Abstract
BackgroundGrowing evidence supports the pivotal role of long non-coding RNAs (lncRNAs) in the regulation of cancer development and progression. Their expression patterns and biological function in muscle invasive bladder cancer (MIBC) remain elusive.MethodsTranscript levels of lncRNA miR-31 host gene (MIR31HG) and its splice variants were measured in our MIBC cohort (n = 102) by qRT-PCR, and validated in silico by the TCGA cohort (n = 370). Kaplan-Meier and multiple Cox regression analysis were conducted to evaluate the survival significance of MIR31HG and its splice variants. Functional experiments were performed to examine the proliferation and migration abilities of MIR31HG and its splice variants by knockdown approaches.ResultsIn this study, a decreased expression of MIR31HG was found in bladder cancer cells and tissues, except in the basal subtype. Survival analysis showed that high expression of MIR31HG was associated with poor overall survival (OS) and disease-free survival (DFS) in patients with MIBC of basal subtype. Two splice variants of MIR31HG lacking exon 1 (MIR31HGΔE1) and exon 3 (MIR31HGΔE3) were identified to have specific expression patterns in different molecular subtypes of our MIBC cohort. MIR31HGΔE3 was highly expressed in basal subtype tumors. A high expression of MIR31HGΔE1 and MIR31HGΔE3 was associated with worse OS and DFS in our cohort. In vitro experiments revealed that knockdown of MIR31HG inhibits cell proliferation, colony formation, and migration in bladder cancer. Cell proliferation and migration assays after knockdown of splice variants of MIR31HG showed corresponding roles for the full-length transcript.ConclusionsOur study demonstrates that MIR31HG and its splice variants could serve as biomarkers for the classification and prognosis prediction of patients with MIBC.
Highlights
Growing evidence supports the pivotal role of long non-coding RNAs in the regulation of cancer development and progression
By clustering according to a trichotomous molecular classifications based on an alternative mRNA clustering of the The Cancer Genome Atlas (TCGA) cohort [33], it is determined that the expression of miR-31 host gene (MIR31HG) was higher in the basal subtype compared to the luminal and infiltrated subtypes (Fig. S1A)
In contrast to a previous study, which reported that miR-31 and MIR31HG are down-regulated in triplenegative breast cancer (TNBC) cell lines of basal subtype [37], the present study shows that MIR31HG is highly expressed in the Bladder urothelial carcinoma (BLCA) cell line of basal subtype and markedly correlates with the survival of patients with muscle invasive bladder cancer (MIBC) basal subtype
Summary
Growing evidence supports the pivotal role of long non-coding RNAs (lncRNAs) in the regulation of cancer development and progression. Their expression patterns and biological function in muscle invasive bladder cancer (MIBC) remain elusive. It is widely accepted that BLCA is a heterogeneous disease, which is classified into two distinct subtypes: non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) [2]. A number of groups have reported molecular classifications of BLCA to evaluate the severity and prognosis of this disease, reliable and effective biomarkers for early diagnosis and prognostic prediction are still lacking [5, 6]. In-depth understanding of molecular events and underlying mechanisms involved in the carcinogenesis of MIBC may provide effective therapeutic targets and predictive biomarkers, which are urgently needed
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