Identification of differentially expressed miRNAs and miRNA-targeted genes in bladder cancer.

Jong-Young Lee,Eun Sang Yoo,Sathiyamoorthy Subramaniyam,Xuan-Mei Piao,Sung-Kwon Moon,Jihye Kim,Young Joon Byun,Pildu Jeong,Wun-Jae Kim,Jung Min Kim,Sung Phil Seo,Isaac Y Kim,Yung Hyun Choi,Ye-Hwan Kim,Seok Joong Yun,Jayoung Kim,Ho Won Kang

doi:10.18632/oncotarget.24441

Abstract

BackgroundDifferentially expressed genes and their post-transcriptional regulator-microRNAs (miRNAs), are potential keys to pioneering cancer diagnosis and treatment. The aim of this study was to investigate how the miRNA-mRNA interactions might affect the tumorigenesis of bladder cancer (BC) and to identify specific miRNA and mRNA genetic markers in the two BC types: non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC).ResultsWe identified 227 genes that interacted with 54 miRNAs in NMIBC, and 14 genes that interacted with 10 miRNAs in MIBC. Based on this data, we found extracellular matrix-related genes are highly enriched in NMIBC while genes related to core nuclear division are highly enriched in MIBC. Furthermore, using a transcriptional regulatory element database, we found indirect regulatory transcription factors (TFs) for enriched genes could regulate tumorigenesis with or without miRNAs.Materials and methodsTissue samples from 234 patients histologically diagnosed with BC and 83 individuals without BC were analyzed using microarray and next-generation sequencing technology, and we used different cut-offs to identify differentially expressed mRNAs and miRNAs in NMIBC and MIBC. The selected mRNAs and miRNAs were paired using validated target datasets and according to inverse expression relationships. MiRNA interacted genes were compared with the TF-regulating genes in BC. Meanwhile, pathway enrichment analysis was performed to identify the functions of selected miRNAs and genes.ConclusionsIdentification of differential gene expression in specific tumor types could facilitate development of cancer diagnosis and aid in the early detection of BC.

Highlights

Bladder cancer (BC) is the second most common urological malignancy in the United States
We extracted 522 genes that were differentially expressed in non-muscle invasive bladder cancer (NMIBC) versus normal tissue, 105 genes differentially expressed in muscle invasive bladder cancer (MIBC) versus normal tissue, and 60 genes differentially expressed in NMIBC versus MIBC
The 402/522 differentially expressed genes in the NMIBC were strongly associated with the extracellular matrix (ECM) (false discovery rate (FDR), 1.35E-17) and extracellular structure organization (FDR, 2.98E13) (Supplementary Table 1)

Summary

Introduction

Bladder cancer (BC) is the second most common urological malignancy in the United States. Conventional diagnosis of BC classifies the tumor into two groups based on its clinico-pathologic features: non-muscle invasive (NMIBC) and muscle-invasive (MIBC). At the time of first diagnosis, a majority of cases are classified as NMIBC. Approximately 20% of BC is confirmed as MIBC in situ, which is the main cause of cancer-specific deaths in BC patients. Even after transurethral resection (TUR) of the primary tumor, the chance of recurrence is common with NMIBC. 30-50% of patients with NMIBC experience recurrence in their lifetime. The aim of this study was to investigate how the miRNA-mRNA interactions might affect the tumorigenesis of bladder cancer (BC) and to identify specific miRNA and mRNA genetic markers in the two BC types: non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC)

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