metastasis via inhibition of tumor angiogenesis. As a result, MT-12 may become a novel drug for BC.
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In an effort to develop novel Bax activators for breast cancer treatment, a series of diverse analogues have been designed and synthesized based on lead compound SMBA1 through several strategies, including introducing various alkylamino side chains to have a deeper access to S184 pocket, replacing carbon atoms with nitrogen, and reducing the nitro group of 9H-fluorene scaffold. Compounds 14 (CYD-2-11) and 49 (CYD-4-61) have been identified to exhibit significantly improved antiproliferative activity compared to SMBA1, with IC50 values of 3.22⯵M and 0.07⯵M against triple-negative breast cancer MDA-MB-231 and 3.81⯵M and 0.06⯵M against ER-positive breast cancer MCF-7â¯cell lines, respectively. Mechanism of action studies of compound 49 indicated that it can activate Bax protein to induce cytochrome c release and regulate apoptotic biomarkers, leading to cancer cell apoptosis. Further in vivo efficacy studies of compounds 14 and 49 in nude mice bearing MDA-MB-231 tumor xenografts demonstrated that these drug candidates can significantly suppress tumor growth, indicating their therapeutic potential for the treatment of breast cancer.
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Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Proteína X Asociada a bcl-2/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Células MCF-7 , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Desnudos , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales Cultivadas , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Cancer stem cells (CSCs) are considered one of the key contributors to chemoresistance and tumor recurrence. Therefore, the precise identification of reliable CSC markers and clarification of the intracellular signaling involved in CSCs remains a great challenge in fields relating to cancer biology. Here, we implemented a novel chemoresistant prostate cancer patient-derived xenograft (PDX) model in NOD/SCID mice and identified CD54 as a candidate gene among the most highly enriched gene expression profiles in prostate tumors exposed to chronic cisplatin administration. Additional in vitro and in vivo assays showed that CD54 played a critical role in the self-renewal and tumorigenesis of prostate CSCs. Moreover, silencing CD54 greatly reduced the tumorigenesis of prostate cancers both in vitro and in vivo and significantly extended the survival time of tumor-bearing mice in a prostate cancer xenograft model. Dissection of the molecular mechanism revealed that the p38-Notch1 axis was the main downstream signaling pathway in CD54-mediated regulation of CSCs in prostate cancers. Together, these results established that CD54 could be a novel reliable prostate CSC marker and provided a new potential therapeutic target in prostate cancer via CD54-Notch1 signaling.
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Molécula 1 de Adhesión Intercelular/metabolismo , Células Madre Neoplásicas/metabolismo , Neoplasias de la Próstata/fisiopatología , Receptor Notch1/metabolismo , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Silenciador del Gen , Xenoinjertos , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Análisis de SupervivenciaRESUMEN
Bladder cancer is one of the most common malignancies. However, there is no ideal therapy to cure bladder cancer so far, especially invasive carcinoma. Here, we developed a new antibody-based drug BCMab1-Ra, which was generated by conjugation of BCMab1 (a new monoclonal antibody that specifically recognized the aberrantly glycosylated Integrin a3b1 in bladder cancer) with the ricin A chain (Ra). A patient with multiple bladder cancer received intravescical administration of BCMab1-Ra treatment as a volunteer. After 30 weeks of treatment, no tumor was observed by cystoscope examination. We did not observe any local or systemic side effects. Human anti-mouse antibody (HAMA) was not detectable in the circulation. Results follow-up showed no tumor had been found in every half year review in 3 years.
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Inmunoconjugados/uso terapéutico , Inmunotoxinas/uso terapéutico , Ricina , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Biopsia , Cistoscopios , Humanos , Inmunoconjugados/administración & dosificación , Inmunotoxinas/administración & dosificación , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/diagnósticoRESUMEN
Postsurgery infection is a common complication after laparoscopic radical cystectomy (LRC) followed by urinary diversion. White blood cell (WBC) values and C-reactive protein (CRP) are routinely used as markers for infection, but lack of specificity and their elevation is often delayed in clinically significant events. In this study, we aimed to investigate the value of procalcitonin (PCT) kinetics in assisting early diagnosis of infection in patients undergoing LRC.The patients' medical records between May 2013 and May 2016 were reviewed retrospectively. WBC, CRP, and PCT plasma levels as well as clinical symptoms were registered in 306 patients preoperatively (day 0), and 5 consecutive days postoperatively. Based on microbiological and clinical data, patients were grouped into noninfection- (NI-) and infection- (I-) groups. The day of new onset infection was observed were defined as day t0 and the day after that as day t1. For the NI-group, the day on which PCT was at the peak was defined as day t1 and the previous day as day t0.Of the 306 patients, 46 (15.03%) have proven infection. PCT levels were analogous at day t0:NI-group [median (interquartile range)]: 0.69(1.99) vs I-group [median (interquartile range)]: 1.0[0.75], Pâ=â.1. PCT levels were significantly increased at day t1 in the I-group[median (interquartile range)]:2.9(1.3) vs NI-group[median (interquartile range)]: 1.3(1.5), Pâ<â.01. The area under the curve for the prediction of infection was 0.72 [95% confidence interval (CI)â=â0.63-0.81] for the absolute value of PCT; and for delta PCT:0.88 (95% CIâ=â0.81-0.94), Pâ<â.01. The optimal cut-off value was 0.79 ng/mL with the highest Youden index of 0.80 for delta-PCT to indicate infection. Neither absolute values nor changes in CRP, or WBC could predict infection better. The "delta" was considered as the changes in the absolute values (subtracting day t0 from day t1) of PCT, CRP, and WBC.This study suggest that early elevation of PCT within the first 24âhours of new onset infection, interpreted with clinical results, appears to be a promising indicator for the diagnosis of infections following LRC.
