Dataset Information

Tissue Proteome Signatures Associated with Five Grades of Prostate Cancer and Benign Prostatic Hyperplasia

ABSTRACT: Prostate cancer (PCa) remains a prevalent and deadly disease. The histology-based Gleason score (GS) of PCa tissue biopsy is the most accurate predictor of disease aggressiveness and an important measure to guide decision-making with respect to treatment strategies and patient management. However, inherent variability associated with PCa tumour sampling and the subjective determination of the GS are still key challenges precluding accurate diagnostication and prognostication. Thus, novel molecular signatures are urgently needed to distinguish between indolent and aggressive forms of PCa for better patient management and outcomes. Herein, we have used label-free LC-MS/MS-based proteomics to profile the proteome of 50 PCa tissues spanning five GS-based PCa grades (n = 10 per group) relative to five tissues from individuals with benign prostatic hyperplasia (BPH). Over 2,000 proteins were consistently identified albeit at different levels between and within the patient groups, revealing biological processes associated with specific grades. Excitingly, a panel of 11 prostate-derived proteins including IGKV3D-20, RNASET2, TACC2, ANXA7, LMOD1, PRCP, GYG1, NDUFV1, H1FX, APOBEC3C, CTSZ displayed the potential to accurately stratify patients displaying low and high GS. This is the first study to characterise the prostate tissue proteome signatures of the five PCa grades relative to BPH. We report a panel of proteins that accurately can distinguish low and high GS PCa tissues. These promising proteins can be further explored as candidate biomarkers for PCa aggressiveness.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Prostate Adenocarcinoma Cell

DISEASE(S): Prostate Cancer

SUBMITTER: Rebeca Kawahara

LAB HEAD: Giuseppe Palmisano

PROVIDER: PXD013837 | Pride | 2019-10-09

REPOSITORIES: Pride

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Tissue Proteome Signatures Associated with Five Grades of Prostate Cancer and Benign Prostatic Hyperplasia.

Kawahara Rebeca R Recuero Saulo S Nogueira Fabio C S FCS Domont Gilberto B GB Leite Katia R M KRM Srougi Miguel M Thaysen-Andersen Morten M Palmisano Giuseppe G

Proteomics 20191020 21-22

The histology-based Gleason score (GS) of prostate cancer (PCa) tissue biopsy is the most accurate predictor of disease aggressiveness and an important measure to guide treatment strategies and patient management. The variability associated with PCa tumor sampling and the subjective determination of the GS are challenges that limit accurate diagnostication and prognostication. Thus, novel molecular signatures are needed to distinguish between indolent and aggressive forms of PCa for better patie ...[more]

PMID: 31576646

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Project description:Background: Aldo-keto reductase (AKR) 1C family member 3 (AKR1C3), one of four identified human AKR enzymes, catalyzes steroid, prostaglandin, and xenobiotic metabolism. In the prostate, AKR1C3 is up-regulated in localized and advanced prostate adenocarcinoma, and is associated with prostate cancer (PCa) aggressiveness. Here we provide initial evidence for potential roles of AKR1C3 in PCa progression. Methods: Spatial distribution of AKR1C3 was analyzed using immunohistochemical staining in prostate adenocarcinoma tissue array. Human PCa PC-3 cells were stably transfected with AKR1C3 cDNA to establish PC3-AKR1C3 transfectants. Microarray and bioinformatics analyses were performed to identify pathways that are activated by elevated AKR1C3 expression in PCa cells. Functional confirmation of microarray and bioinformatics results was performed by immunoblot analysis and an in vitro Matrigel angiogenesis assay. Results: Elevated AKR1C3 expression was specifically limited to human prostate adenocarcinoma. Microarray and bioinformatics analysis suggested that elevated AKR1C3 expression in PC-3 cells modulates estradiol and androgen metabolism and activates insulin growth factor (IGF)-1 and Akt signaling pathways. Immunoblots confirmed that phosphorylated levels of IGF-1 receptor (IGF-1R) and Akt are significantly up-regulated in PC3-AKR1C3 as compared to mock transfectants. PC3-AKR1C3 transfectants promoted endothelial cell tube formation in Matrigel as compared to parental PC-3 cells and mock transfectants. Conclusion: Microarray and bioinformatics data followed by biological analyses suggest that elevated AKR1C3 expression in PC-3 cells promotes PCa angiogenesis and aggressiveness. These results suggest AKR1C3 can promote the aggressiveness of PCa through modulating estrogen and androgen metabolism with subsequent activation of growth factor IGF-1 and cytoplasmic Akt signaling pathways. Total RNA from mock- and ACR1C3 transfected PC-3 cells was isolated, with 2 or 3 biological replicates each. Gene expression data from AKR1C3 transfected PC-3 cells were compared with mock-transfected data.

Project description:We assessed differential gene expression in tissue specimens of PCa and BPH patients who underwent radical prostatectomy by customized expression microarrays (Agilent). To detect gene signatures of diagnostic and prognostic value, we assessed fresh frozen radical prostatectomy (RP) samples of PCa and BPH patients by transcriptome-wide sequencing and Agilent custom microarrays. We stratified PCa patients according to seven clinical risk groups based on Gleason Score (GS), the presence of regional lymph node metastases (pN) and the occurrence of death of disease (DoD): (i) very low risk (group V: GS<7, pN0), (ii) low risk (group L: GS=7, pN0), (iii) medium risk (group M: GS<=7, pN1), (iv) high risk survivors without lymph node infiltration (group H-s: GS>7, pN0), (v) high risk non-survivors without lymph node infiltration (group H-d: GS>7, pN0, DoD), (vi) high risk survivors with lymph node infiltration (group H+s: GS>7, pN1), (vii) high risk non-survivors with lymph node infiltration (group H+d: GS>7, pN1, DoD). For high risk groups adjacent tumor-free prostate tissue samples were obtained (groups H+sf, H-sf, H+df, H+df). The control group contained patients with benign prostate hyperplasia (group C). Information on the course of the disease, survival of the patients and the cause of death were obtained from the general practitioners or treating urologists or from records of the regional tumor registry. Clinicopathological parameters were obtained by routine histopathological examination of the surgical specimens. Serum levels of the prostate-specific antigen (PSA) were determined preoperatively (Abbott, Wiesbaden, Germany). Frozen tissue samples were embedded in Tissue-Tek OCT-compound (Sakura Finetek GmbH, Staufen im Breisgau, Germany) and fixed on metal indenters by freezing. Cryo-sections were prepared using a cryo-microtome (Leica Biosystems, Nußloch, Germany) equipped with a microtome blade C35 cooled to -28 °C. For every tissue three stacks of consecutive cryo-sections (10 µm) were generated, each bordered/flanked by HE-stained cryo-sections (4 µm), which were evaluated by a pathologist with regard to tumor and stroma cell content. PCa tissue stacks had to be flanked on either side by sections containing at least 50 % tumor cells to be used for further analyses. Sections of the tissue stacks were immediately transferred to 1 ml Qiazol (Qiagen, Hilden, Germany) and stored at -80 °C until RNA isolation.

			Action	DRS
	HUMAN.fasta	Fasta
	QE-0681_Giusepe_A1.raw	Raw
	QE-0683_Giusepe_A2.raw	Raw
	QE-0685_Giusepe_A3.raw	Raw
	QE-0687_Giusepe_A4.raw	Raw