RESUMEN
Novel components in the noncanonical Hippo pathway that mediate the growth, metastasis, and drug resistance of breast cancer (BC) cells need to be identified. Here, we showed that expression of SAM and SH3 domain-containing protein 1 (SASH1) is negatively correlated with expression of mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) in a subpopulation of patients with luminal-subtype BC. Downregulated SASH1 and upregulated MAP4K4 synergistically regulated the proliferation, migration, and invasion of luminal-subtype BC cells. The expression of LATS2, SASH1, and YAP1 and the phosphorylation of YAP1 were negatively regulated by MAP4K4, and LATS2 then phosphorylated SASH1 to form a novel MAP4K4-LATS2-SASH1-YAP1 cascade. Dephosphorylation of Yes1 associated transcriptional regulator (YAP1), YAP1/TAZ nuclear translocation, and downstream transcriptional regulation of YAP1 were promoted by the combined effects of ectopic MAP4K4 expression and SASH1 silencing. Targeted inhibition of MAP4K4 blocked proliferation, cell migration, and ER signaling both in vitro and in vivo. Our findings reveal a novel MAP4K4-LATS2-SASH1-YAP1 phosphorylation cascade, a noncanonical Hippo pathway that mediates ER signaling, tumorigenesis, and metastasis in breast cancer. Targeted intervention with this noncanonical Hippo pathway may constitute a novel alternative therapeutic approach for endocrine-resistant BC.
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Proteínas Adaptadoras Transductoras de Señales , Neoplasias de la Mama , Péptidos y Proteínas de Señalización Intracelular , Proteínas Serina-Treonina Quinasas , Factores de Transcripción , Proteínas Supresoras de Tumor , Proteínas Señalizadoras YAP , Humanos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Femenino , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Animales , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Ratones , Transducción de Señal , Metástasis de la Neoplasia , Movimiento Celular , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Fosforilación , Ratones Desnudos , Carcinogénesis/genética , Carcinogénesis/metabolismoRESUMEN
Dyschromatosis universalis hereditaria (DUH) is characterized by diffuse symmetrically distributed hypopigmented macules mixed with hyperpigmentation. DUH is divided into three types by Online Mendelian inheritance in man (OMIM) that is, DUH1 (OMIM 127500), DUH2 (OMIM 612715) and DUH3 (OMIM 615402) according to the different linkage regions. Although each condition possesses corresponding phenotypic characteristics and the prognosis for each is somewhat different, these disorders are highly overlapped and difficult to differentiate in the clinical setting. Our latest study reveals a novel DUH subtype that presents a mild phenotype of pigmentation anomalies and is named PER3rs772027021 SNP related DUH or DUH4 by us, which make the DUH subtype can be further retyped. Heterozygous distribution or mosaic-like distribution of melanin is a newly discovered pathological features that is uniquely demonstrated in the affected layers of DUH1 and DUH4 patients. In this review, DUH is further divided into four subtypes according the causative genes and their mutational sites, and the mutation regions described in the previous reports. To make an accurate diagnosis, we suggest that Sanger sequencing or the target region sequencing (TRS) to the candidate causative genes related melanogenesis may be the most effective and convenient method of clinical diagnosis or/and prenatal diagnosis for DUH and DUH-like patients. More importantly, heterozygous distribution or mosaic-like distribution of melanin can be utilized for differential diagnosis of DUH. We also investigate the underlying molecular mechanism to form mosaic-like melanin in the affected layers of hyper- and/or hypo-pigmented macules from DUH1 and DUH4 patients. This review provides a molecular and pathological delineation of four types of DUH and aims to establish a concise diagnostic strategy to allow clinical dermatologists to make an accurate diagnosis.
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Hiperpigmentación , Enfermedades Cutáneas Genéticas , Humanos , Patología Molecular , Melaninas/genética , Enfermedades Cutáneas Genéticas/diagnóstico , Enfermedades Cutáneas Genéticas/genética , Enfermedades Cutáneas Genéticas/patología , Hiperpigmentación/diagnóstico , Hiperpigmentación/genética , LinajeAsunto(s)
Cromosomas Humanos Par 19 , Proteínas del Ojo , Retinitis Pigmentosa , Humanos , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/diagnóstico , Proteínas del Ojo/genética , Cromosomas Humanos Par 19/genética , Masculino , Electrorretinografía , Femenino , Tomografía de Coherencia Óptica , Reordenamiento Génico , Adulto , Análisis Mutacional de ADN , LinajeRESUMEN
p53-Transcriptional-regulated proteins interact with a large number of other signal transduction pathways in the cell, and a number of positive and negative autoregulatory feedback loops act upon the p53 response. P53 directly controls the POMC/α-MSH productions induced by ultraviolet (UV) and is associated with UV-independent pathological pigmentation. When identifying the causative gene of dyschromatosis universalis hereditaria (DUH), we found three mutations encoding amino acid substitutions in the gene SAM and SH3 domain containing 1 (SASH1), and SASH1 was associated with guanine nucleotide-binding protein subunit-alpha isoforms short (Gαs). However, the pathological gene and pathological mechanism of DUH remain unknown for about 90 years. We demonstrate that SASH1 is physiologically induced by p53 upon UV stimulation and SASH and p53 is reciprocally induced at physiological and pathophysiological conditions. SASH1 is regulated by a novel p53/POMC/α-MSH/Gαs/SASH1 cascade to mediate melanogenesis. A novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype. Our study demonstrates that a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype.
Asunto(s)
Cromograninas/metabolismo , Retroalimentación Fisiológica , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Hiperpigmentación/genética , Hiperpigmentación/patología , Mutación/genética , Proopiomelanocortina/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Adolescente , Secuencia de Bases , Línea Celular , Humanos , Masculino , Melaninas/metabolismo , Melanosomas/metabolismo , Trastornos de la Pigmentación/congénito , Trastornos de la Pigmentación/genética , Trastornos de la Pigmentación/patología , Unión Proteica/efectos de la radiación , Transducción de Señal/efectos de la radiación , Enfermedades Cutáneas Genéticas/genética , Enfermedades Cutáneas Genéticas/patología , Rayos Ultravioleta , Regulación hacia Arriba/efectos de la radiaciónRESUMEN
We previously reported that three point mutations in SASH1 and mutated SASH1 promote melanocyte migration in dyschromatosis universalis hereditaria (DUH) and a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype. However, the underlying mechanism of molecular regulation to cause this hyperpigmentation disorder still remains unclear. In this study, we aimed to investigate the molecular mechanism undergirding hyperpigmentation in the dyschromatosis disorder. Our results revealed that SASH1 binds with MAP2K2 and is induced by p53-POMC-MC1R signal cascade to enhance the phosphorylation level of ERK1/2 and CREB. Moreover, increase in phosphorylated ERK1/2 and CREB levels and melanogenesis-specific molecules is induced by mutated SASH1 alleles. Together, our results suggest that a novel SASH1/MAP2K2 crosstalk connects ERK1/2/CREB cascade with p53-POMC-MC1R cascade to cause hyperpigmentation phenotype of DUH.
Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hiperpigmentación/metabolismo , MAP Quinasa Quinasa 2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Línea Celular Tumoral , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Quinasas MAP Reguladas por Señal Extracelular/genética , Células HEK293 , Humanos , Hiperpigmentación/genética , MAP Quinasa Quinasa 2/genética , Modelos Biológicos , Mutación , Trastornos de la Pigmentación/congénito , Trastornos de la Pigmentación/genética , Trastornos de la Pigmentación/metabolismo , Unión Proteica , Interferencia de ARN , Transducción de Señal/genética , Enfermedades Cutáneas Genéticas/genética , Enfermedades Cutáneas Genéticas/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
Immunotherapy is currently one of the most viable therapies for head and neck squamous cell carcinoma (HNSCC), characterized by high immune cell infiltration. The Wnt-signaling inhibitor and immune activation mediator, Dickkopf-1 (DKK1), has a strong correlation with tumor growth, tumor microenvironment, and, consequently, disease prognosis. Nevertheless, it is still unclear how DKK1 expression, HNSCC prognosis, and tumor-infiltrating lymphocytes are related. To better understand these associations, we examined how DKK1 expression varies across different tumor and normal tissues. In our study, we investigated the association between DKK1 mRNA expression and clinical outcomes. Next, we assessed the link between DKK1 expression and tumor immune cell infiltration. Additionally, using immunohistochemistry, we evaluated the expression of DKK1 in 15 healthy head and neck tissue samples, and the expression of CD3, CD4, and DKK1 in 27 HNSCC samples. We also explored aberrant DKK1 expression during tumorigenesis. DKK1 expression was remarkably higher in HNSCC tissues than in healthy tissues, and was shown to be associated with tumor stage, grade, lymph node metastasis, histology, and a dismal clinical prognosis in HNSCC. DKK1 expression in HNSCC tissues was inversely correlated with CD3+ (P < 0.0001) and CD4+ (P < 0.0001) immune cell infiltration, while that in immune cells was inversely associated with HNSCC prognosis. These findings offer a bioinformatics perspective on the function of DKK1 in HNSCC immunotherapy and provide justification for clinical research on DKK1-targeted HNSCC treatments. DKK1 is a central target for improving the efficacy of HNSCC immunotherapy.
