A human bone morphogenetic protein antagonist is down-regulated in renal cancer.
We analyzed expression of candidate genes encoding cell surface or secreted proteins in normal kidney and kidney cancer. This screen identified a bone morphogenetic protein (BMP) antagonist, SOSTDC1 (sclerostin domain-containing-1) as down-regulated in kidney tumors. To confirm screening results, we probed cDNA dot blots with SOSTDC1. The SOSTDC1 message was decreased in 20/20 kidney tumors compared with normal kidney tissue. Immunohistochemistry confirmed significant decrease of SOSTDC1 protein in clear cell renal carcinomas relative to normal proximal renal tubule cells (p < 0.001). Expression of SOSTDC1 was not decreased in papillary and chromophobe kidney tumors. SOSTDC1 was abundantly expressed in podocytes, distal tubules, and transitional epithelia of the normal kidney. Transfection experiments demonstrated that SOSTDC1 is secreted and binds to neighboring cells and/or the extracellular matrix. SOSTDC1 suppresses both BMP-7-induced phosphorylation of R-Smads-1, -5, and -8 and Wnt-3a signaling. Restoration of SOSTDC1 in renal clear carcinoma cells profoundly suppresses proliferation. Collectively, these results demonstrate that SOSTDC1 is expressed in the human kidney and decreased in renal clear cell carcinoma. Because SOSTDC1 suppresses proliferation of renal carcinoma cells, restoration of SOSTDC1 signaling may represent a novel target in treatment of renal clear cell carcinoma.
Blish
Kimberly Rose
KR
Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157-0001, USA.
Wang
Wei
W
Willingham
Mark C
MC
Du
Wei
W
Birse
Charles E
CE
Krishnan
Surekha R
SR
Brown
Julie C
JC
Hawkins
Gregory A
GA
Garvin
A Julian
AJ
D'Agostino
Ralph B
RB
Torti
Frank M
FM
Torti
Suzy V
SV
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D051153:Wnt Proteins / Q000378:metabolism; D060508:Wnt3 Protein; D060509:Wnt3A Protein
D048868:Adaptor Proteins, Signal Transducing; C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; C480733:SOSTDC1 protein, human; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse