Abstract
Bladder cancer causes an estimated 150,000 deaths per year worldwide. Although 15% of the recurrent bladder cancer becomes an invasive type, currently used targeted therapy for malignant bladder cancer is still not efficient. We focused on the miR-130 family (miR-130b, miR-301a, and miR-301b) that was significantly upregulated in bladder cancer specimens than that of the normal urothelial specimens. We analyzed the functional significance of miR-130 family using a 5637 bladder cancer cell line and revealed that miR-130 family of inhibitors suppressed cell migration and invasion by downregulating focal adhesion kinase (FAK) and Akt phosphorylation. Mechanistic analyses indicate that the miR-130 family directly targets phosphatase and tensin homolog deleted from chromosome 10 (PTEN), resulting in the upregulation of FAK and Akt phosphorylation. In clinical bladder cancer specimens, downregulation of PTEN was found to be closely correlated with miR-130 family expression levels. Overall, the miR-130 family has a crucial role in malignant progression of bladder cancer and thus the miR-130 family could be a promising therapeutic target for invasive bladder cancer.
Highlights
Bladder cancer is a major malignancy worldwide with an estimated 380,000 new cases resulting in 150,000 deaths annually[1]
We recently found by miRNA microarray analysis, that the miR-130 family molecules including miR-130b, miR-301a and miR-301b, which have a common seed sequence (Fig. 1a,b) were significantly upregulated in invasive renal pelvis and ureter carcinoma, compared to normal upper tract urothelium and their non-invasive counterparts
Since the bladder is lined with a layer of urothelium, we investigated the expression of the miR-130 family molecules in bladder cancer
Summary
Bladder cancer is a major malignancy worldwide with an estimated 380,000 new cases resulting in 150,000 deaths annually[1]. Radical cystectomy has been regarded as the first choice treatment for muscle-invasive bladder cancer, even though it lowers quality of life (QOL) for patients[4]. MiRNA can modulate various cellular processes including cell growth, migration or invasion, gaining attention as attractive therapeutic targets for cancer treatment[10,11,12] Recently, several studies showed that targeting miRNAs known as miRNA cluster (e.g. miR-17–92 cluster, miRNA-23b/27b/24 cluster)[13,14,15] or miRNA family sharing a common seed sequence (e.g. miR-34 family, miR-200 family)[16,17], significantly affected tumour progression. We show here for the first time that the miR-130 family is upregulated in bladder cancer clinical specimens and coordinately promotes bladder cancer cell migration and invasion through the phosphorylation of focal adhesion kinase (FAK) as well as Akt by regulating PTEN expression or sub-cellular localization
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