RESUMEN
Inflammatory bowel diseases are known to be the origin of colitis-associated colon cancer (CAC). We previously reported that dextran sulfate sodium (DSS)-induced colitis is exacerbated in mouse-IL-21-isoform transgenic (Tg) mice. In this study, we assessed the CAC development induced by azoxymethane (AOM) and DSS in our Tg mice. AOM-DSS-induced tumor development was dramatically increased in the Tg mice compared with wild-type mice. IL-21 is known to enhance activation-induced cytidine deaminase (AID) expression in B cells and induce Ab class switching. In contrast, the AID expression in cells other than B cells initiates tumor development in many tissues. Therefore, we investigated whether IL-21 induces the AID expression in the large intestinal epithelial cells (IECs) during CAC development. AID gene and protein expression was increased in the IECs of AOM-DSS- or DSS-treated Tg mice compared with those of wild-type mice. Furthermore, we confirmed IL-21 induced AID gene expression in the purified IECs ex vivo. The present study also showed IL-21R gene expression in unstimulated wild-type mouse IECs, and this gene expression was augmented by TNF-α stimulation. The IL-21R expression and IL-21-induced AID gene activation were further confirmed in the Colon-38 cell line. Taken together, IL-21 may be involved in increasing the risk of CAC by enhancing the AID expression in IECs.
Asunto(s)
Linfocitos B/inmunología , Colitis/inmunología , Neoplasias del Colon/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Interleucinas/metabolismo , Mucosa Intestinal/fisiología , Animales , Azoximetano , Línea Celular Tumoral , Colitis/inducido químicamente , Neoplasias del Colon/inducido químicamente , Citidina Desaminasa/genética , Citidina Desaminasa/metabolismo , Sulfato de Dextran , Modelos Animales de Enfermedad , Humanos , Cambio de Clase de Inmunoglobulina , Enfermedades Inflamatorias del Intestino/inducido químicamente , Interleucinas/genética , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones TransgénicosRESUMEN
Cryptococcus gattii is a fungal pathogen, endemic in tropical and subtropical regions, the west coast of Canada, and the United States, that causes a potentially fatal infection in otherwise healthy individuals. Because the cryptococcal polysaccharide capsule is a leading virulence factor due to its resistance against innate immunity, the inhibition of capsule formation may be a promising new therapeutic strategy for C. gattii Macrolides have numerous nonantibiotic effects, including immunomodulation of mammalian cells and suppression of bacterial (but not fungal) pathogenicity. Thus, we hypothesized that a macrolide would inhibit cryptococcal capsule formation and improve the host immune response. Coincubation with clarithromycin (CAM) and azithromycin significantly reduced the capsule thickness and the amount of capsular polysaccharide of both C. gattii and C. neoformans CAM-treated C. gattii cells were significantly more susceptible to H2O2 oxidative stress and opsonophagocytic killing by murine neutrophils. In addition, more C. gattii cells were phagocytosed by murine macrophages, resulting in increased production of tumor necrosis factor alpha (TNF-α) by CAM exposure. After CAM exposure, dephosphorylation of Hog1, one of the mitogen-activated protein kinase (MAPK) signaling pathways of Cryptococcus, was observed in Western blot analysis. In addition, CAM exposure significantly reduced the mRNA expression of LAC1 and LAC2 (such mRNA expression is associated with cell wall integrity and melanin production). These results suggest that CAM may aid in inhibiting capsular formation via the MAPK signaling pathway and by suppressing virulent genes; thus, it may be a useful adjunctive agent for treatment of refractory C. gattii infection.
