miR-663 sustains NSCLC by inhibiting mitochondrial outer membrane permeabilization (MOMP) through PUMA/BBC3 and BTG2

Micol E Fiori; Lidia Villanova; Chiara Barbini; Maria Laura De Angelis; Ruggero De Maria

doi:10.1038/s41419-017-0080-x

miR-663 sustains NSCLC by inhibiting mitochondrial outer membrane permeabilization (MOMP) through PUMA/BBC3 and BTG2

Cell Death Dis. 2018 Jan 19;9(2):49. doi: 10.1038/s41419-017-0080-x.

Authors

Micol E Fiori^{1

2}, Lidia Villanova³, Chiara Barbini³, Maria Laura De Angelis³, Ruggero De Maria⁴

Affiliations

¹ Institute of General Pathology, Catholic University of the Sacred Heart and Gemelli Polyclinic, Rome, Italy. fiorimicol@gmail.com.
² Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy. fiorimicol@gmail.com.
³ Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
⁴ Institute of General Pathology, Catholic University of the Sacred Heart and Gemelli Polyclinic, Rome, Italy. Ruggero.DeMaria@unicatt.it.

Abstract

Treatment of lung cancer is an unmet need as it accounts for the majority of cancer deaths worldwide. The development of new therapies urges the identification of potential targets. MicroRNAs' expression is often deregulated in cancer and their modulation has been proposed as a successful strategy to interfere with tumor cell growth and spread. We recently reported on an unbiased high-content approach to identify miRNAs regulating cell proliferation and tumorigenesis in non-small cell lung cancer (NSCLC). Here we studied the oncogenic role of miR-663 in NSCLC biology and analyzed the therapeutic potential of miR-663 targeting. We found that miR-663 regulates apoptosis by controlling mitochondrial outer membrane permeabilization (MOMP) through the expression of two novel direct targets PUMA/BBC3 and BTG2. Specifically, upon miR-663 knockdown the BH3-only protein PUMA/BBC3 directly activates mitochondrial depolarization and cell death, while BTG2 accumulation further enhances this effect by triggering p53 mitochondrial localization. Moreover, we show that miR-663 depletion is sufficient to elicit cell death in NSCLC cells and to impair tumor growth in vivo.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Animals
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism*
Carcinoma, Non-Small-Cell Lung / genetics*
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Carcinoma, Non-Small-Cell Lung / therapy
Cell Line, Tumor
Female
HeLa Cells
Heterografts
Humans
Immediate-Early Proteins / genetics
Immediate-Early Proteins / metabolism*
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Lung Neoplasms / therapy
Mice
Mice, Nude
MicroRNAs / genetics
MicroRNAs / metabolism*
Mitochondrial Membrane Transport Proteins / genetics
Mitochondrial Membrane Transport Proteins / metabolism
Mitochondrial Membranes / metabolism*
Permeability
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism*
Signal Transduction
Transfection
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*

Substances

Apoptosis Regulatory Proteins
BBC3 protein, human
Immediate-Early Proteins
MIRN663 microRNA, human
MicroRNAs
Mitochondrial Membrane Transport Proteins
Proto-Oncogene Proteins
Tumor Suppressor Proteins
BTG2 protein, human