RESUMO
BACKGROUND: Proteasome 26S subunit, non-ATPase 7 (PSMD7) is a deubiquitinating enzyme that is involved in the stability of ubiquitinated proteins and participates in the development of multiple types of cancer. The roles of PSMD7 and its potential mechanisms in bladder cancer (BC) remain elusive. METHODS: In this study, we identified that PSMD7 was overexpressed in BC tissues based on gene expression omnibus (GEO) database and TNMplot web. To investigate the functional role of PSMD7, two BC cell lines, T24 and 5637, were selected. The cells were transfected with vectors containing short hairpin RNAs against PSMD7 or plasmids containing full-length PSMD7 to knockdown or overexpress PSMD7. RESULTS: Our results revealed that silencing PSMD7 inhibited cell proliferation, cycle progression, migration, invasion, and promoted cell apoptosis, whereas PSMD7 overexpression led to the opposite effects in the BC cells. Mechanically, PSMD7 influenced the protein expression but not the mRNA expression of the Ras-related protein Rab-1 A (RAB1A). PSMD7 combined with RAB1A and negatively regulated its ubiquitination, indicating that PSMD7 enhanced the stability of RAB1A through post-transcriptional modification. Moreover, the rescue experiment demonstrated that RAB1A was an important downstream effector molecule of PSMD7. Besides, the negative regulation of silencing PSMD7 on tumor growth was confirmed in mice. CONCLUSIONS: Our study substantiated a novel mechanism by which PSMD7 stabilized RAB1A to accelerate the progression of BC.
Assuntos
MicroRNAs , Neoplasias da Bexiga Urinária , Animais , Camundongos , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Enzimas Desubiquitinantes/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Interferente Pequeno , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , HumanosRESUMO
The thymus regulates a specific microenvironment for the growth and maturation of naive T cells. Involution of immune function was an important factor during body aging. Preventing the senescence of immune organs has become a major medical issue. Resveratrol (RSV) has been proved to delay the aging of many organs including the thymus. However, the underlying mechanism remains indefinite and the dosages of RSV on thymus involution need to be further clarified. In the current study, the senescence-accelerated mice were produced using d-galactose for two months. RSV at different dosages (25, 50, 100 mg kg-1 day-1 ) was then administered. The alteration of the thymic morphological structure was observed. It showed that three dosages of RSV significantly decreased cellular senescence of the thymus and no dosage difference was detected. For cellular proliferation and apoptosis of the thymus, 50 and 25 mg/kg per day of RSV displayed the best effects on cellular proliferation and apoptosis in the thymus, respectively. Furthermore, 50 mg/kg per day of RSV increased the expression of FoxN1 both at transcription and translation levels. These findings indicated that RSV could delay thymus atrophy in a dosage-dependent pattern and FoxN1 might involve in the beneficial mechanism of RSV, which was of great significance for the enhancement of thymic health and organic immunity. PRACTICAL APPLICATIONS: Resveratrol has been proved to delay aging of many organs including of thymus. In the present study, we explored the dosage of resveratrol on thymus involution and the expression of transcription factors forkhead box protein N1 (FoxN1) in the senescenceaccelerated mice induced by D-galactose. The results indicated that resveratrol could delay thymus atrophy in a dosage-dependent pattern within a certain dose range, and higher RSV concentration may have drug toxicity, which suggests that the dosage of RSV requires attention, And FoxN1 might involve in the beneficial mechanism of resveratrol supplement, which was of great significance to explore the mechanism for the enhancement of thymus immunity.
Assuntos
Fatores de Transcrição Forkhead , Galactose , Animais , Senescência Celular , Fatores de Transcrição Forkhead/genética , Camundongos , Resveratrol/farmacologia , Linfócitos TRESUMO
Senescence-related decline of thymus affects immune function in the elderly population and contributes to the prevalence of many relevant diseases like cancer, autoimmune diseases, and other chronic diseases. In this study, we investigated the therapeutic effects of curcumin, an agent that could counter aging, and explored its optimal intake and the alteration of autoimmune regulator (Aire) after curcumin treatment in the D-galactose (D-gal)-induced accelerated aging mice. ICR mice were intraperitoneally injected with D-gal for 8 weeks to establish the accelerated aging model and given curcumin with 50, 100, and 200 mg/kg body weight per day by gavage, respectively, for 6 weeks. It indicated that the D-gal-treated mice developed structural changes in the thymi compared with the control group without D-gal and curcumin treatment. As the supplements of curcumin, it resulted in a restoration of the normal thymic anatomy with an increase of proliferating cells and a reduction of apoptotic cells in the thymi of the D-gal-induced aging model mice. Curcumin administration could also expand the expression level of Aire from mRNA level and protein level. The current study demonstrated that curcumin could ameliorate senescence-related thymus involution via upregulating Aire expression, suggesting that curcumin can rejuvenate senescence-associated alterations of thymus induced by D-gal accumulation.
Assuntos
Senescência Celular/efeitos dos fármacos , Curcumina/farmacologia , Substâncias Protetoras/farmacologia , Timo/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Galactose , Camundongos Endogâmicos ICR , Timo/metabolismo , Fatores de Transcrição/genética , Proteína AIRERESUMO
Senescence is an inevitable and complicated phenomenon. Age-associated thymic involution increases the risk of infectious diseases, which results in the immunosenescence and leads to a poor immune function. d-galactose (d-gal) can cause damages that resemble accelerated aging in mice. Gallic acid (GA), as one of the natural phenolic compounds, has been demonstrated to act in antioxidant and anti-tumor effects. In this study, we explored the effects of GA in preventing the age-related thymic involution and the alterations of the forkhead box protein N1 (FoxN1) in d-gal induced accelerated aging mice. The accelerated aging mice model was established by intraperitoneal injection d-gal for eight weeks and given GA with 200, 250, 500 mg/kg body weight per day, respectively, for six weeks. It showed that the d-gal-treated mice developed structural changes in the thymi compared to normal control mice. With supplement of GA, the mice restored the normal thymic anatomy, including the thickening cortex compartment and clearer cortico-medullary junction. The d-gal-treated mice showed a severe reduction in the number of thymocytes, GA mice also displayed the increased numbers of CD4 + T cells through flow cytometric analysis. GA treatment increased the proliferative cells by BrdU incorporation assay and reduced the numbers of apoptotic cells with FITC-12-dUTP labeling (TUNEL). The expression of FoxN1 was also found increased in GA treated mice by immunohistochemistry and quantitative reverse transcriptase PCR (qRT-PCR). Taken together, our results suggested that the administration of GA opposed the involution of thymus via stimulation of FoxN1 expression and proliferation of cells in a dose-dependent manner.