Mevalonate pathway inhibition reduces bladder cancer metastasis by modulating RhoB protein stability and integrin β1 localization
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE252007 | GEO | 2024/09/08
REPOSITORIES: GEO
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Project description:Metastasis is an important factor affecting the prognosis and survival of bladder cancer (BLCA) patients. Our previous study found that the mevalonate pathway is associated with the migratory ability of bladder cancer cells, but the exact mechanism is unclear. Here, we found that BLCA patients with mevalonate pathway activation had a poorer prognosis. Inhibition of the mevalonate pathway (simvastatin or zoledronic acid) resulted in a significant decrease in the migratory ability of BLCA cells. Therefore, we used proteomics to detect simvastatin- or zoledronic acid-treated BLCA cells to explore the effect of the mevalonate pathway on key proteins in BLCA cells.
2024-09-09 | PXD048067 |
Project description:This study utilized Mendelian randomization (MR) analysis and genome-wide association study (GWAS) data to investigate the association between commonly prescribed drugs and bladder cancer (BLCA) risk. Our results revealed that HMGCR inhibitors, specifically simvastatin, are significantly associated with a reduced BLCA risk. We further showed that simvastatin could significantly inhibit BLCA proliferation and epithelial-mesenchymal transition in animal models, with transcriptomic data identifying several associated pathways. Higher levels of HMGCR were linked with BLCA development and progression, and certain blood lipids, such as lipoprotein particles and VLDL cholesterol, might influence BLCA risk. These findings suggested that HMGCR inhibitors, particularly simvastatin, could be potential treatment options or adjuvant therapies for BLCA. Meanwhile, RhoB is a key protein involved in the regulation of bladder cancer cell metastasis by simvastatin. Therefore, we tested the changes of key genes in bladder cancer cells after simvastatin (HMGCR inhibitor) treatment and overexpression of RhoB, respectively, using RNA sequencing.
2024-09-08 | GSE270394 | GEO
Project description:Simvastatin has been widely used for treatment of hypercholesterolemia due to its ability to inhibit HMG-CoA reductase, the rate limiting enzyme of de novo cholesterol synthesis via mevalonate pathway. Its inhibitory action causes also depletion of pathway intermediates, farnesyl pyrophosphate (FPP) and geranyl-geranyl pyrophosphate (GGPP), which are inevitable for proper targeting of small GTPases (e.g. Ras proteins) to their site of action. We profiled by array the gene expression of MIA PaCa-2 cells treated with simvastatin, FPP, GGPP and their combinations. The inhibitory effect of statins on GFP-K-Ras protein trafficking were partially prevented by addition of the mevalonate pathway intermediates. We conclude that the anticancer effect of simvastatin is to a large extent mediated through isoprenoid intermediates of the mevalonate pathway.
2018-03-31 | E-MTAB-3263 | biostudies-arrayexpress
Project description:RNA-binding proteins (RBPs) are pivotal mediators of the alternative splicing (AS) machinery of pre-mRNA, allowing the generation of diverse protein structures and functions from a single gene. Research has demonstrated that the AS process in bladder cancer (BLCA) is significantly dysregulated and plays a crucial role in the development, progression, aggressiveness, and therapeutic resistance of this disease. We conducted comprehensive screening and analysis of the TCGA-BLCA cohort, specifically focusing on genes with significant differences in expression levels between carcinoma and adjacent non-cancerous tissues. Among the 500 differentially expressed genes, 5 RNA-binding proteins were identified. Only the RNA-binding protein mRNA processing factor (RBPMS) demonstrated a consistent downregulation in BLCA and was correlated with an unfavorable prognosis for affected patients. Subsequent in vitro and in vivo experiments revealed that RBPMS exerted inhibitory effects on the epithelial-mesenchymal transition (EMT) pathway and the migratory potential of BLCA cells. RNA-Seq analysis identified ANKRD10 as a key target mRNA regulated by RBPMS in BLCA. RBPMS depletion in BLCA cells resulted in AS of ANKRD10 and increased ANKRD10-2 expression. ANKRD10-2 functioned as a transcriptional co-activator of MYC proteins, thereby augmenting their transcriptional activity. Furthermore, ANKRD10-2 knockdown significantly rescued the migration enhancement induced by RBPMS depletion in BLCA cells. Taken together, this study revealed a mechanism whereby RBPMS suppresses the migration and invasion of BLCA cells by attenuating MYC pathway activity via the AS of ANKRD10.
