RESUMO
BACKGROUND: Previous studies reported significant differences in the clinical presentation and outcomes of papillary thyroid carcinoma (PTC) in pediatric patients compared with adults. Previous studies have suggested that the clinicopathological differences observed between pediatric and adult PTCs may be due the existence of distinct genetic alterations. However, the knowledge of genetic events in pediatric PTCs is based primarily on studies in radiation-exposed PTCs or in the few studies that enrolled predominantly adolescent patients. The aim of this study was to characterize the known oncogenic alterations of the MAPK pathway found in adult and radiation-exposed PTCs in a cohort of predominantly sporadic pediatric PTC patients. METHODS: Thirty-five pediatric PTCs were screened for the most prevalent fusions (RET/PTC1, RET/PTC2, RET/PTC3, ETV6-NTRK3, and AGK-BRAF) and point mutations (BRAFV600E and NRASQ61) described in sporadic pediatric PTCs. The mutational status was correlated with clinicopathological data. RESULTS: Mutations were found in 20 out of 35 (57%) PTC cases. Fusion oncogenes were the main genetic alterations found. RET/PTC1-3 rearrangements were found in 13 (37%), ETV6-NTRK3 in 3 (9%), AGK-BRAF in 4 (11%), and BRAFV600E in 3 (9%). No mutation was found in NRASQ61. BRAFV600E was associated with older age and larger tumor size (p < 0.05), and RET/PTC3 was associated with a larger tumor size and multifocality (p < 0.05). CONCLUSIONS: The genetic signature in this cohort was remarkably different than that observed in adults. Although observed at a lower prevalence, the spectrum of mutations was quite similar to that described in radiation-exposed pediatric PTCs. As mutations were unidentifiable in over 40% of the PTC cases, more comprehensive studies conducted in these patients will help to decipher the genetic landscape of sporadic pediatric PTCs.
Assuntos
Carcinoma Papilar/genética , Fusão Oncogênica/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , GTP Fosfo-Hidrolases/genética , Humanos , Masculino , Proteínas de Membrana/genética , Coativadores de Receptor Nuclear/genética , Receptor Patched-1/genética , Receptor Patched-2/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Mutação Puntual , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ret/genética , Receptor trkC/genética , Proteínas Repressoras/genética , Câncer Papilífero da Tireoide , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
Dear Editor, A recent paper (Casseb et al., 2016) published in the journal Genetics and Molecular Research described the interesting concept that dengue virus (DENV)-4 infection, in the human cell line A-549, leads to the downregulation of expression of key components of microRNA (miRNA) biogenesis, such as Drosha, Dicer, and DGCR8. For this, the authors performed a time course infection of A-549 cells for 5 days. The highest viral load was observed at 3 days post-infection, which corresponded with the maximum downregulation of expression of Drosha, Dicer, and DGCR8, assayed by quantitative PCR (RT-qPCR). These results supported the recent notion of a complex interaction between DENV and the host miRNA machinery and of the host miRNA response to this particular infection. Extensive evidence has shown that DENV can take advantage of host miRNAs for its own replication (Zhu et al., 2014) and that host miRNAs can inhibit DENV replication (Wu et al., 2013).
Assuntos
Vírus da Dengue/fisiologia , Coativadores de Receptor Nuclear/genética , Ribonuclease III/genética , Regiões 3' não Traduzidas , Animais , Chlorocebus aethiops , Regulação para Baixo , Expressão Gênica , Regulação Viral da Expressão Gênica , Humanos , Coativadores de Receptor Nuclear/metabolismo , Ribonuclease III/metabolismo , Células VeroRESUMO
Here we assessed the effects of perinatal exposure to bisphenol A (BPA) on the uterine response to 17ß-estradiol (E2) in aged rats. Pregnant rats were orally exposed to 0.5 or 50 µg BPA/kg/day from gestational day 9 until weaning. On postnatal day (PND) 360, the rats were ovariectomized and treated with E2 for three months. The uterine tissue of BPA50 and BPA0.5 rats showed increased density of glands with squamous metaplasia (GSM) and glands with daughter glands respectively. Wnt7a expression was lower in GSM of BPA50 rats than in controls. The expression of estrogen receptor 1 (ESR1) and its 5'- untranslated exons ESR1-O and ESR1-OT was lower in BPA50 rats. Both doses of BPA modified the expression of coactivator proteins and epigenetic regulatory enzymes. Thus, perinatal BPA-exposed rats showed different glandular abnormalities associated with deregulated expression of E2-target genes. Different mechanisms would be involved depending on the BPA dose administered.
Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Estradiol/farmacologia , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Coativadores de Receptor Nuclear/genética , Coativadores de Receptor Nuclear/metabolismo , Especificidade de Órgãos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos Wistar , Testículo/metabolismo , Útero/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismoRESUMO
The present study describes the role of the ubiquitin ligase Siah-2 and corepressor N-CoR in controlling androgen receptor (AR) and estrogen receptors (ERα and ERß) signaling in an appropriate animal model (Fischer 344 female rats) of non-muscle invasive bladder cancer (NMIBC), especially under conditions of anti-androgen therapy with flutamide. Furthermore, this study describes the mechanisms of a promising therapeutic alternative for NMIBC based on Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) intravesical immunotherapy combined with flutamide, involving the interaction among steroid hormone receptors, their regulators and Toll-like receptors (TLRs). Our results demonstrated that increased Siah-2 and AR protein levels and decreased N-CoR, cytochrome P450 (CYP450) and estrogen receptors levels played a critical role in the urothelial carcinogenesis, probably leading to escape of urothelial cancer cells from immune system attack. P-MAPA immunotherapy led to distinct activation of innate immune system TLRs 2 and 4-mediated, resulting in increase of interferon signaling pathway, which was more effective in recovering the immunosuppressive tumor immune microenvironment and in recovering the bladder histology features than BCG (Bacillus Calmette-Guerin) treatments. The AR blockade therapy was important in the modulating of downstream molecules of TLR2 and TLR4 signaling pathway, decreasing the inflammatory cytokines signaling and enhancing the interferon signaling pathway when associated with P-MAPA. Taken together, the data obtained suggest that interferon signaling pathway activation and targeting AR and Siah-2 signals by P-MAPA intravesical immunotherapy alone and/ or in combination with AR blockade may provide novel therapeutic approaches for NMIBC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Imunoterapia/métodos , Neoplasias da Bexiga Urinária/patologia , Administração Intravesical , Antagonistas de Androgênios/administração & dosagem , Animais , Western Blotting , Modelos Animais de Doenças , Feminino , Flutamida/administração & dosagem , Ácidos Linoleicos/administração & dosagem , Coativadores de Receptor Nuclear/metabolismo , Compostos Organofosforados/administração & dosagem , Ratos , Ratos Endogâmicos F344 , Receptores Androgênicos/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
RAC3 is an oncogene naturally overexpressed in several tumors. Besides its role as coactivator, it can exert several protumoral cytoplasmic actions. Autophagy was found to act either as a tumor suppressor during the early stages of tumor development, or as a protector of the tumor cell in later stages under hypoxic conditions. We found that RAC3 overexpression inhibits autophagy when induced by starvation or rapamycin and involves RAC3 nuclear translocation-dependent and -independent mechanisms. Moreover, hypoxia inhibits the RAC3 gene expression leading to the autophagy process, allowing tumor cells to survive until angiogenesis occurs. The interplay between RAC3, hypoxia, and autophagy could be an important mechanism for tumor progression and a good target for a future anticancer therapy.
