RESUMEN
Background: Metastasis in penile corpus cavernosum from adenocarcinoma of lung is a rare but fatal disease, which was reported in cases without series studies. It causes various clinical symptoms seriously affecting the quality of life. Case presentation: A 72-year-old male smoker patient, who had a history of adenocarcinoma of lung after targeted therapy 36 months before, was admitted to Jiangxi Cancer Hospital because of presenting with aggressive dysuria and penis pain for one hour. A Foley catheter was inserted into the patient's bladder with difficulty. Immediately do a bladder puncture. Emergency pelvic computed tomography (CT): a soft tissue nodule of 1.1 cm×1.4 cm was found in the cavernous area of the middle part of the penis, and the proximal urethra was dilated with a wide diameter of about 1.5 cm. The diagnosis of metastatic lung adenocarcinoma from the primary was made by CT-guided biopsy. Conclusion: The penis may be a site of metastasis from primary lung cancer, especially for old patient. Metastasis to the penis usually indicates that the primary lung cancer is at an advanced stage and the prognosis is very poor. More research is necessary to understand the underlying mechanism of adenocarcinoma of lung metastasis.
RESUMEN
Zika virus (ZIKV), a positive-sense single-stranded RNA virus, causes congenital ZIKV syndrome in children and Guillain-Barré Syndrome (GBS) in adults. ZIKV expresses nonstructural protein 5 (NS5), a large protein that is essential for viral replication. ZIKV NS5 confers the ability to evade interferon (IFN) signalling; however, the exact mechanism remains unclear. In this study, we employed affinity pull-down and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses and found that splicing factor 3b subunit 3 (SF3B3) is associated with the NS5-Flag pull-down complex through interaction with NS5. Functional assays showed that SF3B3 overexpression inhibited ZIKV replication by promoting IFN-stimulated gene (ISG) expression whereas silencing of SF3B3 inhibited expression of ISGs to promote ZIKV replication. GTP cyclohydrolase I (GCH1) is the first and rate-limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis. NS5 upregulates the expression of GCH1 during ZIKV infection. And GCH1 marginally promoted ZIKV replication via the IFN pathway. Additionally, GCH1 expression is related to the regulation of SF3B3. Overexpression of the SF3B3 protein effectively reduced GCH1 protein levels, whereas SF3B3 knockdown increased its levels. These findings indicated that ZIKV NS5 binding protein SF3B3 contributed to the host immune response against ZIKV replication by modulating the expression of GCH1.
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Infección por el Virus Zika , Virus Zika , Niño , Humanos , Proteínas Portadoras/metabolismo , Proteínas Portadoras/farmacología , Cromatografía Liquida , Unión Proteica , Factores de Empalme de ARN/metabolismo , Espectrometría de Masas en Tándem , Proteínas no Estructurales Virales/genética , GTP Ciclohidrolasa/metabolismoRESUMEN
BACKGROUND: Ovarian cancer is the leading cause of gynecological cancer-related mortality. The novel oncogene S100A10 has been reported to be involved in cancer cell proliferation, invasion and metastasis. The role of S100A10 in ovarian cancer has not been well studied and the effect of S100A10 on chemotherapy remains unclear. The aims of the present study were to investigate the functional role of S100A10 in the progression and carboplatin sensitivity of ovarian cancer. METHODS: We examined the expression levels in tissues of S100A10 in 138 cases of ovarian cancer by IHC. To determine the functional roles of downregulated S100A10 in ovarian cancer, cell proliferation, colony formation, cell migration and invasion assays were performed. Chemoresistance was analyzed by apoptosis assay. A xenograft tumor model was established to confirm the role of S100A10 in carboplatin resistance in vivo. Using Western blot assays, we also explored the possible mechanisms of S100A10 in ovarian cancer. RESULTS: The results showed that increased expression of S100A10 was positively associated with carboplatin resistance (P < 0.001), tumor grade (P = 0.048) and a poorer prognosis (P = 0.0053). Functional analyses demonstrated that S100A10 suppression significantly suppressed ovarian cancer cell proliferation, colony formation, cell migration and invasion, remarkably increased carboplatin-induced apoptosis in SKOV3 and A2780 cells and inhibited tumor growth in vivo. Downregulation of S100A10 expression could inhibit cell proliferation and enhance ovarian cancer cell sensitivity to carboplatin, possibly involving the regulation of cleaved-Caspase3 and cleaved-PARP. CONCLUSIONS: Together, the results of the present study reveal that S100A10 expression can be used as a predictive marker for the prognosis of ovarian cancer and chemosensitivity to carboplatin.
