MicroRNA‑92a promotes cell proliferation, migration and survival by directly targeting the tumor suppressor gene NF2 in colorectal and lung cancer cells

Alcantara,Krizelle Mae   M.; Garcia,Reynaldo   L.

doi:10.3892/or.2019.7020

MicroRNA‑92a promotes cell proliferation, migration and survival by directly targeting the tumor suppressor gene NF2 in colorectal and lung cancer cells

Authors:
- Krizelle Mae M. Alcantara
- Reynaldo L. Garcia
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Affiliations: National Institute of Molecular Biology and Biotechnology, University of the Philippines, Diliman, Quezon City 1101, Philippines
Published online on: February 19, 2019 https://doi.org/10.3892/or.2019.7020
Pages: 2103-2116
Copyright: © Alcantara et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Inactivation of the tumor suppressor protein Merlin leads to the development of benign nervous system tumors in neurofibromatosis type2 (NF2). Documented causes of Merlin inactivation include deleterious mutations in the encoding neurofibromin2 gene (NF2) and aberrant Merlin phosphorylation leading to proteasomal degradation. Rare somatic NF2 mutations have also been detected in common human malignancies not associated with NF2, including colorectal and lung cancer. Furthermore, tumors without NF2 mutations and with unaltered NF2 transcript levels, but with low Merlin expression, have been reported. The present study demonstrated that NF2 is also regulated by microRNAs (miRNAs) through direct interaction with evolutionarily conserved miRNA response elements (MREs) within its 3'‑untranslated region (3'UTR). Dual‑Luciferase assays in human colorectal carcinoma (HCT116) and lung adenocarcinoma (A549) cells revealed downregulation of NF2 by miR‑92a‑3p via its wild‑type 3'UTR, but not NF2‑3'UTR with mutated miR‑92a‑3p MRE. HCT116 cells overexpressing miR‑92a‑3p exhibited significant downregulation of endogenous NF2 mRNA and protein levels, which was rescued by co‑transfection of a target protector oligonucleotide specific for the miR‑92a‑3p binding site within NF2‑3'UTR. miR‑92a‑3p overexpression in HCT116 and A549 cells promoted migration, proliferation and resistance to apoptosis, as well as altered F‑actin organization compared with controls. Knockdown of NF2 by siRNA phenocopied the oncogenic effects of miR‑92a overexpression on HCT116 and A549 cells. Collectively, the findings of the present study provide functional proof of the unappreciated role of miRNAs in NF2 regulation and tumor progression, leading to enhanced oncogenicity.

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