Asunto(s)
Macrólidos/farmacología , Animales , Cryptococcus gattii/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Ratones , Estrés Oxidativo/efectos de los fármacos , ARN Mensajero/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , VirulenciaRESUMEN
The cytokine interleukin-21 (IL-21) is mainly produced from activated CD4+ T cells and natural killer T (NKT) cells. IL-21 enhances the proliferation and differentiation of T cells and B cells and also increases cytotoxicity of CD8+ T cells and NK cells through the IL-21 receptor and its downstream signaling molecules such as signal transducers and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2). SH2 domain-containing tyrosine phosphatase (SHP-2) is ubiquitously expressed, including hematopoietic cells. SHP-2 has been implicated in the regulation of IL-6 and IL-3 signaling, but its function in IL-21 signaling has not been investigated. Therefore, we studied the role of SHP-2 in IL-21 signaling by SHP-2 overexpression and knockdown experiments. For the SHP-2 overexpression, we used 293T human embryonic kidney cells, in which the IL-21 receptor system were easily reconstituted and high amounts of exogenous SHP-2 were expressed by vector transfection. In 293T cells, overexpressed SHP-2 caused the increase in the degree of the IL-21-induced ERK1/2 activation. Subsequently, SHP-2 knockdown experiments were performed in the mouse pro-B cell line, BAF21RWT-1, which constitutively expresses human IL-21 receptor and proliferates in an IL-21-dependent manner. SHP-2 knockdown reduced the degree of the IL-21-induced ERK1/2 activation and suppressed cell proliferation. These results suggest that SHP-2 may augment the ERK1/2 activity and cell proliferation activity in IL-21 signaling. We propose that SHP-2 is involved in the IL-21-mediated ERK1/2 activation and cell proliferation.
Asunto(s)
Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Interleucinas/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Quinasas Janus/metabolismo , Ratones , Fosforilación/efectos de los fármacos , Factores de Transcripción STAT/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Quinasas raf/metabolismoRESUMEN
Caloric restriction (CR) has been shown to cause tumor regression in models of triple-negative breast cancer (TNBC), and the regression is augmented when coupled with ionizing radiation (IR). In this study, we sought to determine if the molecular interaction between CR and IR could be mediated by microRNA (miR). miR arrays revealed 3 miRs in the miR-17~92 cluster as most significantly down regulated when CR is combined with IR. In vivo, CR and IR down regulated miR-17/20 in 2 TNBC models. To elucidate the mechanism by which this cluster regulates the response to CR, cDNA arrays were performed and the top 5 statistically significant gene ontology terms with high fold changes were all associated with extracellular matrix (ECM) and metastases. In silico analysis revealed 4 potential targets of the miR-17~92 cluster related to ECM: collagen 4 alpha 3, laminin alpha 3, and metallopeptidase inhibitors 2 and 3, which were confirmed by luciferase assays. The overexpression or silencing of miR-17/20a demonstrated that those miRs directly affected the ECM proteins. Furthermore, we found that CR-mediated inhibition of miR-17/20a can regulate the expression of ECM proteins. Functionally, we demonstrate that CR decreases the metastatic potential of cells which further demonstrates the importance of the ECM. In conclusion, CR can be used as a potential treatment for cancer because it may alter many molecular targets concurrently and decrease metastatic potential for TNBC.
Asunto(s)
MicroARNs/genética , Familia de Multigenes , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Animales , Secuencia de Bases , Sitios de Unión , Restricción Calórica , Línea Celular Tumoral , Movimiento Celular , Modelos Animales de Enfermedad , Proteínas de la Matriz Extracelular/química , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Expresión Génica , Humanos , Ratones , MicroARNs/química , Metástasis de la Neoplasia , ARN Mensajero/química , ARN Mensajero/genética , Radiación Ionizante , Alineación de Secuencia , Inhibidor Tisular de Metaloproteinasa-2/genética , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Inhibidor Tisular de Metaloproteinasa-3/genética , Inhibidor Tisular de Metaloproteinasa-3/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismoRESUMEN
BACKGROUND: Although the fusion of the transmembrane serine protease 2 gene (TMPRSS2) with the erythroblast transformation-specific-related gene (ERG), or TMPRSS2-ERG, occurs frequently in prostate cancer, its impact on clinical outcomes remains controversial. Roughly half of TMPRSS2-ERG fusions occur through intrachromosomal deletion of interstitial genes and the remainder via insertional chromosomal rearrangements. Because prostate cancers with deletion-derived TMPRSS2-ERG fusions are more aggressive than those with insertional fusions, we investigated the impact of interstitial gene loss on prostate cancer progression. METHODS: We conducted an unbiased analysis of transcriptome data from large collections of prostate cancer samples and employed diverse in vitro and in vivo models combined with genetic approaches to characterize the interstitial gene loss that imposes the most important impact on clinical outcome. RESULTS: This analysis identified FAM3B as the top-ranked interstitial gene whose loss is associated with a poor prognosis. The association between FAM3B loss and poor clinical outcome extended to fusion-negative prostate cancers where FAM3B downregulation occurred through epigenetic imprinting. Importantly, FAM3B loss drives disease progression in prostate cancer. FAM3B acts as an intermediator of a self-governing androgen receptor feedback loop. Specifically, androgen receptor upregulates FAM3B expression by binding to an intronic enhancer to induce an enhancer RNA and facilitate enhancer-promoter looping. FAM3B, in turn, attenuates androgen receptor signaling. CONCLUSION: Loss of FAM3B in prostate cancer, whether through the TMPRSS2-ERG translocation or epigenetic imprinting, causes an exit from this autoregulatory loop to unleash androgen receptor activity and prostate cancer progression. These findings establish FAM3B loss as a new driver of prostate cancer progression and support the utility of FAM3B loss as a biomarker to better define aggressive prostate cancer.