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Anexina A2/genética , Neoplasias Ováricas , Proteínas S100/genética , Animales , Anexina A2/metabolismo , Antineoplásicos/farmacología , Apoptosis , Carboplatino/farmacología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Silenciador del Gen , Células HEK293 , Humanos , Estimación de Kaplan-Meier , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/mortalidad , Proteínas S100/metabolismo , Cicatrización de HeridasRESUMEN
Ubiquitinspecific protease 39 (USP39), as one of the deubiquitinating enzymes (DUBs), exhibits aberrant an expression and has oncogenic functions in several types of cancer. However, the function and underlying molecular mechanisms of action of USP39 in ovarian cancer remain largely undetermined. The present study thus aimed to investigate whether USP39 is a promising tumorassociated gene and whether it could be a viable target for overcoming chemotherapeutic resistance in ovarian cancer. The present study identified that USP39 was highly expressed in ovarian cancer samples with carboplatin resistance. A series of functional assays revealed that the knockdown of USP39 in ES2 and SKOV3 cells significantly decreased cell proliferation, induced cell cycle arrest at the G2/M phase and impaired the cell colony formation ability. USP39 deficiency enhanced the carboplatininduced apoptosis of the SKOV3 cells via the activation of polyADP ribose polymerase and caspase3. USP39 knockdown led to the inhibition of cell migration and invasion. The opposite effects were observed when USP39 was overexpressed in the ES2 and SKOV3 cells. In vivo animal models revealed that the subcutaneous transplantation and intraperitoneal injection of USP39overexpressing ES2 cells increased tumor burden with or without treatment with carboplatin. However, the knockdown of USP39 suppressed SKOV3 cell growth in vivo. Mechanistic analyses also demonstrated that USP39 induced the phosphorylation of extracellular signalregulated kinase and AKT and increased the expression of epidermal growth factor receptor and cyclin B1. Collectively, the findings of this study suggest that USP39 may paly a vital role in regulating ovarian cancer malignant phenotypes and carboplatin resistance. Therefore, USP39 may prove to be a promising therapeutic target for patients with ovarian cancer.
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Carboplatino/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/enzimología , Proteasas Ubiquitina-Específicas/metabolismo , Animales , Línea Celular Tumoral , Resistencia a Antineoplásicos , Femenino , Células HEK293 , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Ováricas/patología , Fenotipo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Distribución Aleatoria , Proteasas Ubiquitina-Específicas/biosíntesisRESUMEN
Mucin 1 (MUC1), as an oncogene, plays a key role in the progression and tumorigenesis of many human adenocarcinomas and is an attractive target in tumor immunotherapy. Our previous study showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific Th1-dominant immune response, simulated MUC1-specific cytotoxic T lymphocyte killing activity, and could significantly inhibit MUC1-expression B16 cells' growth in mice. To help move the vaccine into a Phase I clinical trial, in the current study, a pre-clinical toxicity and immunogenicity evaluation of the vaccine was conducted. The evaluation was comprised of a single-dose acute toxicity study in mice, repeat-dose chronic toxicity and immunogenicity studies in rats, and pilot toxicity and immunogenicity studies in cynomolgus monkeys. The results showed that treatment with the MUC1-MBP/BCG anti-tumor vaccine did not cause any organ toxicity, except for arthritis or local nodules induced by BCG in several rats. Furthermore, the vaccine significantly increased the levels of IFN-γ in rats, indicating that Th1 cells were activated. In addition, the results showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific IgG antibody response both in rats and cynomolgus monkeys. Collectively, these data are beneficial to move the MUC1-MBP/BCG anti-tumor vaccine into a Phase I clinical trial.
