Abstract
Invasive bladder cancer (BC) is one of the most lethal malignant urological tumors. Although miR-200a has been reported as an onco-miRNA that targets the PTEN gene in endometrioid carcinoma, its biological significance in BC invasion has been poorly explored. In the current study, we found that miR-200a was markedly overexpressed in both human BC tissues and BBN-induced muscle-invasive BC tissues. We further showed that miR-200a overexpression specifically promoted human BC cell invasion, but not migration, via transcriptional upregulation of matrix metalloproteinase (MMP)-2. Mechanistic studies indicated that the increased phosphorylation of c-Jun mediated the increasing levels of MMP-2 mRNA transcription. Further investigation revealed that Dicer was decreased in miR-200a overexpressed BC cells; this resulted in inhibition of miR-16 maturation and consequently led to increased JNK2 protein translation and c-Jun activation. Taken together, the studies here showed that miR-200a overexpression inhibited Dicer expression, in turn, resulted in inhibition of miR-16 maturation, leading to upregulation of JNK2 expression, c-Jun phosphorylation, MMP-2 transcription and, ultimately, BC invasion. Collectively, these results demonstrate that miR-200a is an onco-miRNA that is a positive regulator for BC invasion. This finding could be very useful in the ongoing development of new strategies to treat invasive BC patients.
Highlights
Bladder cancer (BC) is one of the common malignant urological tumors [1,2,3,4]
To explore the potential role of miR-200 in BC invasion, we first analyzed the potential change of miR-200 family in human BCs in comparison to normal human bladder tissues in TCGA database and the results showed that the expressions of miR-200a, miR-200b, miR-429, and miR-141 were remarkably upregulated in comparison to grouped normal human bladder tissues or their paired adjacent normal bladder tissues, whereas there was no significant alteration of miR-200c between human bladder tumors and normal bladder tissues (Fig. S1)
To confirm the unexpected finding of miR-200a upregulation in human BCs, we evaluated the expression status of miR-200a in both human BC tissues and N-butyl-N(4-hydroxybutyl) nitrosamine (BBN)-induced mouse invasive BC tissues
Summary
Bladder cancer (BC) is one of the common malignant urological tumors [1,2,3,4]. The most common type of BC is non-muscle-invasive bladder cancer (NMIBC), which accounts for 75% of newly diagnosed BC, while muscleinvasive bladder cancer (MIBC) accounts for 25% of all new diagnoses [5]. Despite the fact that NMIBC can be managed by a combination of transurethral resection and intravesical chemotherapy, >50–70% of NMIBC will recur. 10–20% of recurrent tumors will invade local. These authors contributed : Rui Yang, Jiheng Xu, Xiaohui Hua
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