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Carcinogénesis , Neoplasias de Cabeza y Cuello , Humanos , Biomarcadores , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello , Microambiente TumoralRESUMEN
Cytochrome P450 (CYP) family CYP11B2/CYP11B1 chimeric genes have been shown to arise from unequal crossing over of the genes encoding aldosterone synthase (CYP11B2) and 11ß-hydroxylase (CYP11B1) during meiosis. The activity deficiency or impaired activity of aldosterone synthase and 11ß-hydroxylase resulting from these chimeric genes are important reasons for 11ß-hydroxylase deficiency (11ß-OHD). Hereï¼two patients with pseudoprecocious puberty and hypokalemia hypertension and three carriers in a consanguineous marriage family were studied. A single CYP11B2/CYP11B1 chimera consisting of the promoter and exons 1 through 5 of CYP11B2, exons 8 and 9 of CYP11B1, and a breakpoint consisting of part of exon 6 of CYP11B2 and part of exon 6, intron 6, and exon 7 of CYP11B1 were detected in the patients and carriers. At the breakpoint of the chimera, a c 0.1086 G > C ( p.Leu.362 =) synonymous mutation in exon 6 of CYP11B2, a c 0.1157 Cï¼G(p. A386V) missense mutation in exon 7 of CYP11B1, and an intronic mutation in intron 6 were detected. The allele model of the CYP11B2/CYP11B1 chimera demonstrated homozygosity and heterozygosity in the patients and the carriers, respectively. Molecular docking and enzymatic activity analyses indicated that the CYP11B2/CYP11B1 chimeric protein interacted with the catalytic substrate of aldosterone synthase and had similar enzymatic activity to aldosterone synthase. Our study indicated that deletion of CYP11B1 and CYP11B2 abolished the enzymatic activity of 11 ß-hydroxylase and aldosterone synthase; however, the compensation of the enzymatic activity of aldosterone synthase by the CYP11B2/CYP11B1 chimeric protein maintained normal aldosterone levels in vitro. All of the above findings explained the 11ß-OHD phenotypes of the proband and patients in the family.
