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Reprogrammed lipid metabolism in bladder cancer with cisplatin resistance.

ABSTRACT: Due to its tendency to recur and acquire chemoresistance quickly, bladder cancer (BC) remains to be an elusive and difficult disease. Patients with recurrent and chemoresistant BC have an extremely poor prognosis. One possible approach that may provide insightful and valuable information regarding resistance mechanisms is looking into the lipid metabolism of BC cells. Metabolism of lipids is essential for cancer cells and is associated with the regulation of a variety of key cellular processes and functions. This study conducted a comparative lipidomic profiling of two isogenic human T24 bladder cancer cell lines, one of which is clinically characterized as cisplatin-sensitive (T24S) and the other as cisplatin-resistant (T24R). Immunohistochemistry analysis revealed that expression of cytosolic acetyl-CoA synthetase 2 (ACSS2) is positively correlated with aggressive BC. Ultra performance liquid chromatography-mass spectrometry (UPLC-MS) analysis profiled a total of 1,864 lipids and levels of differentially expressed lipids suspected of being associated with cisplatin resistance were determined. In addition, we found that ACSS2 inhibition greatly perturbed levels of metabolites, including CE(18:1), CE(22:6), TG(49:1), and TG(53:2). This study broadens our current knowledge on the links between cisplatin resistance and lipid metabolism in aggressive BC and suggests potential biomarkers for identifying higher-risk patients.

SUBMITTER: Lee MY

PROVIDER: S-EPMC5862574 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Reprogrammed lipid metabolism in bladder cancer with cisplatin resistance.

Lee Min Young MY Yeon Austin A Shahid Muhammad M Cho Eunho E Sairam Vikram V Figlin Robert R Kim Khae-Hwan KH Kim Jayoung J

Oncotarget 20180113 17

Due to its tendency to recur and acquire chemoresistance quickly, bladder cancer (BC) remains to be an elusive and difficult disease. Patients with recurrent and chemoresistant BC have an extremely poor prognosis. One possible approach that may provide insightful and valuable information regarding resistance mechanisms is looking into the lipid metabolism of BC cells. Metabolism of lipids is essential for cancer cells and is associated with the regulation of a variety of key cellular processes a ...[more]

PMID: 29568353

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Project description:PurposeThe overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic difference, and drug resistance. The genes that associated with cisplatin resistance remain unclear. Herein, we aimed to identify the cisplatin resistance associated genes in BUC. EXPERIMENTAL DESIGN: The cytotoxicity of cisplatin was evaluated in six bladder cancer cell lines to compare their responses to cisplatin. The T24 cancer cells exhibited the lowest sensitivity to cisplatin and was therefore selected to explore the mechanisms of drug resistance. We performed genome-wide CRISPR screening in T24 cancer cells in vitro, and identified that the gene heterogeneous nuclear ribonucleoprotein U (HNRNPU) was the top candidate gene related to cisplatin resistance. Epigenetic and transcriptional profiles of HNRNPU-depleted cells after cisplatin treatment were analyzed to investigate the relationship between HNRNPU and cisplatin resistance. In vivo experiments were also performed to demonstrate the function of HNRNPU depletion in cisplatin sensitivity.ResultsSignificant correlation was found between HNRNPU expression level and sensitivity to cisplatin in bladder cancer cell lines. In the high HNRNPU expressing T24 cancer cells, knockout of HNRNPU inhibited cell proliferation, invasion, and migration. In addition, loss of HNRNPU promoted apoptosis and S-phase arrest in the T24 cells treated with cisplatin. Data from The Cancer Genome Atlas (TCGA) demonstrated that HNRNPU expression was significantly higher in tumor tissues than in normal tissues. High HNRNPU level was negatively correlated with patient survival. Transcriptomic profiling analysis showed that knockout of HNRNPU enhanced cisplatin sensitivity by regulating DNA damage repair genes. Furthermore, it was found that HNRNPU regulates chemosensitivity by affecting the expression of neurofibromin 1 (NF1).ConclusionsOur study demonstrated that HNRNPU expression is associated with cisplatin sensitivity in bladder urothelial carcinoma cells. Inhibition of HNRNPU could be a potential therapy for cisplatin-resistant bladder cancer.

