NOVA1 inhibition by miR-146b-5p in the remnant tissue microenvironment defines occult residual disease after gastric cancer removal

Oncotarget. 2016 Jan 19;7(3):2475-95. doi: 10.18632/oncotarget.6542.

Abstract

Occult residual disease in remnant tissues could be the cause of tumor relapse. To identify signal molecules and target cells that may be indicative of occult residual disease within a remnant microenvironment, proximal resection margin tissues of gastric cancers were used, as these correspond to the nearest remnant tissues after gastrectomy. Increased miR-146b-5p in the remnant microenvironment was determined to be a strong risk factor for tumor relapse and poor survival rate. NOVA1, a target gene of miR-146b-5p, was decreased in remnant tissues of patients with a poor prognosis. NOVA1 was enriched in stromal spindle cells such as fibroblasts within normal tissues. In non-neoplastic inflammation, such as gastritis, NOVA1 was highly enriched in T lymphocytes and stromal spindle cells, while expression of this protein was frequently decreased in those types of cells within gastric cancer tissues. Particularly, decreased NOVA1 in T cells within the gastric cancer tissues was correlated with decreased FOXP3-positive regulatory T cells and was associated with poor patient prognosis. In vitro analysis showed that the NOVA1 gene was inhibited by miR-146b-5p. In immune cells as well as stromal spindle cells, decreased NOVA1, possibly inhibited by miR-146b-5p, is a candidate biomarker predicting poor prognosis of gastric cancer patients and is also a biomarker of occult residual disease in remnant tissues after gastric cancer removal.

Keywords: NOVA1; hsa-microRNA-146b-5p; microenvironment; residual disease; stromal cells.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Blotting, Western
  • Cell Proliferation
  • Cells, Cultured
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Humans
  • Immunoenzyme Techniques
  • MicroRNAs / genetics*
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / pathology*
  • Neoplasm Staging
  • Neoplasm, Residual / genetics
  • Neoplasm, Residual / metabolism
  • Neoplasm, Residual / pathology*
  • Prognosis
  • RNA, Messenger / genetics
  • RNA-Binding Proteins / antagonists & inhibitors*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology*
  • Stromal Cells / metabolism
  • Stromal Cells / pathology*
  • Survival Rate
  • Tumor Microenvironment / genetics*

Substances

  • MIRN146 microRNA, human
  • MicroRNAs
  • NOVA1 protein, human
  • RNA, Messenger
  • RNA-Binding Proteins