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1.
Aging (Albany NY) ; 15(18): 9438-9452, 2023 09 20.
Article in English | MEDLINE | ID: mdl-37733667

ABSTRACT

In recent years, the incidence of urothelial carcinoma (UC) has been high in men. The aim of this study was to investigate whether astragalus polysaccharide (APS) could inhibit the development of UC and the specific molecular mechanism. Our data showed that APS inhibited the proliferation of UC cells in a dose-dependent manner, and APS reduced the migratory capacity of RT4 and T24 cells. Further studies revealed that the ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed APS-induced cell death, intracellular Fe2+ and malondialdehyde (MDA) accumulation, and lipid peroxidation product deposition. The Western blot and immunofluorescence results showed that APS significantly inhibited the expression of glutathione peroxidase 4 (GPX4) but did not alter the protein level of solute carrier family 7 member 11 (xCT, SLC7A11). Further analysis revealed that APS reduced the activity of xCT in RT4 and T24 cells. Moreover, APS significantly increased the phosphorylation levels of protein kinase AMP-activated catalytic subunit alpha 1 (AMPK) and BECN1 in RT4 and T24 cells, which induced the formation of the BECN1-xCT complex. However, when AMPK was silenced in RT4 and T24 cells, APS-induced ferroptosis was reversed to some extent, indicating that APS-mediated ferroptosis involves AMPK signaling. Moreover, APS has been shown to inhibit tumor growth in nude mice in vivo. In summary, our study demonstrated for the first time that APS could promote the formation of the BECN1-xCT complex in UC cells by activating AMPK/BECN1 signaling, which inhibited the activity of xCT to reduce GPX4 expression, thereby inducing ferroptosis and ultimately inhibiting UC progression.


Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Male , Mice , Animals , Humans , AMP-Activated Protein Kinases/metabolism , Mice, Nude , Polysaccharides/pharmacology
2.
Front Genet ; 13: 922358, 2022.
Article in English | MEDLINE | ID: mdl-35812727

ABSTRACT

Background: M7G modification is extremely vital for the development of many cancers, especially tumor immunity. M7G modification is a novel functional regulator of miRNA, and the researches on m7G-related miRNAs in kidney renal clear cell carcinoma (KIRC) are still insufficient. This research aims to establish a risk signature on the foundation of m7G-associated miRNAs, which can precisely forecast the prognosis of KIRC patients. Methods: Transcriptome data and clinical data used in this study come from The Cancer Genome Atlas database. Our team utilized univariable Cox, Lasso and multivariable Cox analyses to construct a m7G-associated miRNAs risk signature that can forecast the prognosis of KIRC patients. Kaplan-Meier method, time-dependent receiver operating characteristic (ROC) curve, and the independent analysis of risk signatures were employed to verify the predictability and accuracy of the risk signature. Subsequently, based on CIBERSORT, ESTIMATE and ssGSEA algorithms, we speculated the potential impact of the proposed risk signature on tumor immune microenvironment. Ultimately, by virtue of the risk signature and tumor immunity, the hub genes affecting the prognosis of KIRC patients were screened out. Results: Our team established and verified a prognostic signature comprising 7 m7G-associated miRNAs (miR-342-3p, miR-221-3p, miR-222-3p, miR-1277-3p, miR-6718-5p, miR-1251-5p, and miR-486-5p). The results of the Kaplan-Meier survival analysis revealed that the prognosis of KIRC sufferers in the high-risk group was often unsatisfactory. The accuracy of the prediction ability of the risk signature was verified by calculating the area under the ROC curve. Univariate-multivariate Cox analyses further showed that this risk signature could be utilized as an independent prognosis-related biomarker for KIRC sufferers. The results of the immune analysis revealed that remarkable diversities existed in immune status and tumor microenvironment between high-risk and low-risk groups. On the foundation of the proposed risk signature and other clinical factors, a nomogram was established to quantitatively forecast the survival of KIRC sufferers at 1, 3 and 5 years. Conclusion: Based on m7G-related miRNAs, a risk signature was successfully constructed, which could precisely forecast the prognosis of sufferers and guide personalized immunotherapy for KIRC patients.

