Dysregulation of miRNAs in bladder cancer: altered expression with aberrant biogenesis procedure

Abstract

Aberrant expression profiles of miRNAs are widely observed in the clinical tissue specimens and urine samples as well as the blood samples of bladder cancer patients. These profiles are closely related to the pathological features of bladder cancer, such as the tumour stage/grade, metastasis, recurrence and chemo-sensitivity. MiRNA biogenesis forms the basis of miRNA expression and function, and its dysregulation has been shown to be essential for variations in miRNA expression profiles as well as tumourigenesis and cancer progression. In this review, we summarize the up-to-date and widely reported miRNAs in bladder cancer that display significantly altered expression. We then compare the miRNA expression profiles among three different sample types (tissue, urine and blood) from patients with bladder cancer. Moreover, for the first time, we outline the dysregulated miRNA biogenesis network in bladder cancer from different levels and analyse its possible relationship with aberrant miRNA expression and the pathological characteristics of the disease.

Keywords: biogenesis procedure; bladder cancer; expression profile; microRNA.

Figure 1. MiRNA biogenesis procedure

The whole biological process basically includes coding gene transcription, pri-miRNA cleavage, pre-miRNA maturation, miRNA-mRNA binding and target mRNA degeneration. miRISC, miRNA-induced silencing complex; TRBP, transactivation-responsive RNA-binding protein.

Figure 2. Venn diagram of multiple reported miRNAs in three biological samples

73 miRNAs are downregulated(A) and 71 are overexpressed(B). Differences of the expression exists among clinical bladder tumor tissues (blue circle), urine samples (yellow circle) and blood (red circle). 21, 12 and 6 miRNAs decrease respectively in subgroups of “Tissue and Urine” (a), “Tissue and Blood” (b) and “Urine and Blood” (c), and 16 (e), 12 (f) and 2 (g) miRNAs are correspondingly over-expressed. The overlapping part of three circles represents miR-1, miR-99a, miR-100 and miR-143 in A, and miR-21 along with miR-210 in B. T&U, Tissue and Urine; T&B, Tissue and Blood; U&B, Urine and Blood; T&U&B, Tissue and Urine and Blood.

Figure 3. Feedback loop of epigenetic modifications of miRNAs in BCa

With the help of DNMTs and HMTs, miRNA coding genes (a) and related histones (A) can be modified epigenetically, thus anti-cancer miRNAs in urothelial cells are silenced (b, B); Some miRNAs can in turn suppress the expression level of DNMTs (c) and HMTs (C). DNMTs, DNA methyltransferases; HMTs, histone methyltransfereases.

Figure 4. Abnormal miRNA biogenesis in bladder cancer development

Abnormalities of miRNA biogenesis in BCa appear at multiple levels of the whole procedure. Genetic variations, epigenetic modifications, different transcription factors, the host genes as well as hypoxia alter the transcriptions of pri-miRNA; With the help of SIRT1, p53 accelerates the processing of pri-miRNAs (like pri-miR-34a); Microprocessor Complex and XPO5, which are transcriptionally upregulated, lead to wide aberrance of miRNAs in BCa; PKC-α, miR-18a and genetic variations induce the dysregulation of DICER and the transcriptional dysregulation of DICER will affect pre-miRNA cleavage in BCa; Loss of macroH2A1 in bladder cancer promote Lin28 to selectively bind to pre-let-7 so that pre-let-7 won't be processed by DICER; The abnormalities at different steps cause the upregulation of oncomiRNAs and the downregulation of tumor suppressors, but the changes of some miRNAs in BCa are still unclear; The variations of miRNA binding sites and ceRNAs lead to malfunction of miRNAs by inhibiting the miRNA-mRNA combination in bladder cancer; Abnormal miRNA expression and function modulate the downstream targets and signaling pathways and eventually lead to carcinogenesis and development of bladder cancer. PTEN, phosphate and tension homology deleted on chromosome ten; Akt, serine/threonine kinase; MLK3, mixed lineage kinase 3; PKC-α, protein kinase C-α; SIRT-1, Sirtuin-1; ZEB1/2, zinc finger e-box binding homeobox 1/2.