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Vacunas contra el Cáncer/administración & dosificación , Inmunoterapia/métodos , Mucina-1/administración & dosificación , Células TH1/inmunología , Vacunas Sintéticas/administración & dosificación , Animales , Artritis/etiología , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/genética , Femenino , Humanos , Interferón gamma/genética , Interferón gamma/metabolismo , Macaca fascicularis , Masculino , Proteínas de Unión a Maltosa/genética , Ratones , Ratones Endogámicos ICR , Mucina-1/efectos adversos , Mucina-1/genética , Mycobacterium bovis/genética , Ratas , Ratas Sprague-Dawley , Vacunas Sintéticas/efectos adversosRESUMEN
Mucin 1 (MUC1) is an oncogene that has a crucial role in the pathogenesis and progression of the majority of epithelial malignant tumors. Our previous study demonstrated that MUC1 gene silencing inhibited the growth of SMMC7721 cells in vitro and in vivo, however, whether this growth inhibition is associated with apoptotic cell death remains to be elucidated. In the present study, it was found that MUC1 gene silencing not only resulted in the inhibition of SMMC7721 cell growth, determined using a clone formation assay in vitro and a tumor xenograft mouse model with an in vivo imaging system, but also induced apoptotic alterations in SMMC7721 cells, determined using Hoechst 33342 staining, flow cytometry with an Annexin V-PE staining and a DNA ladder assay. Further investigation using western blotting revealed that cytochrome c was released from the mitochondria into the cytoplasm, and caspase8 and caspase9 were activated in MUC1 genesilenced SMMC7721 cells. The proapoptotic protein Bcl2associated X protein (Bax) and the tumor suppressor p53 were increased, while the antiapoptotic protein Bcell lymphoma 2 was decreased in MUC1 genesilenced cells. In addition, results from the coimmunoprecipitation experiments demonstrated that the MUC1 cytoplasmic tail can bind directly to Bax or caspase8 and these interactions were reduced upon MUC1 gene silencing in SMMC7721 cells. The above results indicate that MUC1 gene silencing induces growth inhibition in SMMC7721 cells through Baxmediated mitochondrial and caspase-8-mediated death receptor apoptotic pathways.
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Apoptosis , Carcinoma Hepatocelular/metabolismo , Proliferación Celular , Neoplasias Hepáticas/metabolismo , Mucina-1/genética , Proteína X Asociada a bcl-2/metabolismo , Animales , Carcinoma Hepatocelular/patología , Caspasa 8/metabolismo , Línea Celular Tumoral , Citocromos c/metabolismo , Humanos , Neoplasias Hepáticas/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Mitocondrias/metabolismo , Mucina-1/metabolismo , Fenotipo , Unión Proteica , Interferencia de ARN , Receptores de Muerte Celular/metabolismo , Transducción de SeñalRESUMEN
Mucin1 (MUC1), as an oncogene, plays a key role in the progression and tumorigenesis of many human adenocarcinomas. In this study, wound-healing, transwell migration and matrigel invasion assays showed that MUC1 promotes human hepatocellular carcinoma (HCC) cell migration and invasion by MUC1 gene silencing and overexpressing. Treatment with exogenous transforming growth factor beta (TGF-ß)1, TGF-ß type I receptor (TßRI) inhibitor, TGF-ß1 siRNAs, or activator protein 1 (AP-1) inhibitor to MUC1-overexpressing HCC cells revealed that MUC1-induced autocrine TGF-ß via JNK/AP-1 pathway promotes the cell migration and invasion. In addition, the migration and invasion of HCC cells were more significantly inhibited by JNK inhibitor compared with that by TßRI inhibitor or TGF-ß1 siRNAs. Further studies demonstrated that MUC1-mediated JNK activation not only enhances the phosphorylation of Smad2 C-terminal at Ser-465/467 site (Smad2C) through TGF-ß/TßRI, but also directly enhances the phosphorylation of Smad2 linker region at Ser-245/250/255 site (Smad2L), and then both of them collaborate to upregulate matrix metalloproteinase (MMP)-9-mediated cell migration and invasion of HCC. These results indicate that MUC1 is an attractive target in liver cancer therapy.