Assuntos
Autofagia , Proteínas rac de Ligação ao GTP/metabolismo , Hipóxia Celular , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Expressão Gênica , Genes Supressores de Tumor , Células HEK293 , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Neoplasias/genética , Coativadores de Receptor Nuclear/genética , Coativadores de Receptor Nuclear/metabolismo , Proteínas rac de Ligação ao GTP/genéticaRESUMO
BACKGROUND: Papillary thyroid carcinoma (PTC) is frequently associated with a RET gene rearrangement that generates a RET/PTC oncogene. RET/PTC is a fusion of the tyrosine kinase domain of RET to the 5' portion of a different gene. This fusion results in a constitutively active MAPK pathway, which plays a key role in PTC development. The RET/PTC3 fusion is primarily associated with radiation-related PTC. Epidemiological studies show a lower incidence of PTC in radiation-exposed regions that are associated with an iodine-rich diet. Since the influence of excess iodine on the development of thyroid cancer is still unclear, the aim of this study is to evaluate the effect of high iodine concentrations on RET/PTC3-activated thyroid cells. METHODS: PTC3-5 cells, a rat thyroid cell lineage harboring doxycycline-inducible RET/PTC3, were treated with 10(-3) M NaI. Cell growth was analyzed by cell counting and the MTT assay. The expression and phosphorylation state of MAPK pathway-related (Braf, Erk, pErk, and pRet) and thyroid-specific (natrium-iodide symporter [Nis] and thyroid-stimulating hormone receptor [Tshr]) proteins were analyzed by Western blotting. Thyroid-specific gene expression was further analyzed by quantitative reverse transcription (RT)-polymerase chain reaction. RESULTS: A significant inhibition of proliferation was observed, along with no significant variation in cell death rate, in the iodine-treated cells. Further, iodine treatment attenuated the loss of Nis and Tshr gene and protein expression induced by RET/PTC3 oncogene induction. Finally, iodine treatment reduced Ret and Erk phosphorylation, without altering Braf and Erk expression. CONCLUSION: Our results indicate an antioncogenic role for excess iodine during thyroid oncogenic activation. These findings contribute to a better understanding of the effect of iodine on thyroid follicular cells, particularly how it may play a protective role during RET/PTC3 oncogene activation.
Assuntos
Iodo/administração & dosagem , Coativadores de Receptor Nuclear/genética , Fusão Oncogênica/efeitos dos fármacos , Oncogenes/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-ret/genética , Glândula Tireoide/efeitos dos fármacos , Análise de Variância , Animais , Western Blotting , Contagem de Células , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Coativadores de Receptor Nuclear/metabolismo , Fusão Oncogênica/genética , Oncogenes/genética , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Isoformas de Proteínas/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Glândula Tireoide/citologia , Glândula Tireoide/metabolismo , Fatores de TempoRESUMO
OBJECTIVE: To study if the endocrinological status of PCOS women affects the endometrial sensitivity to steroids by evaluating the expression of androgen receptor (AR), estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), co-activators AIB1 and ARA70, and co-repressor NCoR. METHODS: Gene and/or protein expression of steroid receptors and co-regulators was measured in 17 samples of normal endometrium (NE), 23 PCOS endometrium without treatment (PCOSE), 11 endometria from PCOS women and with endometrial hyperplasia (HPCOSE), and 10 endometria from patients with endometrial hyperplasia (HE), using RT-PCR and/or immunohistochemistry and Western blot. RESULTS: Gene and protein expression of AR was relatively elevated in PCOSE and HPCOSE compared with NE. A significant increase in ERalpha protein expression was observed in PCOSE, preferentially in the nucleus of endometrial cells, whereas ERbeta gene and protein expression increased gradually from PCOSE to HPCOSE and HE, mainly in the epithelial compartment. Importantly, we found a gradual increase in the ERbeta/ERalpha gene and protein expression ratio in endometria from the four groups of women. AIB1 showed increased nuclear protein expression in PCOSE compared to NE, in the presence of a high expression of ARA70 in all groups. High expression of ARA70 together with a normal expression level of AIB1 was observed in HPCOSE. The cytoplasmic immunostaining of NCoR was similar between the four groups of patients. CONCLUSION: The PCOS endometrium exhibits a higher sensitivity to steroid action. We can inferred that these alterations could deregulate the transcription of genes involved in the cell cycle, which may lead to the development of endometrial hyperplasia in PCOS women.