Aggressive melanoma cells escape from BMP7-mediated autocrine growth inhibition through coordinated Noggin upregulation.
Bone morphogenetic proteins (BMPs) are members of the TGF-beta 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-beta, 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.
Hsu
Mei-Yu
MY
Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. mhsu@rics.bwh.harvard.edu
Rovinsky
Sherry A
SA
Lai
Chiou-Yan
CY
Qasem
Shadi
S
Liu
Xiaoming
X
How
Joan
J
Engelhardt
John F
JF
Murphy
George F
GF
D000256:Adenoviridae / Q000235:genetics; D019898:Autocrine Communication; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D006131:Growth Inhibitors / Q000378:metabolism*; D006801:Humans; D008544:Melanocytes / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000099176:Noggin Protein
D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D006131:Growth Inhibitors; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein; C525819:BMP7 protein, human