2025-02-26 | GSE267762 | GEO
Project description:Acetyl-CoA acetyltransferase 1 (ACAT1) played a key role in regulating gene expression and tumorigenesis. Nevertheless, the biological function of ACAT1 in bladder cancer (BLCA) has yet to be elucidated. This study aimed to elucidate the bioinformatics features and biological functions of ACAT1 in BLCA. Here, we demonstrate for the first time that ACAT1 is elevated in BLCA tissues, correlating with specific clinicopathological features and an unfavorable prognosis for survival in BLCA patients. ACAT1 emerged as an independent risk factor in BLCA. Phenotypically, ACAT1 knockdown inhibited the proliferation and migration of BLCA cells both in vivo and in vitro, whereas ACAT1 overexpression yielded the opposite phenotype. Mechanistically, ACAT1 enhances BLCA cells proliferation by activating cell cycle through AKT/GSK3β/c-Myc signaling pathway. In conclusion, this study identifies ACAT1 as an oncogene in BLCA, demonstrating its capability to promote proliferation and metastasis of BLCA. This suggests that ACAT1 may serve as a potential molecular target for the diagnosis and treatment of BLCA.
2024-06-12 | GSE248825 | GEO
Project description:Farnesyl diphosphate synthase (FDPS), an essencial enzyme involved in mevalonate pathway, is implicated in cancers and osteoporosis by catalyzing head to tail condensation of two molecules of isopentenyl pyrophosphate with dimethylallyl pyrophosphate to form farnesyl pyrophosphate. It has also been identified as an RNA-binding protein (RBP). However, it’s exactly RNA-binding function in diseases, up to now, remain unknown. In the present study, the function of FDPS in HeLa cells was investigated with FDPS overexpression. The results showed that FDPS overexpression promoted proliferation in HeLa cells. FDPS overexpression extensively regulated the expression of genes in cell proliferation, cytokine-mediated signaling pathway, and extracellular matrix organization. In addition, FDPS extensively regulated the alternative splicing of numbers of genes related with osteoporosis, including NAB1, FGFR3, and ALPL, and FDPS-regulated DEGs and ASEs were highly validated by RT-qPCR. This is the first study to investigate the properties of FDPS as an RBP from a genome-wide perspective, our results suggested that FDPS acts as an RBP playing an important role in cancer progression and osteoporosis by altering gene expression and regulating alternative splicing, which contributes to a precise understanding of potentially FDPS-targeted therapies.
2023-02-06 | GSE151605 | GEO
Project description:Background: The tumor suppressor gene TP53 is frequently mutated or inactivated in bladder cancer (BLCA), which is implicated in the pathogenesis of tumor. However, the cellular mechanisms of TP53 mutations are complicated, yet well-defined, but their clinical prognostic value in the management of BLCA remains controversial. This study aimed to explore the role of TP53 mutation in regulating the tumor microenvironment (TME), elucidate the effects of TP53 activity on BLCA prognosis and immunotherapy response. Methods: A TP53-related signature based on TP53-induced and TP53-repressed genes was used to construct a TP53 activity-related score and classifier. The abundance of different immune cell types was determined using CIBERSORT to estimate immune cell infiltration. Moreover, the heterogeneity of the tumor immune microenvironment between the high and low TP53 score groups was further evaluated using single-cell mass cytometry (CyTOF) and imaging mass cytometry (IMC). Moreover, pathway enrichment analysis was performed to explore the differential biological functions between tumor epithelial cells with high and low TP53 activity scores. Finally, the receptor–ligand interactions between immune cells and tumor epithelial cells harboring distinct TP53 activity were analyzed by single-cell RNA-sequencing. Results: The TP53 activity-related gene signature differentiated well between TP53 functional retention and inactivation in BLCA. BLCA patients with low TP53 scores had worse survival prognosis, more TP53 mutations, higher grade, and stronger lymph node metastasis than those with high TP53 scores. Additionally, CyTOF and IMC analyses revealed that BLCA patients with low TP53 scores exhibited a potent immunosuppressive TME. Consistently, single-cell sequencing results showed that tumor epithelial cells with low TP53 scores were significantly associated with high cell proliferation and stemness abilities and strongly interacted with immunosuppressive receptor–ligand pairs. Conclusions: Patients with BLCA with low TP53 scores have a worse prognosis and a more immunosuppressive TME. This TP53 activity-related signature can serve as a potential prognostic signature for predicting the immune response, which may facilitate the development of new strategies for immunotherapy in BLCA. Keywords: bladder cancer, TP53, immunosuppression, tumor microenvironment
