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Cellular Oncology

, Volume 39, Issue 1, pp 23–33 | Cite as

miR-101-2, miR-125b-2 and miR-451a act as potential tumor suppressors in gastric cancer through regulation of the PI3K/AKT/mTOR pathway

  • Ismael Riquelme
  • Oscar Tapia
  • Pamela Leal
  • Alejandra Sandoval
  • Matthew G. Varga
  • Pablo Letelier
  • Kurt Buchegger
  • Carolina Bizama
  • Jaime A. Espinoza
  • Richard M. Peek
  • Juan Carlos Araya
  • Juan Carlos RoaEmail author
Original Paper

Abstract

Background

Gastric cancer (GC) is a deadly malignancy worldwide. In the past, it has been shown that cellular signaling pathway alterations play a crucial role in the development of GC. In particular, deregulation of the PI3K/AKT/mTOR pathway seems to affect multiple GC functions including growth, proliferation, metabolism, motility and angiogenesis. Targeting alterations in this pathway by microRNAs (miRNAs) represents a potential therapeutic strategy, especially in inhibitor-resistant tumors. The objective of this study was to evaluate the expression of 3 pre-selected miRNAs, miR-101-2, miR-125b-2 and miR-451a, in a series of primary GC tissues and matched non-GC tissues and in several GC-derived cell lines, and to subsequently evaluate the functional role of these miRNAs.

Methods

Twenty-five primary GC samples, 25 matched non-GC samples and 3 GC-derived cell lines, i.e., AGS, MKN28 and MKN45, were included in this study. miRNA and target gene expression levels were assessed by quantitative RT-PCR and western blotting, respectively. Subsequently, cell viability, clone formation, cell death, migration and invasion assays were performed on AGS cells.

Results

miR-101-2, miR-125b-2 and miR-451a were found to be down-regulated in the primary GC tissues and the GC-derived cell lines tested. MiRNA mimic transfections significantly reduced cell viability and colony formation, increased cell death and reduced cell migration and invasion in AGS cells. We also found that exogenous expression of miR-101-2, miR-125b-2 and miR-451a decreased the expression of their putative targets MTOR, PIK3CB and TSC1, respectively.

Conclusions

Our expression analyses and in vitro functional assays suggest that miR-101-2, miR-125b-2 and miR-451a act as potential tumor suppressors in primary GCs as well as in GC-derived AGS cells.

Keywords

Gastric cancer microRNAs miR-101-2 miR-125b-2 miR-451a PI3K/AKT/mTOR pathway 

Notes

Acknowledgments

This study was supported by the Chilean National Fund for Scientific and Technological Development (FONDECYT NO. 1090171), the Chilean National Commission for Scientific and Technological Research (CONICYT) through a PhD scholarship and financial support for a doctoral thesis (NO. 24121456) and a Postdoctoral Scholarship from the Universidad de La Frontera.

The FV-1000 microscope experiments/data analyses were performed in part through use of the VUMC Cell Imagining Shared Resource (supported by NIH grants CA68485, DK20593, DK58404, DK59637, and EY08126).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interests.

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Copyright information

© International Society for Cellular Oncology 2015

Authors and Affiliations

  • Ismael Riquelme
    • 1
  • Oscar Tapia
    • 1
  • Pamela Leal
    • 2
  • Alejandra Sandoval
    • 1
  • Matthew G. Varga
    • 3
  • Pablo Letelier
    • 4
  • Kurt Buchegger
    • 1
  • Carolina Bizama
    • 5
  • Jaime A. Espinoza
    • 5
  • Richard M. Peek
    • 3
  • Juan Carlos Araya
    • 6
  • Juan Carlos Roa
    • 5
    Email author
  1. 1.Laboratory of Molecular Pathology, Pathology Department, School of Medicine, BIOREN-CEGINUniversidad de La FronteraTemucoChile
  2. 2.Molecular Biology and Biomedicine Lab, CEGIN-BIORENUniversidad de La FronteraTemucoChile
  3. 3.Division of Gastroenterology, Departments of Medicine and Cancer BiologyVanderbilt University School of MedicineNashvilleUSA
  4. 4.School of Health SciencesUniversidad Catolica de TemucoTemucoChile
  5. 5.Department of Pathology, UC Centre for Investigational Oncology (CITO), Advanced Centre for Chronic Diseases (ACCDiS), School of MedicinePontificia Universidad Catolica de ChileSantiagoChile
  6. 6.Department of Pathology, School of MedicineUniversidad de La FronteraTemucoChile

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