Abstract
Loss of epigenetic gene regulation through altered long noncoding RNA (lncRNA) expression seems important in human cancer. LncRNAs have diagnostic and therapeutic potential, and offer insights into the biology disease, but little is known of their expression in urothelial cancer. Here, we identify differentially expressed lncRNAs with potential regulatory functions in urothelial cancer. The expression of 17,112 lncRNAs and 22,074 mRNAs was determined using microarrays in 83 normal and malignant urothelial (discovery) samples and selected RNAs with qPCR in 138 samples for validation. Significantly differentially expressed RNAs were identified and stratified according to tumor phenotype. siRNA knockdown, functional assays, and whole-genome transcriptomic profiling were used to identify potential roles of selected lncRNAs. We observed upregulation of many lncRNAs in urothelial cancer that was distinct to corresponding, more balanced changes for mRNAs. In general, lncRNA expression reflected disease phenotype. We identified 32 lncRNAs with potential roles in disease progression. Focusing upon a promising candidate, we implicate upregulation of AB074278 in apoptosis avoidance and the maintenance of a proproliferative state in cancer through a potential interaction with EMP1, a tumor suppressor and a negative regulator of cell proliferation. We report differential expression profiles for numerous lncRNA in urothelial cancer. We identify phenotype-specific expression and a potential mechanistic target to explain this observation. Further studies are required to validate lncRNAs as prognostic biomarkers in this disease.
Highlights
Bladder cancer (BC) is the fourth commonest male malignancy and one of the most expensive human cancers to manage [1, 2]
Results long noncoding RNA (lncRNA) expression in bladder cancer We investigated the expression of 17,112 lncRNAs and
We filtered to 9,351 lncRNAs and 7,922 mRNAs, for which the microarray probe signals were concordant (Fig. 1A and Supplementary Table S1)
Summary
Bladder cancer (BC) is the fourth commonest male malignancy and one of the most expensive human cancers to manage [1, 2]. The majority of tumors are urothelial carcinoma in histologic type. Clinicopathological data suggest that urothelial cancers are best stratified into two distinct phenotypes characterized by low- and highgrade cellular differentiation. Low-grade urothelial cancers frequently have mutations of FGFR3 and STAG2, partial deletion of chromosome 9 [3], and rarely progress to muscle invasion or metastases following endoscopic. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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