Dataset Information

MPC1, a key gene in cancer metabolism, is regulated by COUPTFII in human prostate cancer.

ABSTRACT: Mitochondrial pyruvate carrier 1 (MPC1) and MPC 2 form a transporter complex in cells to control pyruvate transportation into mitochondria. Reduced expression of MPC1 disrupts the transporter function, induces metabolic shift to increase glycolysis, and thus plays important roles in several diseases, including cancer. However, the role of MPC1 in prostate cancer and the underlying mechanism causing the down-regulation of MPC1 in tumor cells remain to be defined. Here, we show that MPC1 serves as a critical regulator of glycolysis in prostate cancer cells, which in turn controls cancer cell growth, invasion, and the tumorigenic capability. More importantly, we identified that chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), a steroid receptor superfamily member, transcriptionally regulates the expression of MPC1. We further demonstrate that COUP-TFII, which is upregulated in the prostate cancer patient, regulates MPC1 and glycolysis to promote tumor growth and metastasis. Our findings reveal that COUP-TFII represses MPC1 expression in prostate cancer cells to facilitate a metabolism switch to increase glycolysis and promote cancer progression. This observation raises an intriguing possibility of targeting COUP-TFII to modulate cancer cell metabolism for prostate cancer intervention.

SUBMITTER: Wang L

PROVIDER: S-EPMC4924743 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

MPC1, a key gene in cancer metabolism, is regulated by COUPTFII in human prostate cancer.

Wang Leiming L Xu Mafei M Qin Jun J Lin Shih-Chieh SC Lee Hui-Ju HJ Tsai Sophia Y SY Tsai Ming-Jer MJ

Oncotarget 20160301 12

Mitochondrial pyruvate carrier 1 (MPC1) and MPC 2 form a transporter complex in cells to control pyruvate transportation into mitochondria. Reduced expression of MPC1 disrupts the transporter function, induces metabolic shift to increase glycolysis, and thus plays important roles in several diseases, including cancer. However, the role of MPC1 in prostate cancer and the underlying mechanism causing the down-regulation of MPC1 in tumor cells remain to be defined. Here, we show that MPC1 serves as ...[more]

PMID: 26895100

Similar Datasets

Project description:In this study we sought if, in their quest to handle hypoxia, prostate tumors express target hypoxia-associated molecules and their correlation with putative functional genetic polymorphisms.Representative areas of prostate carcinoma (n?=?51) and of nodular prostate hyperplasia (n?=?20) were analysed for hypoxia-inducible factor 1 alpha (HIF-1?), carbonic anhydrase IX (CAIX), lysyl oxidase (LOX) and vascular endothelial growth factor (VEGFR2) immunohistochemistry expression using a tissue microarray. DNA was isolated from peripheral blood and used to genotype functional polymorphisms at the corresponding genes (HIF1A +1772 C?>?T, rs11549465; CA9?+?201 A?>?G; rs2071676; LOX +473 G?>?A, rs1800449; KDR - 604 T?>?C, rs2071559).Immunohistochemistry analyses disclosed predominance of positive CAIX and VEGFR2 expression in epithelial cells of prostate carcinomas compared to nodular prostate hyperplasia (P?=?0.043 and P?=?0.035, respectively). In addition, the VEGFR2 expression score in prostate epithelial cells was higher in organ-confined and extra prostatic carcinoma compared to nodular prostate hyperplasia (P?=?0.031 and P?=?0.004, respectively). Notably, for LOX protein the immunoreactivity score was significantly higher in organ-confined carcinomas compared to nodular prostate hyperplasia (P?=?0.015). The genotype-phenotype analyses showed higher LOX staining intensity for carriers of the homozygous LOX +473?G-allele (P?=?0.011). Still, carriers of the KDR-604 T-allele were more prone to have higher VEGFR2 expression in prostate epithelial cells (P?<?0.006).Protein expression of hypoxia markers (VEGFR2, CAIX and LOX) on prostate epithelial cells was different between malignant and benign prostate disease. Two genetic polymorphisms (LOX +473 G?>?A and KDR-604 T?>?C) were correlated with protein level, accounting for a potential gene-environment effect in the activation of hypoxia-driven pathways in prostate carcinoma. Further research in larger series is warranted to validate present findings.