2022-10-24 | GSE216037 | GEO
Project description:Recent findings suggested a benefit of anti-EGFR therapy for basal-like muscle invasive bladder cancer (MIBC). However, impact on bladder cancer with substantial squamous differentiated (Sq-BLCA) and especially pure squamous cell carcinoma (SCC) remains unknown. Therefore, we comprehensively characterized pure and mixed Sq-BLCA (n=125) on genetic and protein expression level, and performed functional pathway and drug-response analyses with cell line models and isolated primary SCC (p-SCC) cells of the human urinary bladder. We identified abundant EGFR expression in 95% of Sq-BLCA without evidence for activating EGFR mutations. Both SCaBER and p-SCC cells were sensitive to EGFR tyrosine kinase inhibitors (TKIs: erlotinib and gefitinib). Combined treatment with anti-EGFR TKIs and varying chemotherapeutics led to a concentration-dependent synergism in SCC cells according to the Chou-Talalay method. In addition, siRNA knockdown of EGFR impaired SCaBER viability suggesting a putative ‘‘Achilles heel’’ of Sq-BLCA. The observed effects seem Sq-BLCA-specific since non-basal urothelial cancer cells were characterized by poor TKI sensitivity associated with a short-term feedback response by upregulating EGFR and ERBB3 expression. Hence, our findings give novel insights into a crucial, Sq-BLCA-specific role of the ERBB signaling pathway proposing improved effectiveness of combined anti-EGFR and chemotherapeutic regimens in squamous bladder cancers with wild-type EGFR-overexpression.
2023-03-12 | GSE146975 | GEO
Project description:Bladder cancer (BLCA) is a highly prevalent malignancy on a global scale, characterized by significant tumor heterogeneity. The investigation of molecular mechanisms that can be leveraged for the management of aggressive BLCA represents a particularly pertinent objective.DLGAP5 is mitosis-related protein widely existed in eukaryotic cells. The molecular mechanism of DLGAP5 in bladder cancer is still not clear, despite its role in tumorigenesis. Bladder cancer tissues exhibit a noteworthy increase in DLGAP5 expression, compared to normal bladder tissues. Furthermore, the expression of DLGAP5 shows a positive correlation with the clinical stage of the tumor and a negative impact on the prognosis. Cell proliferation and migration are significantly impacted by alterations in DLGAP5 expression, as demonstrated by in vitro and in vivo experiments. Further investigation reveals that DLGAP5 regulated E2F1 protein stability via USP11 deubiquitinase activity, and DLGAP5 is a direct target of E2F1. DLGAP5-E2F1 forms a positive feedback loop and influences the efficacy of BLCA progression. Collectively, DLGAP5 could potentially serve as a new therapeutic target for the treatment of bladder cancer.
2023-12-31 | GSE241523 | GEO
Project description:Hitherto, most studies on POLD1 have mainly focused on the effect of POLD1 inactivation mutation in tumors. Nonetheless, the mechanism underlying high POLD1 expression in tumorigenesis remains elusive. Herein, we substantiated the pro-carcinogenic role of POLD1 in bladder cancer (BLCA) and found that POLD1 expression is related to malignancy and prognosis of BLCA. Next, we demonstrated that POLD1 could promote proliferation and metastasis of BLCA via MYC. Mechanistically, we demonstrated that POLD1 was able to stabilize MYC in a manner independent of DNA polymerase activity. POLD1 attenuated the FBXW7-mediated ubiquitination degradation of MYC by directly binding to the MYC homology box 1 domain competitively with FBXW7. Moreover, we found that POLD1 can form a complex with MYC to promote the transcriptional activity of MYC. MYC could also transcriptionally activate POLD1, forming a POLD1-MYC positive feedback loop to enhance the pro-carcinogenic effect of POLD1-MYC on BLCA. Overall, our study suggests a novel MYC-driven mechanism for BLCA, and POLD1 has the potential as a biomarker for BLCA.
2023-03-29 | PXD040806 | Pride