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Calcitonina/sangre , Cistectomía/efectos adversos , Laparoscopía/efectos adversos , Complicaciones Posoperatorias/diagnóstico , Infecciones Urinarias/diagnóstico , Anciano , Área Bajo la Curva , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Cistectomía/métodos , Diagnóstico Precoz , Femenino , Humanos , Cinética , Laparoscopía/métodos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/microbiología , Valor Predictivo de las Pruebas , Periodo Preoperatorio , Estudios Prospectivos , Valores de Referencia , Estudios Retrospectivos , Sensibilidad y Especificidad , Derivación Urinaria/efectos adversos , Derivación Urinaria/métodos , Infecciones Urinarias/microbiologíaRESUMEN
Homo sapiens longevity assurance homolog 2 of yeast LAG1 (LASS2) is a novel suppressor of human cancer metastasis, and downregulation of LASS2 has been associated with a poor prognosis in patients with bladder cancer (BC). However, the molecular mechanism underlying LASS2-mediated inhibition of tumor invasion and metastasis in BC remains unclear. LASS2 has been reported to directly bind to subunit C of vacuolar H+-ATPase (V-ATPase) in various types of cancer, suggesting that LASS2 may inhibit cancer invasion and metastasis by regulating the function of V-ATPase. The present study investigated the effect of LASS2-specific small interfering (si)RNA on the invasion and metastasis of the RT4 human BC cell line, which has a low metastatic potential, and its functional interaction with V-ATPase. Silencing of LASS2 in RT4 cells was able to increase V-ATPase activity, the extracellular hydrogen ion concentration and, in turn, the activation of secreted matrix metalloproteinase (MMP)-2 and MMP-9, which occurred simultaneously with enhanced cell proliferation, cell survival and cell invasion in vitro, as well as acceleration of BC growth in vivo. In this process, it was found that siRNA-LASS2 treatment was able to suppress cell apoptosis induced by doxorubicin. These findings suggest that silencing of LASS2 may enhance the growth, invasion and metastasis of BC by regulating ATPase activity.
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OBJECTIVE: A mouse model of orthotopic bladder cancer simulating its human counterpart is of great importance in preclinical evaluation of new treatment modalities such as immunotxin therapy. The aim of the present study is to establish a novel nude mouse model with xenografted human bladder cancer. METHODS: Single cell suspension of an established human bladder transitional cell carcinoma (TCC) cell line BIU-87 was instilled into nude mouse bladders which were pretreated with mild acid washing. The tumor growth in mouse bladder was assessed weekly by magnetic resonance imaging (MRI). At intervals following implantation and MRI tumor detection, the animals were sacrificed for necropsy, histological examination and immunocytochemical studies. RESULTS: The overall tumor establishment was 92.9% (52/56 mice) at 7 - 36 days, while in the subgroup of animals sacrificed at 12 - 13 days, 40 out of 42 animals (95.2%) developed TCC, the majority of which was superficial. The tumor stages were assessed by gross and histopathology. Histological examination confirmed the presence of grade II - III TCC. Immunocytochemistry confirmed that the tumor model maintained the biological and immunological features of BIU-87 cells. The changes seen on MRI images well correlated with the extent of tumor invasion identified by histology. Carcinoma in situ could be detected histologically at 7 - 9 days post-inoculation and progressed into papillary or invasive tumors thereafter. CONCLUSION: The orthotopic BIU-87 TCC model in nude mice is highly reproducible and is ideal for preclinical studies on experimental intravesical therapies.
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Carcinoma de Células Transicionales/patología , Neoplasias de la Vejiga Urinaria/patología , Animales , Anticuerpos Monoclonales/análisis , Carcinoma de Células Transicionales/inmunología , Línea Celular Tumoral , Femenino , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Ratones , Ratones Desnudos , Estadificación de Neoplasias , Trasplante de Neoplasias , Neoplasias Experimentales/patología , Trasplante Heterólogo , Neoplasias de la Vejiga Urinaria/inmunologíaRESUMEN
The existence of bladder cancer stem cells (BCSC) has been suggested to underlie bladder tumor initiation and recurrence. Sonic Hedgehog (SHH) signaling has been implicated in promoting cancer stem cell (CSC) self-renewal and is activated in bladder cancer, but its impact on BCSC maintenance is unclear. In this study, we generated a mAb (BCMab1) against CD44(+) human bladder cancer cells that recognizes aberrantly glycosylated integrin α3ß1. The combination of BCMab1 with an anti-CD44 antibody identified a BCMab1(+)CD44(+) cell subpopulation as BCSCs with stem cell-like properties. Gene expression analysis revealed that the hedgehog pathway was activated in the BCMab1(+)CD44(+) subpopulation and was required for BCSC self-renewal. Furthermore, the glycotransferase GALNT1 was highly expressed in BCMab1(+)CD44(+) cells and correlated with clinicopathologic features of bladder cancers. Mechanistically, GALNT1 mediated O-linked glycosylation of SHH to promote its activation, which was essential for the self-renewal maintenance of BCSCs and bladder tumorigenesis. Finally, intravesical instillation of GALNT1 siRNA and the SHH inhibitor cyclopamine exerted potent antitumor activity against bladder tumor growth. Taken together, our findings identify a BCSC subpopulation in human bladder tumors that appears to be responsive to the inhibition of GALNT1 and SHH signaling, and thus highlight a potential strategy for preventing the rapid recurrence typical in patients with bladder cancer.