Oncotarget

Research Papers:

Osteoactivin (GPNMB) ectodomain protein promotes growth and invasive behavior of human lung cancer cells

Moses O. Oyewumi _, Dharani Manickavasagam, Kimberly Novak, Daniel Wehrung, Nikola Paulic, Fouad M. Moussa, Gregory R. Sondag and Fayez F. Safadi

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Oncotarget. 2016; 7:13932-13944. https://doi.org/10.18632/oncotarget.7323

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Abstract

Moses O. Oyewumi1,2, Dharani Manickavasagam1,2, Kimberly Novak1,3, Daniel Wehrung1, Nikola Paulic1, Fouad M. Moussa2,3, Gregory R. Sondag2,3, Fayez F. Safadi2,3

1Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA

2School of Biomedical Sciences, Kent State University, Kent, OH 44240, USA

3Department of Anatomy and Neurobiology, College of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272, USA

Correspondence to:

Moses O. Oyewumi, e-mail: [email protected]

Keywords: GPNMB, cell adhesion, NSCLC, integrin, lung cancer

Received: September 08, 2015     Accepted: January 23, 2016     Published: February 11, 2016

ABSTRACT

The potential application of GPNMB/OA as a therapeutic target for lung cancer will require a greater understanding of the impact of GPNMB/OA ectodomain (ECD) protein shedding into tumor tissues. Thus, in this work we characterized GPNMB/OA expression and extent of shedding of its ECD protein while evaluating the impact on lung cancer progression using three non-small cell lung cancer (NSCLC) cell lines: A549, SK-MES-1 and calu-6. We observed a direct correlation (R2 = 0.89) between GPNMB/OA expression on NSCLC cells and the extent of GPNMB/OA ECD protein shedding. Meanwhile, siRNA-mediated knockdown of GPNMB/OA in cancer cells significantly reduced GPNMB/OA ECD protein shedding, migration, invasion and adhesion to extracellular matrix materials. Also, exogenous treatment of cancer cells (expressing low GPNMB/OA) with recombinant GPNMB/OA protein (rOA) significantly facilitated cell invasion and migration, but the effects of rOA was negated by inclusion of a selective RGD peptide. Further studies in athymic (nu/nu) mice-bearing calu-6 showed that intratumoral supplementation with rOA effectively facilitated in vivo tumor growth as characterized by a high number of proliferating cells (Ki67 staining) coupled with a low number of apoptotic cells. Taken together, our results accentuate the relevance of GPNMB/OA ECD protein shedding to progression of lung cancer. Thus, strategies that suppress GPNMB/OA expression on lung cancer cells as well as negate shedding of GPNMB/OA ECD protein are worthy of consideration in lung cancer therapeutics.


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