Expanding the miRNA Transcriptome of Human Kidney and Renal Cell Carcinoma.

Adam P Sage,Greg L Stewart,Wan L Lam,Katey S S Enfield,Brenda C Minatel,Victor D Martinez,Erin A Marshall

doi:10.1155/2018/6972397

Adam P Sage, Greg L Stewart + Show 5 more

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https://doi.org/10.1155/2018/6972397

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Abstract

Despite advancements in therapeutic strategies, diagnostic and prognostic molecular markers of kidney cancer remain scarce, particularly in patients who do not harbour well-defined driver mutations. Recent evidence suggests that a large proportion of the human noncoding transcriptome has escaped detection in early genomic explorations. Here, we undertake a large-scale analysis of small RNA-sequencing data from both clear cell renal cell carcinoma (ccRCC) and nonmalignant samples to generate a robust set of miRNAs that remain unannotated in kidney tissues. We find that these novel kidney miRNAs are also expressed in renal cancer cell lines. Moreover, these sequences are differentially expressed between ccRCC and matched nonmalignant tissues, implicating their involvement in ccRCC biology and potential utility as tumour-specific markers of disease. Indeed, we find some of these miRNAs to be significantly associated with patient survival. Finally, target prediction and subsequent pathway analysis reveals that miRNAs previously unannotated in kidney tissues may target genes involved in ccRCC tumourigenesis and disease biology. Taken together, our results represent a new resource for the study of kidney cancer and underscore the need to characterize the unexplored areas of the transcriptome.

Highlights

Despite recent advancements in the diagnosis and treatment of kidney cancer, patients are faced with a poor prognosis, especially when diagnosed at a later stage [1]
We sought to further examine the role that these unannotated and validated miRNAs expressed in kidney tissues may have in clear cell renal cell carcinoma (ccRCC) tumourigenesis and their potential clinical relevance
NGF signaling Signaling by NGF Signaling by SCF-KIT Signaling by FGFR Prolonged ERK activation events Signaling by vascular endothelial growth factor (VEGF) Downstream signal transduction VEGFR2-mediated cell proliferation Interleukin-3, 5 and GM-CSF signaling VEGFA-VEGFR2 pathway Signaling by leptin Signaling by EGFR FRS-mediated FGFR signaling Interleukin-2 signaling ARMS-mediated activation Signaling by PDGF GRB2 events in EGFR signaling SHC1 events in EGFR signaling SOS-mediated signaling Frs2-mediated activation Interleukin receptor SHC signaling Signaling to p38 via RIT and RIN Signaling to ERKs DAP12 signaling Signaling by interleukins Fc epsilon receptor (FCERI) signaling Signaling to RAS Cholinergic synapse Integration of energy metabolism IGF1R signaling cascade IRS-mediated signaling Regulation of actin cytoskeleton Insulin receptor signaling cascade FCERI-mediated MAPK activation

Summary

Introduction

Despite recent advancements in the diagnosis and treatment of kidney cancer, patients are faced with a poor prognosis, especially when diagnosed at a later stage [1]. While environmental risk factors including hypertension, smoking, obesity, and a history of chronic kidney disease may modulate an individual’s susceptibility, ccRCC arises from molecular aberrations that can be both sporadic and inherited [2, 3]. Many of these alterations result from DNA copy number losses, mutations, and hypermethylation events, commonly affecting genes associated with cellular metabolism [4, 5]. Considering the close association of metabolic reprogramming with ccRCC development and progression, remarkable advances have been made in the treatment of ccRCC patients with the use of antiangiogenic therapies [7]. Despite the increased treatment efficacy of antiangiogenic therapies, patient outcome is impaired by the lack of clinically relevant diagnostic or prognostic markers [8, 9]

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