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Carcinoma Hepatocelular/genética , Movimiento Celular/fisiología , Neoplasias Hepáticas/metabolismo , Sistema de Señalización de MAP Quinasas , Mucina-1/metabolismo , Proteína Smad2/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Mucina-1/genética , Fosforilación , Proteína Smad2/genética , TransfecciónRESUMEN
Mucin1 (MUC1) is a transmembrane glycoprotein that acts as an oncogene in human hepatic tumorigenesis. Hepatocellular carcinoma (HCC) cells often gain advantage by reducing the tumor-suppressive activity of transforming growth factor beta (TGF-ß) together with stimulation of its oncogenic activity as in MUC1 expressing HCC cells; however, molecular mechanisms remain largely unknown. Type I TGF-ß receptor (TßRI) and c-Jun NH2-terminal kinase (JNK) differentially phosphorylate Smad3 mediator to create 2 phosphorylated forms: COOH-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). Here, we report that MUC1 overexpression in HCC cell lines suppresses TßRI-mediated pSmad3C signaling which involves growth inhibition by up-regulating p21(WAF1). Instead, MUC1 directly activates JNK to stimulate oncogenic pSmad3L signaling, which fosters cell proliferation by up-regulating c-Myc. Conversely, MUC1 gene silencing in MUC1 expressing HCC cells results in preserved tumor-suppressive function via pSmad3C, while eliminating pSmad3L-mediated oncogenic activity both in vitro and in vivo. In addition, high correlation between MUC1 and pSmad3L/c-Myc but not pSmad3C/p21(WAF1) expression was observed in HCC tissues from patients. Collectively, these results indicate that MUC1 shifts Smad3 signaling from a tumor-suppressive pSmad3C/p21(WAF1) to an oncogenic pSmad3L/c-Myc pathway by directly activating JNK in HCC cells, suggesting that MUC1 is an important target for HCC therapy.
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Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Mucina-1/metabolismo , Transducción de Señal/fisiología , Proteína smad3/metabolismo , Animales , Western Blotting , Línea Celular Tumoral , Transformación Celular Neoplásica/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Xenoinjertos , Humanos , Inmunoprecipitación , MAP Quinasa Quinasa 4/metabolismo , Ratones , Ratones Endogámicos BALB C , Microscopía Confocal , Proteínas Proto-Oncogénicas c-myc/metabolismo , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Maltose-binding protein (MBP), a component of the maltose transport system of Escherichia coli, has been commonly thought to have minimal bioactivity. Our previous studies demonstrated that MBP could significantly enhance Bacillus Calmette-Guerin (BCG)-induced T helper 1 (Th1) cell activation in mice. In the present study, we analyzed the effect of MBP on mouse T cells and found that MBP promoted the proliferation and IFN-γ production of CD4(+) T cells, suggesting that MBP directly induces Th1 activation. To explore the mechanism of Th1 activation, the expression of Toll-like receptor 2/4 (TLR2/4) on purified mouse CD4(+) T cells was detected. The results showed that MBP up-regulated TLR2 while down-regulated TLR4 expression, accompanied by a clear increase in MyD88 expression and IκB phosphorylation. Notably, the addition of anti-TLR2 antibody abrogated the MBP-induced CD4(+) T cells proliferation, IFN-γ secretion and MyD88 expression, whereas the addition of anti-TLR4 antibody exhibited a contradictive effect. Besides, the block of either TLR2 or TLR4 both reduced IκB phosphorylation. These results above suggest that TLR2-mediated MyD88-dependent pathway contributes to MBP-induced Th1 activation, while TLR4 appears to counteract this effect via MyD88-independent pathway.
