MicroRNA-1826 targets VEGFC, beta-catenin (CTNNB1) and MEK1 (MAP2K1) in human bladder cancer

• Published in: Carcinogenesis (New York) Vol. 33; no. 1; pp. 41 - 48
• Main Authors: Hirata, Hiroshi, Hinoda, Yuji, Ueno, Koji, Shahryari, Varahram, Tabatabai, Z.Laura, Dahiya, Rajvir
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.01.2012
• Subjects: Apoptosis; beta Catenin - antagonists & inhibitors; beta Catenin - genetics; Biological and medical sciences; Biology, Genetics and Epigenetics; Carcinogenesis, carcinogens and anticarcinogens; Cell Cycle; Cell Movement; Cell Survival; Cells, Cultured; Gene Expression Regulation; Humans; Male; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase 1 - genetics; Medical sciences; MicroRNAs - genetics; MicroRNAs - physiology; Neoplasm Invasiveness; Nephrology. Urinary tract diseases; Signal Transduction; Transfection; Tumors; Tumors of the urinary system; Urinary Bladder Neoplasms - genetics; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; Vascular Endothelial Growth Factor C - antagonists & inhibitors; Vascular Endothelial Growth Factor C - genetics; Human; Urinary system disease; RNA interference; Targeting; Micro RNA; Urinary tract disease; Malignant tumor; Bladder cancer; Chenopodiaceae; Beta; Gene silencing; Target; Dicotyledones; Angiospermae; Bladder disease; Spermatophyta; Catenin; Cancer
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgr239

The Wnt/beta-catenin (CTNNB1) and Ras-Raf-MEK-ERK signaling pathway play an important role in bladder cancer (BC) progression. Tumor-suppressive microRNAs (miRNAs) targeting these cancer pathways may provide a new therapeutic approach for BC. We initially identified miRNA-1826 potentially targeting CTNNB1, VEGFC and MEK1 using several target scan algorithms. Also 3′ untranslated region luciferase activity and protein expression of these target genes were significantly downregulated in miR-1826-transfected BC cells (J82 and T24). The expression of miR-1826 was lower in BC tissues and inverse correlation of miR-1826 with several clinical parameters (pT, grade) was observed. Also the expression of miR-1826 was much lower in three BC cell lines (J82, T24 and TCCSUP) compared with a normal bladder cell line (SV-HUC-1). We then performed analyses to look at miR-1826 function and found that miR-1826 inhibited BC cell viability, invasion and migration. We also found increased apoptosis and G1 cell cycle arrest in miR-1826-transfected BC cells. To examine whether the effect of miR-1826 was through CTNNB1 (beta-catenin) or MEK1 knockdown, we knocked down CTNNB1/MEK1 messenger RNA using a small interfering RNA (siRNA) technique. We observed that CTNNB1 or MEK1 siRNA knockdown resulted in effects similar to those with miR-1826 in BC cells. In conclusion, our data suggest that the miR-1826 plays an important role as tumor suppressor via CTNNB1/MEK1/VEGFC downregulation in BC.