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1.
J Cell Mol Med ; 23(10): 6578-6594, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31449345

RESUMO

Quaking homolog (QKI) is a member of the RNA-binding signal transduction and activator of proteins family. Previous studies showed that QKI possesses the tumour suppressor activity in human cancers by interacting with the 3'-untraslated region (3'-UTR) of various gene transcripts via the STAR domain. This study first assessed the association of QKI-6 expression with clinicopathological and survival data from bladder cancer patients and then investigated the underlying molecular mechanisms. Bladder cancer tissues (n = 223) were subjected to immunohistochemistry, and tumour cell lines and nude mice were used for different in vitro and in vivo assays following QKI-6 overexpression or knockdown. QKI-6 down-regulation was associated with advanced tumour TNM stages and poor patient overall survival. QKI-6 overexpression inhibited bladder cancer cell growth and invasion capacity, but induced tumour cell apoptosis and cell cycle arrest. Furthermore, ectopic expression of QKI-6 reduced tumour xenograft growth and expression of proliferation markers, Ki67 and PCNA. However, knockdown of QKI-6 expression had opposite effects in vitro and in vivo. QKI-6 inhibited expression of E2 transcription factor 3 (E2F3) by directly binding to the E2F3 3'-UTR, whereas E2F3 induced QKI-6 transcription by binding to the QKI-6 promoter in negative feedback mechanism. QKI-6 expression also suppressed activity and expression of nuclear factor-κB (NF-κB) signalling proteins in vitro, implying a novel multilevel regulatory network downstream of QKI-6. In conclusion, QKI-6 down-regulation contributes to bladder cancer development and progression.


Assuntos
Fator de Transcrição E2F3/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , NF-kappa B/metabolismo , Proteínas de Ligação a RNA/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Regiões 3' não Traduzidas , Animais , Apoptose/genética , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo , Fator de Transcrição E2F3/genética , Feminino , Humanos , Antígeno Ki-67/metabolismo , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , NF-kappa B/antagonistas & inibidores , Estadiamento de Neoplasias , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas de Ligação a RNA/genética , Transdução de Sinais/genética , Transplante Heterólogo , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia
2.
Prostate ; 77(7): 708-717, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28168722

RESUMO

BACKGROUND: Complications after a thulium laser resection of the prostate (TmLRP) are related to re-epithelialization of the prostatic urethra. Since prostate growth and development are induced by androgen, the aim of this study was to determine the role and explore the mechanism of androgen in wound healing of the prostatic urethra. METHODS: Beagles that received TmLRPs were randomly distributed into a castration group, a testosterone undecanoate (TU) group, and a control group. The prostate wound was assessed once a week using a cystoscope. Histological analysis was then carried out to study the re-epithelialization of the prostatic urethra in each group. The inflammatory response in the wound tissue and urine was also investigated. RESULTS: The healing of the prostatic urethra after a TmLRP was more rapid in the castration group and slower in the TU group than that in the control group. Castration accelerated re-epithelialization by promoting basal cell proliferation in the wound surface and beneath the wound and by accelerating the differentiation of basal cells into urothelial cells. Castration reduced the duration of the inflammatory phase and induced the conversion of M1 macrophages to M2 macrophages, thus accelerating the maturation of the wound. By contrast, androgen supplementation enhanced the inflammatory response and prolonged the inflammatory phase. Moreover, the anti-inflammatory phase was delayed and weakened. CONCLUSION: Androgen deprivation promotes re-epithelialization of the wound, regulates the inflammatory response, and accelerates wound healing of the prostatic urethra after a TmLRP. Prostate 77:708-717, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Androgênios , Complicações Intraoperatórias , Próstata , Testosterona/análogos & derivados , Ressecção Transuretral da Próstata/efeitos adversos , Uretra , Androgênios/administração & dosagem , Androgênios/efeitos adversos , Androgênios/metabolismo , Animais , Modelos Animais de Doenças , Cães , Complicações Intraoperatórias/metabolismo , Complicações Intraoperatórias/fisiopatologia , Complicações Intraoperatórias/terapia , Macrófagos/patologia , Macrófagos/fisiologia , Masculino , Próstata/patologia , Próstata/cirurgia , Reepitelização/efeitos dos fármacos , Reepitelização/fisiologia , Estatística como Assunto , Testosterona/administração & dosagem , Testosterona/efeitos adversos , Testosterona/metabolismo , Túlio/farmacologia , Ressecção Transuretral da Próstata/métodos , Uretra/lesões , Uretra/patologia , Cicatrização/efeitos dos fármacos , Cicatrização/fisiologia
3.
Biochem Biophys Res Commun ; 470(3): 721-727, 2016 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-26797523

RESUMO

Long non-coding RNAs (lncRNAs) are emerging as key molecules in human cancer genesis and progression, including prostate cancer. Large amount of lncRNAs have been found that differentially expressed between prostate cancer tissues and normal prostate tissues. Whether these lncRNAs could serve as a novel biomarker for prostate cancer diagnosis or prognosis, and their biological functions in prostate cancer need further investigation. In the present study, we identified that lncRNA lnc-MX1-1 is over-expressed in prostate cancer tissues compared with their adjacent normal prostate tissues by gene expression array profiling. The expression of lnc-MX1-1 in 60 prostate cancer cases was determined by real-time quantitative PCR and the correlations between lnc-MX1-1 expression and patients' clinical features were further analyzed. Next, we impaired lnc-MX1-1 expression using RNAi in LNCaP and 22Rv1 prostate cancer cells to explore the effects of lnc-MX1-1 on proliferation and invasiveness of the cells. Our results showed that there was a significant association between over-expression of lnc-MX1-1 and patients' clinical features such as PSA, Gleason score, metastasis, and recurrence free survival. Moreover, knockdown of lnc-MX1-1 reduced both proliferation and invasiveness of LNCaP and 22Rv1 cells. In conclusion, the results suggest that lnc-MX1-1 may serve as a potential biomarker and therapeutic target for prostate cancer.