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Proteínas de Escherichia coli/inmunología , Activación de Linfocitos/inmunología , Proteínas de Unión a Maltosa/inmunología , Células TH1/inmunología , Células TH1/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Citocinas/metabolismo , Regulación de la Expresión Génica , Proteínas I-kappa B/metabolismo , Inmunofenotipificación , Ratones , Factor 88 de Diferenciación Mieloide/metabolismo , Fosforilación , Bazo/citología , Bazo/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Receptor Toll-Like 2/genética , Receptor Toll-Like 4/genéticaRESUMEN
In a previous study, we observed by global gene expression analysis that oncogene mucin1 (MUC1) silencing decreased transforming growth factor beta (TGF-ß) signaling in the human hepatocellular carcinoma (HCC) cell line SMMC-7721. In this study, we report that MUC1 overexpression enhanced the levels of phosphorylated Smad3 linker region (p-Smad3L) (Ser-213) and its target gene MMP-9 in HCC cells, suggesting that MUC1 mediates TGF-ß signaling. To investigate the effect of MUC1 on TGF-ß signaling, we determined TGF-ß secretion in MUC1 gene silencing and overexpressing cell lines. MUC1 expression enhanced not only TGF-ß1 expression at the mRNA and protein levels but also luciferase activity driven by a TGF-ß promoter, as well as elevated the activation of c-Jun N-terminal kinase (JNK) and c-Jun, a member of the activation protein 1 (AP-1) transcription factor family. Furthermore, pharmacological reduction of TGF-ß receptor (TßR), JNK and c-Jun activity inhibited MUC1-induced autocrine TGF-ß signaling. Moreover, a co-immunoprecipitation assay showed that MUC1 directly bound and activated JNK. In addition, both MUC1-induced TGF-ß secretion and exogenous TGF-ß1 significantly increased Smad signaling and cell migration, which were markedly inhibited by either TßR inhibitor or small interfering RNA silencing of TGF-ß1 gene in HCC cells. The high correlation between MUC1 and TGF-ß1 or p-Smad3L (Ser-213) expression was shown in tumor tissues from HCC patients by immunohistochemical staining analysis. Collectively, these results indicate that MUC1 mediates autocrine TGF-ß signaling by activating the JNK/AP-1 pathway in HCC cells. Therefore, MUC1 plays a key role in HCC progression and could serve as an attractive target for HCC therapy.
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Comunicación Autocrina , Carcinoma Hepatocelular/enzimología , Neoplasias Hepáticas/enzimología , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Mucina-1/metabolismo , Factor de Transcripción AP-1/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular , Activación Enzimática , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Células HEK293 , Humanos , Neoplasias Hepáticas/patología , Mucina-1/genética , Fosforilación , Unión Proteica , Proteína smad3/metabolismoRESUMEN
Mucin1 (MUC1) is a transmembrane glycoprotein that plays a key role as an oncogene in the tumorigenesis of many human adenocarcinomas. However, the role of MUC1 in human hepatocellular carcinoma (HCC) progression remains unclear. In the present study, we silenced MUC1 to investigate its effect on the human HCC cell line SMMC-7721 and found that knockdown of MUC1 signiï¬cantly inhibited cell proliferation, enhanced cell-cell aggregation and induced apoptosis. No significant differences were found in in vitro migration or invasion. We also observed that knockdown of MUC1 decreased the translocation of ßcatenin to the nucleus, reduced the activity of T cell factor and blocked the expression of cyclin D1 and c-Myc. In addition, MUC1 knockdown enhanced the expression of E-cadherin, a molecular chaperone of ßcatenin that plays an important role in cell-cell aggregation. In vivo assays demonstrated that there was no tumor growth in mice injected with MUC1-silenced cells. Global gene expression analysis showed that a series of genes encoding molecules in the Wnt/ßcatenin, nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), insulin, transforming growth factor ß (TGF-ß) and vascular endothelial growth factor (VEGF) signaling pathways were all influenced by the knockdown of MUC1, and these may contribute to the phenotypic alterations observed. Collectively, our results indicate that MUC1 plays a key role in HCC tumorigenesis.