Use of Thiazolidinediones and Risk of Bladder Cancer: Disease or Drugs?

AbstractLate endosomes/lysosomes (endolysosomes) emerge as a potential regulatory hub during cancer. Here, we investigate the intracellular landscape of this organelle in a collection of bladder cancer cell lines and normal human urothelium cells under standardized culture conditions. We find that high-grade bladder cancer cells are characterized by scattered endolysosomes that are accompanied by an altered cellular pH homeostasis and major changes of mTORC1 regulation. Mechanistically, we reveal that mTORC1 substrate specificity is altered, and mTORC1 responsiveness to endolysosome positioning is lost in high-grade cancer cells compared to low-grade cells, highlighting unexpected mechanisms of mTORC1 deregulation in the bladder cancer model. Because endolysosome positioning was critical for invasion from 3D spheroids, our results indicate that changes in their cellular positioning and ability to support signaling, strongly impact cancer cell behavior. Thus, monitoring detailed changes of endolysosomes at different steps of cancer disease reveals intricate spatial and temporal dimensions of tumorigenesis.Statement of significanceOur study reveals significant changes of endolysosomes in bladder cancer progression, highlighting endolysosome dysfunction as a fundamental driving progress in malignancies. The identified alterations in endolysosome positioning and associated mTORC1 signaling regulation could help to stratify emerging therapeutic strategies targeting the endolysosomal compartment.

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Metastatic Bladder Cancer Disease and Its Treatment

Urologic Oncology ◽

10.1007/978-3-319-42603-7_26-1 ◽

2017 ◽

pp. 1-9

Author(s):

Anja Lorch ◽

Günter Niegisch

Keyword(s):

Bladder Cancer ◽

Cancer Disease ◽

Metastatic Bladder Cancer

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Significance and Mechanisms Analyses of RB1 Mutation in Bladder Cancer Disease Progression and Drug Selection by Bioinformatics Analysis

Bladder Cancer ◽

10.3233/blc-200368 ◽

2021 ◽

pp. 1-10

Author(s):

Dingguo Zhang ◽

Jinjun Tian ◽

Qier Xia ◽

Zhenyu Yang ◽

Bin Gu

Keyword(s):

Bladder Cancer ◽

Disease Progression ◽

Drug Sensitivity ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Functional Enrichment ◽

Drug Selection ◽

Cancer Disease ◽

Ezh2 Expression ◽

Bladder Cancer Cells

BACKGROUND: Bladder cancer is still a disease of significant morbidity and mortality. In bladder cancer, RB1 is one of the most common mutant genes. METHODS: In this study, we explored the Genomics of Drug Sensitivity in Cancer (GDSC) database for drug sensitivity. The latest TCGA data were downloaded for analysis. To deal with functional enrichment analysis, GSEA, KEGG and GO were used. Prognostic analyses have been carried out using the GEPIA online tool. RESULTS: Results from the GDSC database showed that bladder cancer cells with RB1 mutation are more resistant to Dactolisib, MK-2206 and GNE-317. RB1 mutation was found in 25%bladder cancer patients. Patients with RB1 mutation often had lower RB1 mRNA expression level and higher histologic grade. In addition, we identified 999 differentially expressed genes in both groups. Functional enrichment analysis suggested that DEGs were primarily enriched in multiple metabolic progressions, cell proliferation and cancer related pathways. There were strong correlations between WT1, GPR37, CHRM2 and EZH2 expression levels and the prognosis. CONCLUSIONS: In all, the significance of RB1 mutation in disease progression and drug selection in bladder cancer was suggested by our results, and multiple genes and pathways related to such a program were identified.

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Identification of GSN and LAMC2 as Key Prognostic Genes of Bladder Cancer by Integrated Bioinformatics Analysis

Cancers ◽

10.3390/cancers12071809 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1809

Author(s):

Jia-Lian Yang ◽

Charles C. N. Wang ◽

Jia-Hua Cai ◽

Che-Yi Chou ◽

Yu-Chao Lin ◽

...

Keyword(s):

Gene Expression ◽

Bladder Cancer ◽

Transitional Cell Carcinoma ◽

Cell Carcinoma ◽

Lymphatic Metastasis ◽

Transitional Cell ◽

The Cancer Genome Atlas ◽

Cancer Disease ◽

Hub Gene ◽

Grade 3

Bladder cancer is a common malignancy with mechanisms of pathogenesis and progression. This study aimed to identify the prognostic hub genes, which are the central modulators to regulate the progression and proliferation in the specific subtype of bladder cancer. The identification of the candidate hub gene was performed by weighted gene co-expression network analysis to construct a free-scale gene co-expression network. The gene expression profile of GSE97768 from the Gene Expression Omnibus database was used. The association between prognosis and hub gene was evaluated by The Cancer Genome Atlas database. Four gene-expression modules were significantly related to bladder cancer disease: the red module (human adenocarcinoma lymph node metastasis), the darkturquioise module (grade 2 carcinoma), the lightgreen module (grade 3 carcinoma), and the royalblue module (transitional cell carcinoma lymphatic metastasis). Based on betweenness centrality and survival analysis, we identified laminin subunit gamma-2 (LAMC2) in the grade 2 carcinoma, gelsolin (GSN) in the grade 3 carcinoma, and homeodomain-interacting protein kinase 2 (HIPK2) in the transitional cell carcinoma lymphatic metastasis. Subsequently, the protein levels of LAMC2 and GSN were respectively down-regulated and up-regulated in tumor tissue with the Human Protein Atlas (HPA) database. Our results suggested that LAMC2 and GSN are the central modulators to transfer information in the specific subtype of the disease.

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