Project description:miRNAs are predicted to control the activity of approximately 60% of all protein-coding genes participating in the regulation of several cellular processes and diseases, including cancer. Recently, we have demonstrated that miR-187 is significantly downregulated in prostate cancer (PCa) and here we propose a proteomic approach to identify its potential targets. For this purpose, PC-3 cells were transiently transfected with miR-187 precursor and miRNA mimic negative control. Proteins were analyzed by a two-dimensional difference gel electrophoresis (2D-DIGE) and defined as differentially regulated if the observed fold change was ±1.06. Then, MALDI-TOF MS analysis was performed after protein digestion and low abundance proteins were identified by LC-MS/MS. Peptides were identified by searching against the Expasy SWISS PROT database, and target validation was performed both in vitro by western blot and qRT-PCR and in clinical samples by qRT-PCR, immunohistochemistry and ELISA. DIGE analysis showed 9 differentially expressed spots (p<0.05) and 7 showed a down-regulated expression upon miR-187 re-introduction. Among these targets we identified aldehyde dehydrogenase 1A3 (ALDH1A3). ALDH1A3 expression was significantly downregulated in PC3, LNCaP and DU-145 cells after miR-187 re-introduction. Supporting these data, the expression of ALDH1A3 was found significantly (p<0.0001) up-regulated in PCa samples and inversely correlated (p<0.0001) with miR-187 expression, its expression being directly associated with Gleason score (p = 0.05). The expression of ALDH1A3 was measured in urine samples to evaluate the predictive capability of this biomarker for the presence of PCa and, at a signification level of 10%, PSA and also ALDH1A3 were significantly associated with a positive biopsy of PCa. In conclusion, our data illustrate for the first time the role of ALDH1A3 as a miR-187 target in PCa and provide insights in the utility of using this protein as a new biomarker for PCa.

Project description:Prostate cancer is still the main male health problem in the world. The role of metabolism in the occurrence and development of prostate cancer is becoming more and more obvious, but it is not clear. Here we firstly identified a metabolism-related gene-based subgroup in prostate cancer. We used metabolism-related genes to divide prostate cancer patients from The Cancer Genome Atlas into different clinical benefit populations, which was verified in the International Cancer Genome Consortium. After that, we analyzed the metabolic and immunological mechanisms of clinical beneficiaries from the aspects of functional analysis of differentially expressed genes, gene set variation analysis, tumor purity, tumor microenvironment, copy number variations, single-nucleotide polymorphism, and tumor-specific neoantigens. We identified 56 significant genes for non-negative matrix factorization after survival-related univariate regression analysis and identified three subgroups. Patients in subgroup 2 had better overall survival, disease-free interval, progression-free interval, and disease-specific survival. Functional analysis indicated that differentially expressed genes in subgroup 2 were enriched in the xenobiotic metabolic process and regulation of cell development. Moreover, the metabolism and tumor purity of subgroup 2 were higher than those of subgroup 1 and subgroup 3, whereas the composition of immune cells of subgroup 2 was lower than that of subgroup 1 and subgroup 3. The expression of major immune genes, such as CCL2, CD274, CD276, CD4, CTLA4, CXCR4, IL1A, IL6, LAG3, TGFB1, TNFRSF4, TNFRSF9, and PDCD1LG2, in subgroup 2 was almost significantly lower than that in subgroup 1 and subgroup 3, which is consistent with the results of tumor purity analysis. Finally, we identified that subgroup 2 had lower copy number variations, single-nucleotide polymorphism, and neoantigen mutation. Our systematic study established a metabolism-related gene-based subgroup to predict outcomes of prostate cancer patients, which may contribute to individual prevention and treatment.

Dataset Information

MPC1, a key gene in cancer metabolism, is regulated by COUPTFII in human prostate cancer.

Publications

MPC1, a key gene in cancer metabolism, is regulated by COUPTFII in human prostate cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure