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PRMT1 expression in renal cell tumors- application in differential diagnosis and prognostic relevance.

ABSTRACT: BACKGROUND:Protein arginine methyltransferase-1 (PRMT1) is associated with the progression of various tumor types and the process of epithelial to mesenchymal transition (EMT). However, the expression of PRMT1 in renal cell tumors (RCT) is unknown. METHODS:We evaluated PRMT1 immunohistochemical (IHC) expression on tissue microarray (TMA) of 208 specimens of RCT, including clear cell renal cell carcinomas (ccRCC), papillary RCC type I and II (pRCC I and II), chromophobe RCC (chRCC), renal oncocytomas (RO), collecting duct carcinomas - Bellini (CDC) and multilocular cystic renal cell neoplasms of low malignant potential (MLCRN-LMP). Moreover, a subset of ccRCC, pRCC, chRCC, RO were also studied using conventional sections. PRMT1 expression in tumor tissue was compared to the IHC expression of EMT-related transcription factors (ZEB1, RUNX1, and TWIST1) and cell surface markers (ß-catenin, N- and E-cadherin). Additionally, qRT-PCR expression of PRMT1 in ccRCC, pRCC, and chRCC was evaluated and the results were compared to the mRNA PRMT1 transcript profiling data in The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) cohort. RESULTS:PRMT1 immunoreactivity was observed in the majority of ccRCC, RO, all MLCRN-LMP, but in a minority of chRCC (p?=?0.044), and it was associated with low grade and low stage ccRCC (p?=?0.014; p?=?0.044, respectively). ZEB1 immunoreactivity was noted in all RO, in minority of chRCC and neither of MLCRN-LMP (p?

SUBMITTER: Filipovic J

PROVIDER: S-EPMC6815371 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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PRMT1 expression in renal cell tumors- application in differential diagnosis and prognostic relevance.

Filipović Jelena J Bosić Martina M Ćirović Sanja S Životić Maja M Dunđerović Duško D Đorđević Dejan D Živković-Perišić Snežana S Lipkovski Aleksandar A Marković-Lipkovski Jasmina J

Diagnostic pathology 20191026 1

<h4>Background</h4>Protein arginine methyltransferase-1 (PRMT1) is associated with the progression of various tumor types and the process of epithelial to mesenchymal transition (EMT). However, the expression of PRMT1 in renal cell tumors (RCT) is unknown.<h4>Methods</h4>We evaluated PRMT1 immunohistochemical (IHC) expression on tissue microarray (TMA) of 208 specimens of RCT, including clear cell renal cell carcinomas (ccRCC), papillary RCC type I and II (pRCC I and II), chromophobe RCC (chRCC) ...[more]

PMID: 31655611

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Project description:Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma, which is characterized by metabolic reprogramming. Cuproptosis, a novel form of cell death, is highly linked to mitochondrial metabolism and mediated by protein lipoylation. However, the clinical impacts of cuproptosis-related genes (CRGs) in ccRCC largely remain unclear. In the current study, we systematically evaluated the genetic alterations of cuproptosis-related genes in ccRCC. Our results revealed that CDKN2A, DLAT, DLD, FDX1, GLS, PDHA1 and PDHB exhibited differential expression between ccRCC and normal tissues (|log2(fold change)| > 2/3 and p < 0.05). Utilizing an iterative sure independence screening (SIS) method, we separately constructed the prognostic signature of CRGs for predicting the overall survival (OS) and progression-free survival (PFS) in ccRCC patients. The prognostic score of CRGs yielded an area under the curve (AUC) of 0.658 and 0.682 for the prediction of 5-year OS and PFS, respectively. In the Kaplan-Meier survival analysis of OS, a higher risk score of cuproptosis-related gene signature was significantly correlated with worse overall survival (HR = 2.72 (2.01-3.68), log-rank p = 1.76 × 10-7). Patients with a higher risk had a significantly shorter PFS (HR = 2.83 (2.08-3.85), log-rank p = 3.66 × 10-7). Two independent validation datasets (GSE40435 (N = 101), GSE53757 (N = 72)) were collected for meta-analysis, suggesting that CDKN2A (log2(fold change) = 1.46, 95%CI: 1.75-2.35) showed significantly higher expression in ccRCC tissues while DLAT (log2(fold change) = -0.54, 95%CI: -0.93--0.15) and FDX1 (log2(fold change) = -1.01, 95%CI: -1.61--0.42) were lowly expressed. The expression of CDKN2A and FDX1 in ccRCC was also significantly associated with immune infiltration levels and programmed cell death protein 1 (PD-1) expression (CDKN2A: r = 0.24, p = 2.14 × 10-8; FDX1: r = -0.17, p = 1.37 × 10-4). In conclusion, the cuproptosis-related gene signature could serve as a potential prognostic predictor for ccRCC patients and may offer novel insights into the cancer treatment.

Project description:Background and Objective: Epigenetic alterations are common events in clear cell renal cell carcinoma (ccRCC), and protein arginine methyltransferase 1 (PRMT1) is an important epigenetic regulator in cancers. However, its role in ccRCC remains unclear. Methods: We investigated PRMT1 expression level and its correlations to clinicopathological factors and prognosis in ccRCC patients based on ccRCC tissue microarrays (TMAs). Genetic knockdown and pharmacological inhibition using a novel PRMT1 inhibitor DCPT1061 were performed to investigate the functional role of PRMT1 in ccRCC proliferation. Besides, we confirmed the antitumor effect of PRMT1 inhibitor DCPT1061 in ccRCC cell-derived tumor xenograft (CDX) models as well as patient-derived tumor xenograft (PDX) models. Results: We found PRMT1 expression was remarkably upregulated in tumor tissues and associated with poor pathologic characters and outcomes of ccRCC patients. Furthermore, genetic knockdown and pharmacological inhibition of PRMT1 by a novel potent inhibitor DCPT1061 dramatically induced G1 cell cycle arrest and suppressed ccRCC cell growth. Mechanistically, RNA sequencing and further validation identified Lipocalin2 (LCN2), a secreted glycoprotein implicated in tumorigenesis, as a crucial regulator of ccRCC growth and functional downstream effector of PRMT1. Epigenetic silencing of LCN2 autocrine secretion by PRMT1 deficiency decreased downstream p-AKT, leading to reduced p-RB and cell growth arrest through the neutrophil gelatinase associated lipocalin receptor (NGALR). Moreover, PRMT1 inhibition by DCPT1061 not only inhibited tumor growth but also sensitized ccRCC to sunitinib treatment in vivo by attenuating sunitinib-induced upregulation of LCN2-AKT-RB signaling. Conclusion: Taken together, our study revealed a PRMT1-dependent epigenetic mechanism in the control of ccRCC tumor growth and drug resistance, indicating PRMT1 may serve as a promising target for therapeutic intervention in ccRCC patients.

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PRMT1 expression in renal cell tumors- application in differential diagnosis and prognostic relevance.

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PRMT1 expression in renal cell tumors- application in differential diagnosis and prognostic relevance.

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