Assuntos
Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Longo não Codificante/metabolismo , Proliferação de Células , Humanos , Masculino , Invasividade Neoplásica , Regulação para Cima
4.
Toxicology ; 406-407: 114-122, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30053495

RESUMO

Maternal exposure to di-n-butyl phthalate (DBP) induces hypospadias, but the underlying mechanisms remain elusive. Here we hypothesize that aberrant activation of autophagy and epithelial-mesenchymal transition (EMT) are the leading cause of DBP-related hypospadias. Pregnant rats received DBP orally at a dose of 750 mg/kg/day during gestational days 14-18. In DBP-induced hypospadiac male offspring, immunohistochemistry (IHC) staining and Western blot showed increased expression of autophagy and EMT markers in genital tubercle (GT) tissue compared to the control. In addition, lower testosterone levels and androgen receptor (AR) expression in GT tissue were detected. In vitro studies revealed that impaired AR signaling was involved in DBP-induced autophagy and autophagy activation furthermore promoted EMT in urethral epithelial cells. DBP combined with chloroquine, an autophagy inhibitor, reduced the expression of EMT markers compared with DBP treatment alone, while DBP combined with the autophagy inducer rapamycin elevated the expression of EMT markers. The autophagy-lysosomal pathway inhibitor CQ but not proteasome inhibitor MG-132 rescued the decrease of E-cadherin after DBP treatment, which indicated autophagy-induced E-cadherin degradation contributes to DBP-related EMT. Taken together, our findings show that prenatal exposure to DBP induces abnormal autophagy and EMT that may play important roles in hypospadias development.


Assuntos
Autofagia/efeitos dos fármacos , Dibutilftalato/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Plastificantes/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Urotélio/efeitos dos fármacos , Animais , Autofagia/fisiologia , Células Cultivadas , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Hipospadia/induzido quimicamente , Hipospadia/metabolismo , Hipospadia/patologia , Masculino , Exposição Materna/efeitos adversos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Sprague-Dawley , Urotélio/metabolismo , Urotélio/patologia
5.
Cell Death Dis ; 9(4): 431, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29568063

RESUMO

The activation of androgen receptor (AR) signaling plays an essential role in both prostate stromal cells and epithelial cells during the development of benign prostatic hyperplasia (BPH). Here we demonstrated that androgen ablation after 5α-reductase inhibitor (5-ARI) treatment induced autophagy in prostate stromal fibroblasts inhibiting cell apoptosis. In addition, we found that ATG9A expression was increased after androgen ablation, which facilitated autophagic flux development. Knockdown of ATG9A not only inhibited autophagy notably in prostate stromal fibroblasts, but also reduced the volumes of prostate stromal fibroblast and epithelial cell recombinant grafts in nude mice. In conclusion, our findings suggested that ATG9A upregulation after long-term 5-ARI treatment constitutes a possible mechanism of BPH progression. Thus, combined treatment with 5-ARI and autophagy inhibitory agents would reduce the risk of BPH progression.


Assuntos
Proteínas Relacionadas à Autofagia/metabolismo , Autofagia , Proteínas de Membrana/metabolismo , Hiperplasia Prostática/patologia , Transdução de Sinais , Proteínas de Transporte Vesicular/metabolismo , Inibidores de 5-alfa Redutase/farmacologia , Animais , Autofagia/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/antagonistas & inibidores , Proteínas Relacionadas à Autofagia/genética , Células Cultivadas , Progressão da Doença , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Camundongos , Camundongos Nus , Proteínas Associadas aos Microtúbulos/metabolismo , Próstata/citologia , Hiperplasia Prostática/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima , Proteínas de Transporte Vesicular/antagonistas & inibidores , Proteínas de Transporte Vesicular/genética
6.
Oncotarget ; 8(19): 31101-31111, 2017 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-28415704

RESUMO

This study was to determine the impact of maternal exposure to di-n-butyl phthalate (DBP) on renal development and fibrosis in adult offspring. Pregnant rats received DBP at a dose of 850 mg/kg BW/day by oral perfusion during gestational days 14-18. In DBP exposed newborn offspring, gross observation and histopathological examination revealed the dysplasia of kidney. The expression of genes related to renal development was also changed. In DBP exposed adult offspring, histopathological examination and Masson's trichrome staining revealed the pathological changes of renal fibrosis. Furthermore, higher expression levels of transforming growth factor- ß (TGF-ß) and alpha-smooth muscle actin (α-SMA) were also detected. In vitro studies reveal that DBP promoted the activation of NRK49F cells and G2/M arrest in NRK52E cells at a sublethal dose. The effect of DBP on these cell lines was linked to the generation of oxidative stress. In addition, DBP induced oxidative stress in both renal fibroblasts and tubular epithelial cells, whereas vitamin C ameliorated the changes caused by DBP. In conclusion, our results showed that prenatal exposure to DBP may generate oxidative stress in both renal fibroblasts and tubular epithelial cells, leading to kidney dysplasia and renal fibrosis.


Assuntos
Dibutilftalato/efeitos adversos , Disruptores Endócrinos/efeitos adversos , Nefropatias/etiologia , Nefropatias/patologia , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal , Animais , Apoptose/efeitos dos fármacos , Ácido Ascórbico/farmacologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Fibrose , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Nefropatias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Ratos , Fator de Crescimento Transformador beta/biossíntese
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