Asunto(s)
Neoplasias de la Próstata , Receptores Androgénicos , Masculino , Humanos , Receptores Androgénicos/genética , Retroalimentación , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Transcriptoma , Proteínas de Fusión Oncogénica/genética , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismo , Proteínas de Neoplasias/genética , Citocinas/genéticaRESUMEN
Calorie restriction (CR), or a diet modification aiming to reduce the total intake of calories by 20%-40%, has been shown to increase longevity across multiple species. Recently, there has been growing interest in investigating the potential role of CR as a treatment intervention for age-related diseases, such as cancer, because an increasing body of literature has demonstrated a metabolic component to both carcinogenesis and tumor progression. In fact, many of the molecular pathways that are altered with CR are also known to be altered in cancer. Therefore, manipulation of these pathways using CR can render cancer cells, and most notably breast cancer cells, more susceptible to standard cytotoxic treatment with radiation and chemotherapy. In this review article we demonstrate the laboratory and clinical evidence that exists for CR and show compelling evidence through the molecular pathways CR induces about how it may be used as a treatment in tandem with radiation therapy to improve our rates of disease control.
Asunto(s)
Restricción Calórica/métodos , Redes y Vías Metabólicas , Neoplasias/dietoterapia , Neoplasias/radioterapia , Ensayos Clínicos como Asunto , Ingestión de Alimentos/fisiología , Ingestión de Energía/fisiología , Humanos , Longevidad/fisiología , Redes y Vías Metabólicas/genética , Redes y Vías Metabólicas/fisiología , Neoplasias/metabolismo , Neoplasias/fisiopatologíaRESUMEN
IL-21 is a pleiotropic cytokine that regulates the function of T cells, B cells, natural killer cells, and myeloid cells. We previously identified an IL-21 isoform, IL-21iso, in humans and mice, and found that IL-21iso was secreted in much smaller amounts than conventional IL-21. In this study, we determined that secreted IL-21iso also has less signaling activity than IL-21. However, the amounts of intracellular IL-21 or IL-21iso, and the level of STAT3 phosphorylation induced by the two IL-21 forms, were similar. IL-21-sensitive reporter cells co-cultured with cells producing IL-21iso showed STAT3 activation, apoptosis, and proliferation. However, when IL-21iso-producing cells were cultured in a transwell chamber, which prevented direct contact with the IL-21-sensitive cells, no IL-21iso-induced signaling was observed. Though IL-21iso is secreted in smaller amounts and has less potent signaling activity than IL-21, IL-21iso acts both on IL-21iso-bearing cells and other IL-21-sensitive cells through direct interactions probably without being secreted. Thus, IL-21iso's regulation of immune cells may be limited to the immediate proximity around the IL-21iso-producing cells, in regions such as immune organs or inflammation sites.
Asunto(s)
Comunicación Celular , Membrana Celular/metabolismo , Interleucinas/metabolismo , Animales , Línea Celular , Proliferación Celular , Supervivencia Celular , Humanos , Ligandos , Ratones , Isoformas de Proteínas/metabolismo , Receptores de Interleucina-21/metabolismo , Transducción de SeñalRESUMEN
Interleukin-21 (IL-21) is overproduced in human intestines affected by inflammatory bowel disease (IBD) and in the gut of mice with DSS-induced colitis. IL-21-deficient mice are largely protected against DSS-induced colitis, indicating that IL-21 plays a key role in the development of IBD. We previously identified a novel IL-21 isoform named IL-21iso. In this study, we found that in addition to the conventional IL-21, IL-21iso mRNA was also expressed in the colon with DSS-induced colitis. To investigate whether IL-21iso plays a role in DSS-induced colitis, we established transgenic mice (mIL-21iso-Tg mice) that expressed mouse IL-21iso under the control of the lck proximal promoter. Although mIL-21iso-Tg mice did not have any gross physical abnormalities, their peripheral lymphocytes counts were higher than those in wild-type littermates. Notably, their CD8(+) T cell and CD4(+) effector memory T-cell populations were elevated. DSS-induced colitis was far more severe in the mIL-21iso-Tg mice than in wild-type mice, and was accompanied by a marked loss of body weight and by colon inflammation with increased cellular infiltration. In DSS-treated mice, colon tissues from mIL-21iso-Tg mice had significantly higher gene activation levels for cytokines such as IL-17A, TNF-α, IL-6, IL-10, and IL-4, and for transcription factors such as T-bet, GATA-3, RORγt, and Foxp3, than were found in wild-type mice. These results indicate that besides IL-21, IL-21iso may be another regulator of gut inflammation.
Asunto(s)
Colitis/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Interleucinas/metabolismo , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Colitis/inducido químicamente , Sulfato de Dextran , Interleucina-10/biosíntesis , Interleucina-17/biosíntesis , Interleucina-4/biosíntesis , Interleucina-6/biosíntesis , Interleucinas/genética , Recuento de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Regiones Promotoras Genéticas , Isoformas de Proteínas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
IL-21 is a pleiotropic cytokine that regulates T-cell and B-cell differentiation, NK-cell activation, and dendritic cell functions. IL-21 activates the JAK-STAT, ERK, and PI3K pathways. We report here that Ape1/Ref-1 has an essential role in IL-21-induced cell growth signal transduction. Overexpression of Ape1/Ref-1 enhances IL-21-induced cell proliferation, but it is suppressed by overexpressing an N-terminal deletion mutant of Ape1/Ref-1 that lacks the redox domain. Furthermore, knockdown of the Ape1/Ref-1 mRNA dramatically compromises IL-21-induced ERK1/2 activation and cell proliferation with increasing cell death. These impaired activities are recovered by the re-expression of Ape1/Ref-1 in the knockdown cells. Our findings are the first demonstration that Ape1/Ref-1 is an indispensable molecule for the IL-21-mediated signal transduction through ERK1/2 activation.
Asunto(s)
ADN-(Sitio Apurínico o Apirimidínico) Liasa/metabolismo , Interleucinas/biosíntesis , Sistema de Señalización de MAP Quinasas/genética , Animales , Línea Celular , Proliferación Celular , Supervivencia Celular/genética , ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , Técnicas de Silenciamiento del Gen , Humanos , Interleucinas/genética , Ratones , Transducción de Señal/genéticaRESUMEN
Expression of the androgen receptor splice variant 7 (AR-V7) is frequently detected in castrate resistant prostate cancer and associated with resistance to AR-targeted therapies. While we have previously noted that homodimerization is required for the transcriptional activity of AR-V7 and that AR-V7 can also form heterodimers with the full-length AR (AR-FL), there are still many gaps of knowledge in AR-V7 stepwise activation. In the present study, we show that neither AR-V7 homodimerization nor AR-V7/AR-FL heterodimerization requires cofactors or DNA binding. AR-V7 can enter the nucleus as a monomer and drive a transcriptional program and DNA-damage repair as a homodimer. While forming a heterodimer with AR-FL to induce nuclear localization of unliganded AR-FL, AR-V7 does not need to interact with AR-FL to drive gene transcription or DNA-damage repair in prostate cancer cells that co-express AR-V7 and AR-FL. These data indicate that AR-V7 can function independently of its interaction with AR-FL in the true castrate state or "absence of ligand", providing support for the utility of targeting AR-V7 in improving outcomes of patients with castrate resistant prostate cancer.
Asunto(s)
Empalme Alternativo/genética , Neoplasias de la Próstata/genética , Isoformas de Proteínas/genética , Receptores Androgénicos/genética , Línea Celular Tumoral , Núcleo Celular/genética , Daño del ADN/genética , Reparación del ADN/genética , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Próstata/patología , Neoplasias de la Próstata/patologíaRESUMEN
OBJECTIVES: It is essential to understand the molecular basis of ovarian cancer etiology and tumor development to provide more effective preventive and therapeutic approaches to reduce mortality. Particularly, the molecular targets and pathways involved in early malignant transformation are still not clear. Pro-inflammatory lipids and pathways have been reported to play significant roles in ovarian cancer progression and metastasis. The major objective of this study was to explore and determine whether platelet activating factor (PAF) and receptor associated networking pathways might significantly induce malignant potential in BRCA1-mutant at-risk epithelial cells. METHODS: BRCA1-mutant ovarian epithelial cell lines including (HOSE-636, HOSE-642), BRCA1-mutant ovarian cancer cell (UWB1.289), wild type normal ovarian epithelial cell (HOSE-E6E7) and cancerous cell line (OVCA429), and the non-malignant BRCA1-mutant distal fallopian tube (fimbria) tissue specimens were used in this study. Mutation analysis, kinase microarray, western blot, immune staining, co-immune precipitation, cell cycle, apoptosis, proliferation and bioinformatic pathway analysis were applied. RESULTS: We found that PAF, as a potent pro-inflammatory mediator, induced significant anti-apoptotic effect in BRCA1-mutant ovarian surface epithelial cells, but not in wild type HOSE cells. With kinase microarray technology and the specific immune approaches, we found that phosphor-STAT1 was activated by 100 nM PAF treatment only in BRCA1-mutant associated at-risk ovarian epithelial cells and ovarian cancer cells, but not in BRCA1-wild type normal (HOSE-E6E7) or malignant (OVCA429) ovarian epithelial cells. Co-immune precipitation revealed that elevated PAFR expression is associated with protein-protein interactions of PAFR-FAK and FAK-STAT1 in BRCA1-mutant ovarian epithelial cells, but not in the wild-type control cells. CONCLUSION: Previous studies showed that potent inflammatory lipid mediators such as PAF and its receptor (PAFR) significantly contribute to cancer progression and metastasis. Our findings suggest that these potent inflammatory lipids and receptor pathways are significantly involved in the early malignant transformation through PAFR-FAK-STAT1 networking and to block apoptosis pathway in BRCA1 dysfunctional at-risk ovarian epithelium.
Asunto(s)
Transformación Celular Neoplásica/genética , Quinasa 1 de Adhesión Focal/fisiología , Redes Reguladoras de Genes/fisiología , Genes BRCA1 , Ovario/patología , Glicoproteínas de Membrana Plaquetaria/fisiología , Receptores Acoplados a Proteínas G/fisiología , Factor de Transcripción STAT1/fisiología , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patología , Transformación Celular Neoplásica/metabolismo , Epitelio/metabolismo , Epitelio/patología , Femenino , Quinasa 1 de Adhesión Focal/genética , Quinasa 1 de Adhesión Focal/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Genes BRCA1/fisiología , Humanos , Mutación/fisiología , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Ovario/metabolismo , Glicoproteínas de Membrana Plaquetaria/genética , Glicoproteínas de Membrana Plaquetaria/metabolismo , Lesiones Precancerosas/genética , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patología , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Riesgo , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismo , Células Tumorales CultivadasRESUMEN
OBJECTIVE: Complications frequently occur in patients with breast cancer after surgery. Anesthesia nursing plays an important role in decreasing complications for such patients. Thus, this study investigated the effects of anesthesia with intensive care nursing (AICN) on complication rates in patients with breast cancer after surgery. METHODS: Eighty-two patients with breast cancer were recruited in this study. Complications were compared between the anesthesia with usual nursing care (AUCN) and AICN groups. RESULTS: The results demonstrated that AICN decreased the rates of incision infection, drug extravasation, and catheter exposure, as well as pain and inflammation scores, compared with the findings in the AUCN group. AICN improved the time to orientation and decreased the incidence of nausea, anxiety, depression, and vomiting versus AUCN. In addition, AICN shortened the time to awakening after anesthesia compared with the effects of AUCN. Furthermore, AICN shortened hospital stay and increased survival rates. Notably, AICN improved health-related quality of life as measured using the EORTC QLQ-C30 questionnaire. CONCLUSION: AICN provided more benefits and better postoperative outcomes than AUCN, suggesting its utility for minimizing complications in patients with breast cancer after surgery.
