Abstract
Our most recent studies demonstrate that miR-137 is downregulated in human bladder cancer (BC) tissues, while treatment of human BC cells with isorhapontigenin (ISO) elevates miR-137 abundance. Since ISO showed a strong inhibition of invasive BC formation in the N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced invasive BC mouse model, the elucidation of a potential biological effect of miR-137 on antagonizing BC invasion and molecular mechanisms underlying ISO upregulation of miR-137 are very important. Here we discovered that ectopic expression of miR-137 led to specific inhibition of BC invasion in human high-grade BC T24T and UMUC3 cells, while miR-137 deletion promoted the invasion of both cells, indicating the inhibitory effect of miR-137 on human BC invasion. Mechanistic studies revealed that ISO treatment induced miR-137 transcription by promoting c-Jun phosphorylation and, in turn, abolishing matrix metalloproteinase-2 (MMP-2) abundance and invasion in BC cells. Moreover, miR-137 was able to directly bind to the 3′ UTR of Glycogen synthase kinase-3β (GSK3β) mRNA and inhibit GSK3β protein translation, consequently leading to a reduction of heat shock protein-70 (HSP70) translation via targeting the mTOR/S6 axis. Collectively, our studies discover an unknown function of miR-137, directly targeting the 3′ UTR of GSK3β mRNA and, thereby, inhibiting GSK3β protein translation, mTOR/S6 activation, and HSP70 protein translation and, consequently, attenuating HSP70-mediated MMP-2 expression and invasion in human BC cells. These novel discoveries provide a deep insight into understanding the biomedical significance of miR-137 downregulation in invasive human BCs and the anti-cancer effect of ISO treatment on mouse invasive BC formation.
Highlights
Consistent with its promotion of matrix metalloproteinases (MMPs)-2 levels, the introduction of miR-137 inhibitor did promote cell invasion, and such increased cell invasion by miR-137 inhibitor could be completely abolished by the knockdown of Heat shock protein70 (HSP70) (Figures 5L and 5M). These results strongly indicated that HSP70 is an miR-137 downstream mediator responsible for the suppression of MMP-2 expression and Bladder cancer (BC) invasion
As a new derivative of stilbene compound discovered to affect the competence of cancers, ISO at relevant applicable concentrations effectively abolishes transcription factor specific protein 1 (Sp1) expression and transactivation, leading to the downregulation of bindings of Sp1 to the promoter region of its regulated genes, cyclin D1 and XIAP, and further suppression of cancer cell anchorage-independent growth and induction of apoptosis in BC cells.[10,12]
The transcription level of MMP-2 is inhibited by forkhead box class O 1 (FOXO1) following ISO treatment in vitro,[7] and this finding in vitro is consistently supported by data obtained from an in vivo mouse model of ISO inhibition, BBN-induced mouse-invasive BC formation.[7]
Summary
Bladder cancer (BC) is the second urological malignancy and causes about 150,000 deaths annually worldwide.[1,2] during initial treatment, approximately 70% of non-muscle-invasive tumors in BC cases still recur, and only 20%–30% of them become to invade the lamina propria and are staged as T1.3 Eventually, 10%–15% of the recurrent tumors progress to being muscle-invasive and metastasized. Molecular Therapy: Nucleic Acids Vol 12 September 2018 a 2018 The Authors. Relative miR-137 Expression A T24T C Vehicle *.
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