Despite SGK1 has been identified and characterized as a tumor-promoting gene, the functions and underlying mechanisms of SGK1 involved in metastasis regulation have not yet been investigated in ...cancer.
We investigated the cellular responses to GSK650394 treatment and SGK1 silencing (or overexpression) in human prostate cancer (PCa) cell lines and PC3 xenografts by wound healing assay, migration and invasion assay, western blotting, immunofluorescence and immunohistochemistry.
In the present study, we found that SGK1 expression positively correlates with human prostate cancer (PCa) progression and metastasis. We show that SGK1 inhibition significantly attenuates EMT and metastasis both in vitro and in vivo, whereas overexpression of SGK1 dramaticlly promoted the invasion and migration of PCa cells. Our further results suggest that SGK1 inhibition induced antimetastatic effects, at least partially via autophagy-mediated repression of EMT through the downregulation of Snail. Moreover, ectopic expression of SGK1 obviously attenuated the GSK650394-induced autophagy and antimetastatic effects. What's more, dual inhibition of mTOR and SGK1 enhances autophagy and leads to synergistic antimetastatic effects on PCa cells.
Taken together, this study unveils a novel mechanism in which SGK1 functions as a tumor metastasis-promoting gene and highlights how co-targeting SGK1 and autophagy restrains cancer progression due to the amplified antimetastatic effects.
Aims: The red blood cell distribution width-to-platelet ratio (RPR) has been reported to be an indicator of hepatic fibrosis in patients with chronic hepatitis B (HBV), nonalcoholic fatty liver ...disease (NAFLD) or chronic hepatitis C (HCV). However, no research has explored the RPR in all patients with hepatic fibrosis. There is a recognized need to establish whether the RPR could assess hepatic fibrosis and reflect the severity of fibrosis, regardless of the patient's etiology.
Methods: Quantitative data from 1282 patients who underwent liver biopsy between January 2010 and December 2014 at the Second Affiliated Hospital of Zhejiang University School of Medicine were included. The etiologies included HBV or HCV infection, NAFLD, schistosomiasis, granulomatous liver disease, and vascular abnormalities. Five noninvasive models were calculated for all patients based on laboratory parameters. The degrees of fibrosis severity were evaluated based on the Metavir scoring scale.
Results: The RPR demonstrated the best accuracy of predicting hepatic fibrosis among the selected five models (0.75, p < .001) regardless of etiology. In addition, the RPR values increased with advanced hepatic fibrosis progression. Furthermore, combining the RPR with the white blood cell (WBC) count improved the accuracy of grading hepatic fibrosis as reflected by the likelihood ratio (LR + 9.03, LR − 0.49).
Conclusion: The RPR is a useful indicator for hepatic fibrosis, regardless of etiology, and can reflect the severity of fibrosis. This study supports further clinical development of the RPR both in a stepwise manner or in combination with inflammatory parameters to improve the accuracy of scoring hepatic fibrosis.
In the progression of castration-resistant prostate cancer (CRPC), the androgen receptor (AR) that serves as a transcription factor becomes the most remarkable molecule. The transcriptional activity ...of AR is regulated by various coregulators. As a result, altered expression levels, an aberrant location or activities of coregulators promote the development of prostate cancer. We describe herein results showing that compared with androgen-dependent prostate cancer (ADPC) cells, AR nuclear translocation capability is enhanced in androgen-independent prostate cancer (AIPC) cells. To gain insight into whether AR coregulators are responsible for AR translocation capability, we performed coimmunoprecipitation (CO-IP) coupled with LC-MS/MS to screen 27 previously reported AR cofactors and 46 candidate AR cofactors. Furthermore, one candidate, myosin heavy chain 9 (MYH9), was identified and verified as a novel AR cofactor. Interestingly, the distribution of MYH9 was in both the cytoplasmic and nuclear compartments yet was enriched in the nucleus when AR was knocked down by AR shRNA, suggesting that the nuclear translocation of MYH9 was negatively regulated by AR. In addition, we found that blebbistatin, an inhibitor of MYH9, not only promoted AR nuclear translocation but also enhanced the expression of the AR target gene PSA, which indicates that MYH9 represses nuclear AR signaling. Taken together, our findings reveal that MYH9 appears to be a novel corepressor of AR plays a pivotal role in the progression of CRPC.
