Characterization of Transcriptional Changes in ERG Rearrangement-Positive Prostate Cancer Identifies the Regulation of Metabolic Sensors Such as Neuropeptide Y

Massoner, Petra; Kugler, Karl G.; Unterberger, Karin; Kuner, Ruprecht; Mueller, Laurin A. J.; Fälth, Maria; Schäfer, Georg; Seifarth, Christof; Ecker, Simone; Verdorfer, Irmgard; Graber, Armin; Sültmann, Holger; Klocker, Helmut

doi:10.1371/journal.pone.0055207

Cited by 32 publications

(42 citation statements)

References 72 publications

(77 reference statements)

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“…We also investigated metabolic pathways connected to glycine and glucose metabolism, as TMPRSS2-ERG has been suggested to be linked to increased glucose uptake [17, 18]. …”

Section: Resultsmentioning

confidence: 99%

“…Citrate and spermine, including choline and creatine are metabolites detectable by in vivo patient magnetic resonance spectroscopy imaging (MRSI), which imply a potential for transferring biomarkers to a clinical setting [16]. A recent study revealed ERG-specific metabolic alterations, particularly connected to fatty acid oxidation [17] and an earlier study found increased glucose uptake to be related to the metabolic sensor neuropeptide gamma ( NPY ) in ERG rearrangement positive prostate cancer [18]. Apart from these two studies, the relationship between cancer metabolism and TMPRSS2-ERG remains unexplored.…”

Section: Introductionmentioning

confidence: 99%

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Presence of TMPRSS2-ERG is associated with alterations of the metabolic profile in human prostate cancer

et al. 2016

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TMPRSS2-ERG has been proposed to be a prognostic marker for prostate cancer. The aim of this study was to identify changes in metabolism, genes and biochemical recurrence related to TMPRSS2-ERG by using an integrated approach, combining metabolomics, transcriptomics, histopathology and clinical data in a cohort of 129 human prostate samples (41 patients). Metabolic analyses revealed lower concentrations of citrate and spermine comparing ERGhigh to ERGlow samples, suggesting an increased cancer aggressiveness of ERGhigh compared to ERGlow. These results could be validated in a separate cohort, consisting of 40 samples (40 patients), and magnetic resonance spectroscopy imaging (MRSI) indicated an in vivo translational potential. Alterations of gene expression levels associated with key enzymes in the metabolism of citrate and polyamines were in consistence with the metabolic results. Furthermore, the metabolic alterations between ERGhigh and ERGlow were more pronounced in low Gleason samples than in high Gleason samples, suggesting it as a potential tool for risk stratification. However, no significant difference in biochemical recurrence was detected, although a trend towards significance was detected for low Gleason samples. Using an integrated approach, this study suggests TMPRSS2-ERG as a potential risk stratification tool for inclusion of active surveillance patients.

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“…We also investigated metabolic pathways connected to glycine and glucose metabolism, as TMPRSS2-ERG has been suggested to be linked to increased glucose uptake [17, 18]. …”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Presence of TMPRSS2-ERG is associated with alterations of the metabolic profile in human prostate cancer

et al. 2016

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“…ECE1 has been implicated in prostate cancer cell invasion, in which different isoforms of the protein were found to play different roles (19). PLA2G4C is regulated by EGR, a gene that is rearranged in approximately 50% of prostate cancer (20). In bladder cancer, very few of the top findings have been published in association with disease.…”

Section: Discussionmentioning

confidence: 99%

Automated analysis of immunohistochemistry images identifies candidate location biomarkers for cancers

Kumar¹,

Rao²,

Bhavani³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Changes in the expression of proteins are often associated with oncogenesis, and are frequently used as cancer biomarkers. Changes in the subcellular location of proteins have been less frequently investigated. In this paper, we describe a robust pipeline for identifying those proteins whose subcellular location undergoes statistically significant changes in cancers of four tissues, and also for identifying biochemical pathways that are enriched for proteins that translocate. Future investigation of these proteins and pathways may provide new insight into oncogenesis. Further, the analysis pipeline is expected to be useful for assessing disease type and severity in a clinical setting.

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“…Furthermore, we analysed data of a PCa meta-analysis study which we performed previously (Massoner et al , 2013). …”

Section: Methodsmentioning

confidence: 99%

EpCAM is overexpressed in local and metastatic prostate cancer, suppressed by chemotherapy and modulated by MET-associated miRNA-200c/205

et al. 2014

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Background:Expression of epithelial cell adhesion molecule (EpCAM) is deregulated in epithelial malignancies. Beside its role in cell adhesion, EpCAM acts as signalling molecule with tumour-promoting functions. Thus, EpCAM is part of the molecular network of oncogenic receptors and considered an interesting therapeutic target.Methods:Here, we thoroughly characterised EpCAM expression on mRNA and protein level in comprehensive tissue studies including non-cancerous prostate specimens, primary tumours of different grades and stages, metastatic lesions, and therapy-treated tumour specimens, as well as in prostate cancer cell lines.Results:Epithelial cell adhesion molecule was overexpressed at mRNA and at protein level in prostate cancer tissues and cell lines. Altered EpCAM expression was an early event in prostate carcinogenesis with an upregulation in low-grade cancers and further induction in high-grade tumours and metastatic lesions. Interestingly, EpCAM was repressed upon induction of epithelial-to-mesenchymal transition (EMT) following chemotherapeutic treatment with docetaxel. Oppositely, re-induction of the epithelial phenotype through miRNAs miR-200c and miR-205, two inducers of mesenchymal-to-epithelial transition (MET), led to re-induction of EpCAM in chemoresistant cells. Furthermore, we prove that EpCAM cleavage, the first step of EpCAM signalling takes place in prostate cancer cells but in contrast to other cancer entities, EpCAM has no measurable impact on the proliferative behaviour of prostate cells, in vitro.Conclusions:In conclusion, our data confirm that EpCAM overexpression is an early event during prostate cancer progression. Epithelial cell adhesion molecule displays a dynamic, heterogeneous expression and associates with epithelial cells rather than mesenchymal, chemoresistant cells along with processes of EMT and MET.

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Characterization of Transcriptional Changes in ERG Rearrangement-Positive Prostate Cancer Identifies the Regulation of Metabolic Sensors Such as Neuropeptide Y

Cited by 32 publications

References 72 publications

Presence of TMPRSS2-ERG is associated with alterations of the metabolic profile in human prostate cancer

Presence of TMPRSS2-ERG is associated with alterations of the metabolic profile in human prostate cancer

Automated analysis of immunohistochemistry images identifies candidate location biomarkers for cancers

EpCAM is overexpressed in local and metastatic prostate cancer, suppressed by chemotherapy and modulated by MET-associated miRNA-200c/205

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