Asunto(s)
Anestesia , Neoplasias de la Mama , Enfermería de Cuidados Críticos , Neoplasias de la Mama/cirugía , Humanos , Complicaciones Posoperatorias/prevención & control , Calidad de Vida , Resultado del TratamientoRESUMEN
BACKGROUND: The objective of this study is to evaluate the accuracy of radionuclide in diagnosis of bone metastasis (BM) after breast cancer surgery (BCS). METHODS: The electronic databases (Cochrane Library, MEDLINE, EMBASE, Web of Science, CBM, and CNKI) will be systematically and comprehensively searched until June 1, 2020 for eligible studies that reported the diagnosis of radionuclide in BM after BCS. In addition, we will also identify grey literatures, such as conference abstracts, and reference lists of included studies. All process of study identification, data extraction, and study methodological quality evaluation will be performed by 2 independent authors. All divergences will be settled by a third author through discussion. All data analysis will be carried out by RevMan 5.3 software (London, UK). RESULTS: This study will scrutinize the most recent evidence of radionuclide in detection of BM after BCS. CONCLUSION: This study may provide evidence of accuracy of radionuclide in diagnosis of BM following BCS. STUDY REGISTRATION NUMBER: PROSPERO CRD42020187646.
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Neoplasias Óseas/diagnóstico , Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Técnicas de Diagnóstico por Radioisótopo , Factores de Edad , Neoplasias de la Mama/cirugía , Errores Diagnósticos , Femenino , Humanos , Proyectos de Investigación , Sensibilidad y Especificidad , Factores SocioeconómicosRESUMEN
Increased expression of the full-length androgen receptor (AR-FL) and AR splice variants (AR-Vs) drives the progression of castration-resistant prostate cancer (CRPC). The levels of AR-FL and AR-V transcripts are often tightly correlated in individual CRPC samples, yet our understanding of how their expression is co-regulated is limited. Here, we report a role of c-Myc in accounting for coordinated AR-FL and AR-V expression. Analysis of gene-expression data from 159 metastatic CRPC samples and 2142 primary prostate tumors showed that the level of c-Myc is positively correlated with that of individual AR isoforms. A striking positive correlation also exists between the activity of the c-Myc pathway and the level of individual AR isoforms, between the level of c-Myc and the activity of the AR pathway, and between the activities of the two pathways. Moreover, the c-Myc signature is highly enriched in tumors expressing high levels of AR, as is the AR signature in c-Myc-high-expressing tumors. Using shRNA knockdown, we confirmed c-Myc regulation of expression and activity of AR-FL and AR-Vs in cell models and a patient-derived xenograft model. Mechanistically, c-Myc promotes the transcription of the AR gene and enhances the stability of the AR-FL and AR-V proteins without altering AR RNA splicing. Importantly, inhibiting c-Myc sensitizes enzalutamide-resistant cells to growth inhibition by enzalutamide. Overall, this study highlights a critical role of c-Myc in regulating the coordinated expression of AR-FL and AR-Vs that is commonly observed in CRPC and suggests the utility of targeting c-Myc as an adjuvant to AR-directed therapy.
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Adenocarcinoma/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Proteínas Proto-Oncogénicas c-myc/fisiología , Receptores Androgénicos/genética , Adenocarcinoma/patología , Empalme Alternativo/genética , Animales , Células Cultivadas , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Neoplasias de la Próstata Resistentes a la Castración/patología , Isoformas de Proteínas/genéticaRESUMEN
Deregulated expression of circular RNAs (circRNAs) is associated with various human diseases, including many types of cancer. Despite their growing links to cancer, there has been limited characterization of circRNAs in metastatic castration-resistant prostate cancer, the major cause of prostate cancer mortality. Here, through the analysis of an exome-capture RNA-seq dataset from 47 metastatic castration-resistant prostate cancer samples and ribodepletion and RNase R RNA-sequencing of patient-derived xenografts (PDXs) and cell models, we identified 13 circRNAs generated from the key prostate cancer driver gene-androgen receptor (AR). We validated and characterized the top four most abundant, clinically relevant AR circRNAs. Expression of these AR circRNAs was upregulated during castration-resistant progression of PDXs. The upregulation was not due to global increase of circRNA formation in these tumors. Instead, the levels of AR circRNAs correlated strongly with that of the linear AR transcripts (both AR and AR variants) in clinical samples and PDXs, indicating a transcriptional mechanism of regulation. In cultured cells, androgen suppressed the expression of these AR circRNAs and the linear AR transcripts, and the suppression was attenuated by an antiandrogen. Using nuclear/cytoplasmic fractionation and RNA in-situ hybridization assays, we demonstrated predominant cytoplasmic localization of these AR circRNAs, indicating likely cytoplasmic functions. Overall, this is the first comprehensive characterization of circRNAs arising from the AR gene. With greater resistance to exoribonuclease compared to the linear AR transcripts and detectability of AR circRNAs in patient plasma, these AR circRNAs may serve as surrogate circulating markers for AR/AR-variant expression and castration-resistant prostate cancer progression.
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Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , ARN Circular/genética , Receptores Androgénicos/genética , Animales , Humanos , Masculino , Ratones SCID , Isoformas de Proteínas , Receptores Androgénicos/clasificación , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This retrospective study assessed the effect of alendronate for treating patients with ankylosing spondylitis (AS).Eighty-six patients with AS were included in this retrospective study, and were divided into 2 groups. Forty-six patients in the intervention group received alendronate plus vitamin D (400âmg/day) and calcium (500âmg/day), while 40 patients in the control group received vitamin D and calcium only, the same dose as the intervention group. The primary outcome included bone densitometry. The secondary outcomes consisted of quality of life, measured by Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire, disease activity, measured by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and functional status, measured by Bath Ankylosing Spondylitis Functional Index (BASFI), as well as the adverse events (AEs).At the end of 6-month treatment, patients in the intervention group were not superior to the patients in the control group in bone densitometry (hip, Pâ=â.47; lumbar, Pâ=â.53), quality of life (Pâ=â.32), disease activity (Pâ=â.39), and functional status (Pâ=â.41). Moreover, no significant differences in AEs were found between 2 groups.The results of the present study showed that alendronate can neither be used to treat bone loss, nor to enhance the quality of life, disease activity, and functional status.
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Alendronato , Calcio , Espondilitis Anquilosante/tratamiento farmacológico , Vitamina D , Adulto , Alendronato/administración & dosificación , Alendronato/efectos adversos , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/efectos adversos , Calcio/administración & dosificación , Calcio/efectos adversos , Densitometría/métodos , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Gravedad del Paciente , Calidad de Vida , Estudios Retrospectivos , Espondilitis Anquilosante/diagnóstico , Espondilitis Anquilosante/fisiopatología , Espondilitis Anquilosante/psicología , Resultado del Tratamiento , Vitamina D/administración & dosificación , Vitamina D/efectos adversosRESUMEN
Triple negative breast cancer (TNBC) is a heterogeneous disease that has no available targeted therapies. Previously, we have shown that caloric restriction (CR) can augment the effects of radiation therapy in a TNBC mouse model. To build upon this, we now present data regarding the combination of chemotherapy and CR in the same 4T1 model. Chemotherapy can induce inflammation that breeds resistance to therapy. We propose CR as a mechanism to decrease chemotherapy-induced inflammation and increase efficacy of therapy. 12-week old Balb/c mice were orthotopically injected with a syngeneic triple negative breast cancer cell line (4T1) and were treated in one of six cohorts: ad lib fed (AL), 30% reduction in calorie intake (CR), cisplatin or docetaxol alone or a combination CR+cisplatin/docetaxol. Mice in the cohorts receiving chemotherapy+CR had longer overall survival (12 ± 2 days) as compared to the AL group. These mice also demonstrated less lung metastases at the final time point of in vivo imaging. In addition, downregulation of the IGF-1R and IRS signaling pathways were noted most significantly in those mice receiving combination therapy. Lastly, serum from these mice demonstrated an increase in inflammatory cytokines TNF-α and IL-1ß in response to chemotherapy alone. This increase was dampened by the addition of CR. Taken together, these data suggest that while chemotherapy is effective in TNBC, it can cause inflammation, which can be a driver of resistance to therapy. This chemotherapy-induced inflammation can be reversed with the use of CR as a nontoxic adjunct to treatment.
