Abstract
Background: Metastasis is the primary cause of cancer deaths, warranting further investigation. This study assessed microRNA-153 (miR-153) expression in bladder cancer tissues and investigated the underlying molecular mechanism of miR-153-mediated regulation of bladder cancer cells.Methods: Paired tissue specimens from 45 bladder cancer patients were collected for qRT-PCR. The Cancer Genome Atlas (TCGA) dataset was used to identify associations of miR-153 with bladder cancer prognosis. Bladder cancer tissues and immortalized cell lines were used for the following experiments: miR-153 mimics and indoleamine 2,3-dioxygenase 1 (IDO1) siRNA transfection; Western blot, cell viability, colony formation, and Transwell analyses; nude mouse xenograft; and chicken embryo chorioallantoic membrane angiogenesis (CAM) assays. Human umbilical vein endothelial cells (HUVECs) were co-cultured with bladder cancer cells for the tube formation assay. The luciferase reporter assay was used to confirm miR-153-targeting genes.Results: miR-153 expression was downregulated in bladder cancer tissues and cell lines, and reduced miR-153 expression was associated with advanced tumor stage and poor overall survival of patients. Moreover, miR-153 expression inhibited bladder cancer cell growth by promoting tumor cell apoptosis, migration, invasion, and endothelial mesenchymal transition (EMT) in vitro and tumor xenograft growth in vivo, while miR-153 expression suppressed HUVEC and CAM angiogenesis. At the gene level, miR-153 targeted IDO1 expression and inhibited bladder cancer cell tryptophan metabolism through inhibiting IL6/STAT3/VEGF signaling.Conclusions: Collectively, our data demonstrate that miR-153 exerts anti-tumor activity in bladder cancer by targeting IDO1 expression. Future studies will investigate miR-153 as a novel therapeutic target for bladder cancer patients.
Highlights
Bladder cancer is one of the most commonly occurring malignancies worldwide, accounting for an estimated 429,800 new cases and more than 165,000 cancer-related deaths in 2012, with an increased prevalence in males [1]
We first measured miR-153 expression in bladder cancer tissue specimens and cell lines compared to normal samples and found that miR-153 expression was significantly downregulated in 45 pairs of bladder cancer compared to adjacent normal tissues (ANT; P < 0.05; Figure 1A)
interleukin 6 (IL-6) expression was significantly suppressed in the experimental groups compared to the control groups, while phosphorylated STAT3 and vascular endothelial growth factor (VEGF) were significantly decreased in miR-153-overexpressing or IDO1 knocked down bladder cancer cells (Figure 7)
Summary
Bladder cancer is one of the most commonly occurring malignancies worldwide, accounting for an estimated 429,800 new cases and more than 165,000 cancer-related deaths in 2012, with an increased prevalence in males [1]. Risk factors of bladder cancer include tobacco smoke, family cancer history, frequent bladder infections, and exposure to certain chemicals [2, 3]. To date, ∼75% of clinically diagnosed bladder cancers are non-muscle invasive and 25% involve bladder muscle [4]. Treatment options for bladder cancer depend on tumor stage and include transurethral resection (TURBt), intravesical instillation, immunotherapy [Bacillus Calmette–Guérin (BCG)], and chemotherapy [5, 6]. Compared to non-muscle invasive bladder cancer, tumors invading the muscle often have a poor prognosis [4]. High rates of tumor recurrence are a clinical burden for all bladder cancer patients. Metastasis is the primary cause of cancer deaths, warranting further investigation. This study assessed microRNA-153 (miR-153) expression in bladder cancer tissues and investigated the underlying molecular mechanism of miR-153mediated regulation of bladder cancer cells
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