1. ¹Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
2. ²Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
3. ³Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA, USA

Correspondence: Dr M-Y Hsu, MD, PhD, Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Suite 401b, Boston, MA 02115, USA. E-mail: mhsu@rics.bwh.harvard.edu

⁴These authors contributed equally to this work.

Received 29 October 2007; Revised 11 April 2008; Accepted 16 April 2008; Published online 16 June 2008.

Abstract

Bone morphogenetic proteins (BMPs) are members of the TGF- superfamily responsible for mediating a diverse array of cellular functions both during embryogenesis and in adult life. Previously, we reported that upregulation of BMP7 in human melanoma correlates with tumor progression. However, melanoma cells are either inhibited by or become resistant to BMP7 as a function of tumor progression, with normal melanocytes being most susceptible. Herein, real-time quantitative reverse transcriptase-polymerase chain reactions and western blotting revealed that the expression of BMP antagonist, Noggin, correlates with resistance to BMP7 in advanced melanoma cells. To test the hypothesis that coordinated upregulation of Noggin protects advanced melanoma cells from autocrine inhibition by BMP7, functional expression of Noggin in susceptible melanoma cells was achieved by adenoviral gene transfer. The Noggin-overexpressing cells exhibited a growth advantage in response to subsequent BMP7 transduction in vitro under anchorage-dependent and -independent conditions, in three-dimensional skin reconstructs, as well as in vivo in severe combined immunodeficient mice. In concordance, Noggin knockdown by lentiviral shRNA confers sensitivity to BMP7-induced growth inhibition in advanced melanoma cells. Our findings suggest that, like TGF-, BMP7 acts as an autocrine growth inhibitor in melanocytic cells, and that advanced melanoma cells may escape from BMP7-induced inhibition through concomitant aberrant expression of Noggin.