Asunto(s)
Citocromo P-450 CYP11B2 , Esteroide 11-beta-Hidroxilasa , Intercambio Genético , Citocromo P-450 CYP11B2/genética , Simulación del Acoplamiento Molecular , Proteínas Recombinantes de Fusión/genética , Esteroide 11-beta-Hidroxilasa/genética , Esteroide 11-beta-Hidroxilasa/metabolismo , Humanos , Linaje , ConsanguinidadRESUMEN
Dyschromatosis universalis hereditaria (DUH) is a pigmentary genodermatosis characterized by a mixture of hyperpigmented and hypopigmented macules distributed randomly over the body. Although Sterile Alpha motif- and SH3 domain-containing protein 1 (SASH1) and ATP-binding cassette subfamily B, member 6 (ABCB6) have been identified as causative genes for this disorder, some cases involve unknown pathogenic genes. In this study, whole-exome sequencing, data analysis, and Sanger sequencing were utilized for a four-generation extended Chinese family with DUH. A single-nucleotide polymorphism (SNP) (c. 517C > T (p.P173S), rs772027021) variant in exon 5 of Period Circadian Regulator 3 (PER3) (NM_001289861) was detected in each affected individual of the DUH family; the c. 517C > T SNP of PER3 (PER3rs772027021 SNP) and a novel mutation in exon 14 of SASH1 (c. 1574C > G (p.T525R)) were both found in the proband. The affected individuals carrying PER3rs772027021 SNP in this family demonstrated mild-pigmented phenotypes compared to those of the proband carrying PER3rs772027021 SNP and SASH1 T525R mutation. Increased melanin synthesis was induced by PER3rs772027021 SNP in the melanocytes of affected epithelial tissues. Mutated SASH1 or PER3rs772027021 SNP alone or cooperation of mutation of SASH1 and PER3rs772027021 SNP synergistically led to increased melanin synthesis and enhanced proliferation of melanoma cells in vitro. We also phenotypically characterized a commercially available zebrafish mutant line harboring the PER3rs772027021 SNP to induce melanocyte proliferation in vivo. Our results are the first to reveal that this PER3 SNP may be pathogenic for a novel DUH subtype with mild hyperpigmented and/or hypopigmented phenotypes and that mutation of SASH1 and PER3 cooperatively promotes hyperpigmentation phenotypes. KEY MESSAGES: PER3 rs772027021 SNP is identified to be associated with hyperpigmentation and/or hypopigmentation phenotype and the novel pathogenic variant of PER3 rs772027021 SNP probably contributed the pathogenesis of DUH. SASH1T525R mutation is confirmed to associate with DUH. A novel autosomal dominant inheritance DUH subtype with mild pigmentated phenotypes is caused by the PER3rs772027021 SNP.
Asunto(s)
Hiperpigmentación , Melaninas , Animales , Hiperpigmentación/genética , Hiperpigmentación/patología , Melaninas/genética , Linaje , Pigmentación/genética , Polimorfismo de Nucleótido Simple , Pez Cebra/genética , HumanosRESUMEN
OBJECTIVES: Platelet count is an independent predictor of mortality in patients with cancer. It remains unknown whether the platelet count is related to in-hospital mortality in severely ill patients with tumours. DESIGN: A retrospective study based on a dataset from a multicentre cohort. SETTING: This was a secondary analysis of data from one Electronic Intensive Care Unit Collaborative Research Database survey cycle (2014-2015). PARTICIPANTS: The data pertaining to severely ill patients with tumours were collected from 208 hospitals located across the USA. This study initially a total of 200 859 participants. After the population was limited to patients with combined tumours and platelet deficiencies, the remaining 2628 people were included in the final data analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: The main measure was the platelet count, and the main outcome was in-hospital mortality. RESULTS: After adjustment for the covariates, the platelet count had a curvilinear relationship with in-hospital mortality (p<0.001). The first inflection point was 18.4 (per 10 change). On the left side of the first inflection point (platelet count ≤184 'x10Ë9/L), an increase of 10 in the platelet count was negatively associated with in-hospital mortality (OR 0.92, 95% CI 0.89 to 0.95, p<0.001). The second inflection point was 44.5 (per 10 change). Additional increases of 10 in the platelet count thereafter were positively associated with hospital mortality (OR 1.13, 95% CI 1.00 to 1.28, p=0.0454). The baseline platelet count was in the range of 184 'x10Ë9/L-445 'x10Ë9/L(p=0.0525), and the hospital mortality was lower than the baseline platelet count in other ranges. CONCLUSIONS: The relationship between platelet count and in-hospital mortality in critically ill patients with tumours was curvilinear. The lowest in-hospital mortality was associated with platelet count between 184 'x10Ë9/Land 445 'x10Ë9/L. This indicates that both high and low platelet count should receive attention in clinical practice.