3.
BMC Med Genomics ; 15(1): 24, 2022 02 08.
Article in English | MEDLINE | ID: mdl-35135561

ABSTRACT

BACKGROUND: Pyroptosis can not only inhibit the occurrence and development of tumors but also develop a microenvironment conducive to cancer growth. However, pyroptosis research in prostate cancer (PCa) has rarely been reported. METHODS: The expression profile and corresponding clinical data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Patients were divided into different clusters using consensus clustering analysis, and differential genes were obtained. We developed and validated a prognostic biomarker for biochemical recurrence (BCR) of PCa using univariate Cox analysis, Lasso-Cox analysis, Kaplan-Meier (K-M) survival analysis, and time-dependent receiver operating characteristics (ROC) curves. RESULTS: The expression levels of most pyroptosis-related genes (PRGs) are different not only between normal and tumor tissues but also between different clusters. Cluster 2 patients have a better prognosis than cluster 1 patients, and there are significant differences in immune cell content and biological pathway between them. Based on the classification of different clusters, we constructed an eight genes signature that can independently predict the progression-free survival (PFS) rate of a patient, and this signature was validated using a GEO data set (GSE70769). Finally, we established a nomogram model with good accuracy. CONCLUSIONS: In this study, PRGs were used as the starting point and based on the expression profile and clinical data, a prognostic signature with a high predictive value for biochemical recurrence (BCR) following radical prostatectomy (RP) was finally constructed, and the relationship between pyroptosis, immune microenvironment, and PCa was explored, providing important clues for future research on pyroptosis and immunity.


Subject(s)
Prostatic Neoplasms , Pyroptosis , Biomarkers, Tumor/genetics , Humans , Kaplan-Meier Estimate , Male , Prognosis , Prostatic Neoplasms/genetics , Pyroptosis/genetics , Tumor Microenvironment/genetics
4.
Med Sci Monit ; 25: 9547-9554, 2019 Dec 14.
Article in English | MEDLINE | ID: mdl-31837261

ABSTRACT

BACKGROUND Orientin is a flavone isolated from medicinal plants used in traditional Chinese medicine (TCM), which suppresses the growth of cancer cells in vitro. The effects of orientin in bladder cancer cells remains unknown. This study aimed to investigate the effect of orientin on proliferation and apoptosis of T24 human transitional cell bladder carcinoma cells in vitro in the presence of an agonist and an inhibitor of nuclear factor-kappaB (NF-kappaB). MATERIAL AND METHODS T24 cells were cultured and divided into four study groups: an untreated control group; a group treated with 100 µM orientin; a group treated with 100 µM orientin with NF-kappaB agonist, phorbol 12-myristate 13-acetate (PMA); and a group treated with 100 µM orientin and the NF-kappaB inhibitor, IkappaBalpha. The MTT assay was performed to assess cell viability, and flow cytometry evaluated the cell cycle. The expression of proteins in the Hedgehog signaling pathway and inflammatory cytokines were determined by Western blot and enzyme-linked immunosorbent assay (ELISA). RESULTS Orientin inhibited the proliferation of T24 cells, caused cell cycle arrest, reduced cell viability, and inhibited the expression of inflammatory mediators. Treatment of T24 cells with orientin inhibited the expression of NF-kappaB and components of the Hedgehog signaling pathway, and the NF-kappaB agonist, PMA, reversed these effects. CONCLUSIONS Treatment of T24 human bladder carcinoma cells in vitro with orientin inhibited cell proliferation and promoted cell apoptosis by suppressing the Hedgehog signaling pathway and NF-kappaB.


Subject(s)
Flavonoids/pharmacology , Glucosides/pharmacology , Urinary Bladder Neoplasms/metabolism , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Cycle Checkpoints , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , China , Flavonoids/metabolism , Glucosides/metabolism , Hedgehog Proteins/metabolism , Humans , I-kappa B Proteins/metabolism , Medicine, Chinese Traditional , NF-kappa B/metabolism , Signal Transduction/drug effects , Urinary Bladder/metabolism , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology
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