Although inhibition of SGK1 has been shown to delay cancer progression, the underlying mechanisms have not yet been elucidated.
We investigated the cellular responses to GSK650394 treatment and SGK1 ...silencing (or overexpression) in human prostate cancer (PCa) cell lines and PC3 xenografts by flow cytometry, western blotting, immunofluorescence, transmission electron microscopy and immunohistochemistry.
In the present study, we demonstrated that SGK1 inhibition, mediated by either GSK650394 or SGK1 shRNA, induced G2/M arrest, apoptosis and autophagy. Furthermore, 3MA-mediated autophagy inhibition attenuated SGK1 inhibition-induced apoptosis, suggesting that induction of autophagy precedes apoptosis. Moreover, ectopic expression of SGK1 significantly attenuated the GSK650394-induced effects. Suppression of mTOR and Foxo3a phosphorylation is critical for blockade of SGK1-induced autophagy and apoptosis, at least partially via pFoxo3a (S253)-LC3 and pFoxo3a (S253)-p27 interactions. Dual inhibition of mTOR and SGK1 enhances autophagy activation and leads to synergistic cytocidal effects in PCa cells.
In summary, our findings show that SGK1 inhibition exhibits significant antitumour effects against PCa in vitro and in vivo. This study uncovered a novel mechanism of SGK1 inhibition in PCa, which is mediated, at least in part, by inducing autophagy-dependent apoptosis via the mTOR-Foxo3a pathway.
Blood transfusion in critically ill individuals such as sepsis was associated with higher morbidity and mortality. During storage, various bioactive substances accumulated, may exacerbate the initial ...immunosuppressive reaction in severely ill patients. The objective of this study is to explore how resin adsorption impacts the accumulation of cytokines and the presence of extracellular microvesicles (EVs) in whole blood. Through comparative analysis and screening, amberchrom CG 300 C was chosen to assess the adsorption efficiency and evaluate the quality of whole blood after adsorption. Subsequently, the supernatants from both the unadsorpted (UA) and adsorpted (A) groups were co-cultured with peripheral blood mononuclear cells (PBMCs) to assess their effects on cellular growth and cytokine concentrations. The findings of our study revealed that resin adsorption effectively eradicated most bioactive components in conserved blood, including IL-8, TGF-β, sCD40L, sFasL, without affecting the quality of the blood. Furthermore, scanning electron microscopy (SEM) revealed a reduction in extracellular microvesicles following adsorption. Compared to UA, A 's supernatant markedly enhanced PBMC growth (p < 0.01). Additionally, the A's supernatant markedly diminished the emission of pro-inflammatory cytokines, like IL-6. The research revealed that adsorbing resin effectively reduced bioactive substances from preserved whole blood, and did not impact red blood cell quality, proving to be a reliable method for extracting bioactive substances from storage blood. The results could pave the way for creating innovative blood bags and hold clinical significance in lowering the frequency of TRIM among patients who have undergone transfusions.