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Plaquetas , Neoplasias , Estudios de Cohortes , Enfermedad Crítica , Mortalidad Hospitalaria , Humanos , Estudios RetrospectivosRESUMEN
The SAM and SH3 domaincontaining 1 (SASH1) genes have been identified as the causal genes of dyschromatosis universalis hereditaria (DUH); these genes cause the pathological phenotypes of DUH, and SASH1 variants have been shown to regulate the abnormal pigmentation phenotype in human skin in various genodermatoses. However, investigations into the mutated SASH1 gene have been limited to in vitro studies. In the present study, to recapitulate the molecular pathological phenotypes of individuals with DUH induced by SASH1 mutations, a heterozygous BALB/c mouse model, in which the human SASH1 c.1654 T>G (p. Tyr 551Asp, Y551D) mutation was knocked in was first generated. The in vivo functional experiments on Y551D SASH1 indicated that the increased expression of microphthalmiaassociated transcription factor (Mitf) was uniformly induced in the tails of heterozygous BALB/c mice, and an increased quantity of Mitfpositive epithelial cells was also detected. An increased expression of Mitf and Mitfpositive cells was also demonstrated in the epithelial tissues of Y551DSASH1 affected individuals. In the present study, Mitf expression was also found to be increased by Y551D SASH1 in vitro. Taken together, these findings indicate that the upregulation of Mitf is the bona fide effector of the Y551D SASH1mediated melanogenesis signaling pathway in vivo. SASH1 may function as a scaffold molecule for the assembly of a SASH1Mitf molecular complex to regulate Mitf expression in the cell nucleus and thus to promote the hyperpigmented phenotype in the pathogenesis of DUH and other genodermatoses related to pigment abnormalities.
Asunto(s)
Factor de Transcripción Asociado a Microftalmía/metabolismo , Trastornos de la Pigmentación/congénito , Enfermedades Cutáneas Genéticas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Núcleo Celular/metabolismo , Femenino , Heterocigoto , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Factor de Transcripción Asociado a Microftalmía/genética , Mutación/genética , Linaje , Trastornos de la Pigmentación/genética , Trastornos de la Pigmentación/metabolismo , Unión Proteica , ARN Mensajero/metabolismo , Transducción de Señal/genética , Transducción de Señal/fisiología , Enfermedades Cutáneas Genéticas/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
Statins are being widely used for the therapy and prevention of several types of tumors, including human chronic myelogenous leukemia, but the underlying molecular mechanisms still remain unknown. Therefore, inhibition of cell proliferation, apoptosis and involved molecules were investigated in K562 cells after incubation with simvastatin.The results showed that simvastatin diminished K562 cell proliferation and induced apoptosis. At the same time, the level of reactive oxygen species (ROS) and intracellular calcium concentration increased. Furthermore, nitric oxide (NO) content and inducible NO synthase (iNOS) mRNA expression were significantly higher in the simvastatin-treated group than in the corresponding control group. The elevated ROS level and intracellular calcium concentration, enhanced mRNA expression of iNOS and total NO content might be responsible for the apoptotic and anti-proliferative effects of simvastatin in K562 cells.
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Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Simvastatina/farmacología , Calcio/metabolismo , Humanos , Células K562 , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Statins, a family of 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase inhibitors, are being investigated for the therapy and prevention of cancers. Here we aimed to investigate the effects of simvastatin on chronic myelogenous leukemia (CML) cells in vitro and in vivo, and to elucidate the mechanisms. METHODS: Cell proliferation and cell cycle were measured after K562 cells were incubated with simvastatin, and differentially expressed genes were determined by oligonucleotide microarray. Changes of 2 genes obtained by oligonucleotide microarray were validated by real-time RT-PCR, and immunohistochemistry was performed to determine expression of proliferating cell nuclear antigen (PCNA). Finally, a xenograft tumor model was constructed to evaluate the effects of simvastatin in vivo. RESULTS: Simvastatin could inhibit K562 cell proliferation, and the inhibition rate was approximately 30% after treatment with 20 mumol/l simvastatin for 48 h. Cell cycle was arrested in G(1) phase, as shown by flow cytometry results. Fifteen downregulated, 9 upregulated cell cycle-related genes and decreased PCNA protein were observed in the presence of simvastatin. Furthermore, simvastatin exhibited impairment of xenograft tumor growth in nude mice and also blocked cell cycle in G(1) phase. CONCLUSION: Simvastatin can inhibit CML cell proliferation in vitro and in vivo, and its mechanisms might be involved in cell cycle regulation.