Asunto(s)
Antineoplásicos/efectos adversos , Restricción Calórica , Inflamación/inducido químicamente , Modelos Biológicos , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/terapia , Animales , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Femenino , Humanos , Inflamación/patología , Proteínas Sustrato del Receptor de Insulina/metabolismo , Ratones Endogámicos BALB C , Metástasis de la Neoplasia , Receptor IGF Tipo 1 , Receptores de Somatomedina/metabolismo , Transducción de SeñalRESUMEN
Pulmonary sclerosing hemangioma (PSH) is relatively rare and is usually considered a benign tumor because of its slow growth and solitary characteristics. However, several cases with lymph node metastasis have been reported, and its pathogenesis has not been fully elucidated. Three sets of PSH specimens from the Korea Lung Tissue Bank, obtained with IRB approval, were analyzed through the construction of an oligo-microarray that contained about 32,000 genes. The resulting data were confirmed by real-time RT-PCR. Protein expression levels were checked by performing immunohistochemistry (IHC) and immunoblot analysis. In the 3 specimens of PSH tissues, 72 of the 32,000 genes were commonly found up-regulated and 290 were commonly found down-regulated as compared to non-tumor tissues from each patient. Paraffin-embedded tissues from 11 cases were used to confirm the expression of matrix metalloproteinase 9 (MMP-9) and tubulin-alpha proteins in the non-tumor and PSH tissues via IHC. In addition, the upregulation of protein expression was confirmed by immunoblot analysis. As expected, in all cases MMP-9 and tubulin-alpha were expressed at significantly higher levels in the PSH than in the non-tumor tissues. This is the first report on a study of the whole genome of PSH. Increased expression of MMP-9 could induce the metastatic ability of PSH and tubulin-alpha might be responsible for the sclerotic character of this disease. The results of this study will be useful in helping to understand and effectively manage patients suffering from PSH.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Perfilación de la Expresión Génica , Metaloproteinasa 9 de la Matriz/metabolismo , Hemangioma Esclerosante Pulmonar/enzimología , Tubulina (Proteína)/metabolismo , Anciano , Biomarcadores de Tumor/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Masculino , Metaloproteinasa 9 de la Matriz/genética , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Hemangioma Esclerosante Pulmonar/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Matrices Tisulares , Tubulina (Proteína)/genéticaRESUMEN
BACKGROUND: To assess the effect of botulinum toxin A (BTA) for treating neuropathic pain in patients with spinal cord injury (SCI). METHODS: A total of 44 patients with SCI with neuropathic pain were randomly divided into the intervention group and the placebo group, each group 21 patients. The subjects in the intervention group received BTA (200 U subcutaneous injection, once daily) at the painful area, whereas those in the placebo group were administered a saline placebo. This study was conducted from December 2014 to November 2016. The primary outcome was measured using the visual analog scale (VAS). The secondary outcomes were measured using the short-form McGill Pain Questionnaire (SF-MPQ), and World Health Organization quality of life (WHOQOL-BREF) questionnaire. All outcome measurements were performed before and after 4 and 8 weeks of intervention. RESULTS: Forty-one participants completed the study. The intervention with BTA showed greater efficacy than placebo in decreasing the VAS score after week 4 and week 8 of treatment. Significant differences in the SF-MPQ and WHOQOL-BREF were also found between the 2 groups. CONCLUSION: The results of this study demonstrated that BTA might decrease intractable neuropathic pain for patients with SCI.
Asunto(s)
Analgésicos/administración & dosificación , Toxinas Botulínicas Tipo A/administración & dosificación , Neuralgia/tratamiento farmacológico , Neuralgia/etiología , Traumatismos de la Médula Espinal/complicaciones , Método Doble Ciego , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Neuralgia/fisiopatología , Fármacos Neuromusculares/administración & dosificación , Dimensión del Dolor , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/fisiopatología , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
BACKGROUND: This study aimed to assess the efficacy and safety of remifentanil as a general anesthetic during cesarean delivery. MATERIAL AND METHODS: Fifty women with singleton pregnancies undergoing cesarean delivery were randomly divided into intervention and control groups, each group containing 25 subjects. Participants in the intervention group received remifentanil (infused at 2âµg/kg/h), whereas subjects in the control group were given dexmedetomidine (infused at 0.4âµg/kg/h). Outcome measurements included mean arterial blood pressure (MAP), heart rate (HR), bispectral index (BIS), Apgar scores at 1 and 5âminutes, and the pH, PCO2, PO2, and base excess (BE) of umbilical venous and arterial blood. RESULTS: Forty-four participants completed the study. Patients in the intervention group did not experience greater effect and safety than those in the control group (Pâ>â.05), although MAP and BIS values decreased significantly immediately before laryngoscopy (Pâ<â.05). In addition, BIS values were reduced significantly at the time of skin incision, at uterine incision, and immediately after fetal delivery when compared with baseline values in both groups (Pâ<â.01). CONCLUSION: This study concluded that remifentanil and dexmedetomidine exhibited similar efficacy and safety during general anesthesia for cesarean delivery.