Abstract Prostate cancer (PCa) has become a worldwide health burden among men. Previous studies have suggested that cellular retinoic acid binding protein 2 (CRABP2) significantly affects the ...regulation of cell proliferation, motility and apoptosis in multiple cancers; however, the effect of CRABP2 on PCa is poorly reported. CRABP2 expression in different PCa cell lines and its effect on different cellular functions varied. While CRABP2 promotes cell migration and invasion, it appears to inhibit cell proliferation specifically in PC-3 cells. However, the proliferation of DU145 and 22RV1 cells did not appear to be significantly affected by CRABP2. Additionally, CRABP2 had no influence on the cell cycle distribution of PCa cells. The RNA-seq assay showed that overexpressing CRABP2 upregulated laminin subunit beta-3 (LAMB3) mRNA expression, and the enrichment analyses revealed that the differentially expressed genes were enriched in the phosphoinositide 3-kinase (PI3K)/activated protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) signalling pathways. The following western blot experiments also confirmed the upregulated LAMB3 protein level and the activation of the PI3K/AKT and MAPK signalling pathways. Moreover, overexpressing CRABP2 significantly inhibited tumour growth in vivo. In conclusion, CRABP2 facilitates cell migration and invasion by activating PI3K/AKT and MAPK signalling pathways through upregulating LAMB3 in PCa.
Prostate cancer (PCa) is a metastatic malignant cancer driven by complex pathological mechanisms and characterized by poor long-term prognosis. Metastasis is the main cause of death of PCa patients, ...yet the molecular mechanisms of this process are poorly understood. In the present study, positive co-expression of RON and c-Met was observed in human clinical PCa tissues (biopsy material), as detected by immunohistochemical staining and quantitative real-time PCR. We investigated this further in PCa cells, demonstrating that the inhibition of RON and c-Met with foretinib (GSK1363089) suppressed metastasis and promoted the reversal of the epithelial-to-mesenchymal transition (EMT) in PCa cells. Furthermore, the invasion and migration of PCa cells were enhanced by the exogenous activation of RON with MSP and c-Met with HGF, whereas silencing of RON and c-Met attenuated the invasion and metastasis of the PCa cells. Our data also demonstrated that HGF/c-Met, but not the MSP-RON signaling pathway may be the dominant mechanism for PCa EMT. We further revealed that RON and c-Met facilitate metastasis via ERK1/2 signaling. These findings indicate that RON and c-Met facilitate metastasis through ERK1/2 signaling and that targeting RON and c-Met with foretinib may be an attractive therapeutic option for suppressing PCa metastasis.
Rhesus D (RhD) is one of the most important immunogenic antigens on red blood cells (RBCs). However, the supply of RhD-negative blood frequently faces critical shortages in clinical practice, and the ...positive-to-negative transition of the RhD antigen remains a great challenge. Here, we developed an alternative approach for sheltering the epitopes on RhD-positive RBCs using a surface-anchored framework, which is flexible but can achieve an optimal shield effect with minimal physicochemical influence on the cell. The chemical framework completely obstructed the RhD antigens on the cell surface, and the assessments of both blood transfusion in a mouse model and immunostimulation with human RhD-positive RBCs in a rabbit model confirmed the RhD-epitope stealth characteristics of the engineered RBCs. This work provides an efficient methodology for improving the cell surface for universal blood transfusion and generally indicates the potential of rationally designed cell surface engineering for transfusion and transplantation medicine.
A molecular beacon (MB) is an oligonucleotide hybridization probe with a hairpin-shaped structure that leads to specific and instantaneous nucleic acid hybridization, enabling a variety of ...applications. However, integration of additional module sequences interferes with the performance of MBs and increases the complexity of sequence design. Herein, we develop and characterize a toehold integrated molecular beacon (ToMB) strategy for nucleic acid hybridization, where the reaction rate can be flexibly regulated by a target-induced MB conformational switch. Using this basic mechanism, the ToMB is capable of identifying nucleic acids with high specificity and a wider linearity range compared with the conventional molecular beacon system. We further applied the ToMB to the construction of a hybridization chain reaction system and a basic OR logic gate VJHto explore its programmability and versatility. Our results strongly suggest that the novel ToMB can act as a powerful nano-module to construct universal and multifunctional biosensors or molecular computations.
Graphical abstract
Molecular beacon is employed as a flexible and switchable spacer to control the toehold-mediated strand displacement reaction.
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