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Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Simvastatina/farmacología , Proteínas Adaptadoras Transductoras de Señales , Animales , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Ratones , Ratones Desnudos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Compared to single gemcitabine treatment, the combination of gemcitabine and erlotinib has shown effective response in patients with locally advanced or metastatic pancreatic cancer. However, the combination therapy has not proven effective in patients with pancreatic cancer after R0 or R1 resection. In the present study, a nude mice model of orthotopic xenotransplantation after tumor resection was established using pancreatic cancer cell lines, BxPC-3 and PANC1. Mice were divided in four groups (each with n=12) and were treated as follows: the control group received a placebo via intraperitoneal injection (i.p.), while the other three groups were treated with gemcitabine (50 mg/kg i.p., twice a week), erlotinib (50 mg/kg oral gavage, once every three days), and combined treatment of gemcitabine and erlotinib, respectively. The treatment lasted for 21 days, after which all mice were sacrificed and tumors were examined ex vivo. We determined that the combination of gemcitabine and erlotinib inhibited recurrent tumor growth and induced apoptosis in vivo by downregulating phosphorylation levels of JAKs and STATs, which in turn downregulated the downstream proteins HIF1α and cyclin D1, and upregulated caspase9 and caspase3 expression. To sum up, the combination of gemcitabine with erlotinib was effective in treating patients with pancreatic cancer after R0 or R1 resection.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biomarcadores de Tumor/metabolismo , Janus Quinasa 1/metabolismo , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Factores de Transcripción STAT/metabolismo , Animales , Apoptosis , Proliferación Celular , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Clorhidrato de Erlotinib/administración & dosificación , Femenino , Humanos , Ratones , Ratones Desnudos , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
One important function of melanocytes (MCs) is to produce and transfer melanin to neighbouring keratinocytes (KCs) to protect epithelial cells from UV radiation. The mechanisms regulating the specific migration and localisation of the MC lineage remain unknown. We have found three heterozygous mutations that cause amino acid substitutions in the SASH1 gene in individuals with a kind of dyschromatosis. In epidermal tissues from an affected individual, we observed the increased transepithelial migration of melanocytes. Functional analyses indicate that these SASH1 mutations not only cause the increased migration of A375 cells and but also induce intensive bindings with two novel cell adhesion partners IQGAP1 and Gαs. Further, SASH1 mutations induce uniform loss of E-Cadherin in human A375 cells. Our findings suggest a new scaffold protein SASH1 to regulate IQGAP1-E-Cadherin signalling and demonstrate a novel crosstalking between GPCR signalling, calmodulin signalling for the modulation of MCs invasion.
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Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Melanocitos/citología , Proteínas Supresoras de Tumor/metabolismo , Proteínas Activadoras de ras GTPasa/metabolismo , Cadherinas/metabolismo , Línea Celular , Movimiento Celular , Subunidades alfa de la Proteína de Unión al GTP Gs/antagonistas & inhibidores , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Células HEK293 , Humanos , Melanocitos/metabolismo , Mutación , Unión Proteica , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Migración Transendotelial y Transepitelial , Proteínas Supresoras de Tumor/genética , Proteínas Activadoras de ras GTPasa/antagonistas & inhibidores , Proteínas Activadoras de ras GTPasa/genéticaRESUMEN
Previous studies have indicated that immune dysregulation is an important cause of HCVmediated damage to the liver. Costimulation signals, including programmed cell death protein 1 (PD1) and inducible Tcell costimulator (ICOS), have been demonstrated to be involved in the pathogenesis of HCV. The purpose of this study was to investigate the soluble PD1 (sPD1) and soluble ICOS (sICOS) serum levels in chronic HCV patients, and to elucidate the association of sPD1 and sICOS levels with pathological injury of chronic HCV infection. Sixtythree patients with chronic HCV and 30 normal controls were recruited for this study. The serum concentration levels of sPD1 and sICOS were measured by enzymelinked immunosorbent assay, and the mRNA levels of PD1 and ICOS were detected using realtime RTPCR. The serum sPD1 and sICOS levels were significantly elevated in the chronic HCV patient group compared with the normal control group. Furthermore, the relative mRNA expression levels of these proteins were also increased in chronic HCV patients. sPD1 and sICOS serum levels were significantly correlated with antiHCV antibody levels, but not with HCV RNA. Aberrant sPD1 and sICOS serum levels may reflect the dysregulation of Tcell activation, and are associated with the pathological injury of chronic HCV infection.