Project description:BackgroundBladder cancer is one of the most common malignancies of the urinary system with an unfavorable prognosis. More and more studies have suggested that lipid metabolism could influence the progression and treatment of tumors. However, there are few studies exploring the relationship between lipid metabolism and bladder cancer. This study aimed to explore the roles that lipid metabolism-related genes play in patients with bladder cancer.MethodsTCGA_BLCA cohort and GSE13507 cohort were included in this study, and transcriptional and somatic mutation profiles of 309 lipid metabolism-related genes were analyzed to discover the critical lipid metabolism-related genes in the incurrence and progression of bladder cancer. Furthermore, the TCGA_BLCA cohort was randomly divided into training set and validation set, and the GSE13507 cohort was served as an external independent validation set. We performed the LASSO regression and multivariate Cox regression in training set to develop a prognostic signature and further verified this signature in TCGA_BLCA validation set and GSE13507 external validation set. Finally, we systematically investigated the association between this signature and tumor microenvironment, drug response, and potential functions and then verified the differential expression status of signature genes in the protein level by immunohistochemistry.ResultsA novel 6-lipidmetabolism-related gene signature was identified and validated, and this risk score model could predict the prognosis of patients with bladder cancer. In addition, the prognostic model was tightly related to immune cell infiltration and tumor mutation burden. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) showed that mTOR signaling pathway, G2M checkpoint, fatty acid metabolism, and hypoxia were enriched in patients in the high-risk score groups. Furthermore, 3 therapies specific for bladder cancer patients in different risk scores were identified.Conclusions. In conclusion, we investigated the lipid metabolism-related genes in bladder cancer through comprehensive bioinformatic analysis. A novel 6-gene signature associated with lipid metabolism for predicting the outcomes of patients with bladder cancer was conducted and validated. Furthermore, the risk score model could be utilized to indicate the choice of therapy in bladder cancer.

Project description:BackgroundCisplatin-based chemotherapy is recommended as the primary treatment for advanced bladder cancer (BC) with unresectable or metastatic disease. However, the benefits are limited due to the acquisition of drug resistance. The mechanisms of resistance remain unclear. Although there are some reports that some molecules are associated with cisplatin resistance in advanced BC, those reports have not been fully investigated. Therefore, we undertook a new search for cisplatin resistance-related genes targeted by tumor suppressive microRNAs as well as genes that were downregulated in cisplatin-resistant BC cells and clinical BC tissues.MethodsFirst, we established cisplatin-resistant BOY and T24 BC cell lines (CDDP-R-BOY, CDDP-R-T24). Then, Next Generation Sequence analysis was performed with parental and cisplatin-resistant cell lines to search for the microRNAs responsible for cisplatin resistance. We conducted gain-of-function analysis of microRNAs and their effects on cisplatin resistance, and we searched target genes comprehensively using Next Generation mRNA sequences.ResultsA total of 28 microRNAs were significantly downregulated in both CDDP-R-BOY and CDDP-R-T24. Among them, miR-486-5p, a tumor suppressor miRNA, was negatively correlated with the TNM classification of clinical BC samples in The Cancer Genome Atlas (TCGA) database. Transfection of miRNA-486-5p significantly inhibited cancer cell proliferation, migration, and invasion, and also improved the cells' resistance to cisplatin. Among the genes targeted by miRNA-486-5p, we focused on enoyl-CoA, hydratase/3-hydroxyacyl CoA dehydrogenase (EHHADH), which is involved in the degradation of fatty acids. EHHADH was directly regulated by miRNA-486-5p as determined by a dual-luciferase reporter assay. Loss-of-function study using EHHADH si-RNA showed significant inhibitions of cell proliferation, migration, invasion and the recovery of cisplatin sensitivity.ConclusionIdentification of EHHADH as a target of miRNA-486-5p provides novel insights into the potential mechanisms of cisplatin resistance in BC.

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Reprogrammed lipid metabolism in bladder cancer with cisplatin resistance.

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Reprogrammed lipid metabolism in bladder cancer with cisplatin resistance.

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