MicroRNA-940 Targets INPP4A or GSK3β and Activates the Wnt/β-Catenin Pathway to Regulate the Malignant Behavior of Bladder Cancer Cells

Oncol Res. 2018 Jan 19;26(1):145-155. doi: 10.3727/096504017X14902261600566. Epub 2017 Mar 23.

Abstract

In this report, we aimed to explore the role and regulatory mechanism of microRNA-940 (miR-940) in bladder cancer development. The expressions of miR-940 in bladder cancer tissues and cells were measured. miR-940 mimics, miR-940 inhibitor small interference RNA against INPP4A (si-INPP4A), and GSK3β (si-GSK3β) and their corresponding controls were then transfected into cells. We investigated the effects of miR-940, INPP4A, or GSK3β on cell proliferation, migration, invasion, and apoptosis. Additionally, target prediction and luciferase reporter assays were performed to investigate the targets of miR-940. The regulatory relationship between miR-940 and the Wnt/β-catenin pathway was also investigated. miR-940 was upregulated in bladder cancer tissues and cells. Overexpression of miR-940 significantly increased bladder cancer cell proliferation, promoted migration and invasion, and inhibited cell apoptosis. INPP4A and GSK3β were the direct targets of miR-940, and knockdown of INPP4A or GSK3β significantly increased cancer cell proliferation, migration, and invasion and inhibited cell apoptosis. After miR-940 overexpression, the protein expression levels of c-Myc, cyclin D1, and β-catenin were significantly increased, and the expression levels of p27 and p-β-catenin were markedly decreased. The opposite effects were obtained after suppression of miR-940. XAV939, a tankyrase 1 inhibitor that could inhibit Wnt/β-catenin signaling, significantly reversed the effects of miR-940 overexpression on cell migration and invasion. Our results indicate that overexpression of miR-940 may promote bladder cancer cell proliferation, migration, and invasion and inhibit cell apoptosis via targeting INPP4A or GSK3β and activating the Wnt/β-catenin pathway. Our findings imply the key roles of suppressing miRNA-940 in the therapy of bladder cancer.

MeSH terms

  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Glycogen Synthase Kinase 3 beta / biosynthesis*
  • Glycogen Synthase Kinase 3 beta / genetics
  • Humans
  • MicroRNAs / genetics*
  • Neoplasm Invasiveness / genetics
  • Phosphoric Monoester Hydrolases / biosynthesis*
  • Phosphoric Monoester Hydrolases / genetics
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / pathology*
  • Wnt Signaling Pathway / physiology*

Substances

  • MIRN940 microRNA, human
  • MicroRNAs
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Phosphoric Monoester Hydrolases
  • phosphatidylinositol-3,4-bisphosphate 4-phosphatase