Decreased expression of bone morphogenetic protein (BMP) receptor type II correlates with insensitivity to BMP-6 in human renal cell carcinoma cells.
OBJECTIVE
Bone morphogenetic proteins (BMPs) are members of a family of pleiotropic growth factors that play a critical role during renal development as well as maintaining kidney homeostasis. In the present study, we investigated the potential role of BMP receptors (BMPRs) in renal cell carcinoma (RCC) cells.


METHODS
Immunohistochemistry was used to investigate the expression of BMPRs in human RCC tissues. As an in vitro model of RCC, three cell lines were used: 112, 117, and 181. Northern blot, immunoblot, and reverse transcription-PCR were used to study the expression of BMPRs in the cell lines. Finally, cells were transfected using LipofectAMINE.


RESULTS
Normal human kidney tissues express the three BMPRs: types RIA, RIB, and RII. In contrast, human RCC cells frequently exhibit a loss of expression of BMP-RII. In tissue culture, BMP-6 inhibits in a dose-dependent manner the proliferation of 112 cells but not of 117 and 181 cells. Assays for BMPRs demonstrated that 117 and 181 cells express low levels of BMP-RII RNA. When these two BMP-6 resistant cell lines were infected with the adenovirus containing the constitutively active form of BMP-RIA or -RIB in combination with a BMP-6-responsive luciferase reporter construct, luciferase activity increased. Finally, when these cell lines were transfected with BMP-RII, BMP-6-sensitivity was restored.


CONCLUSIONS
These results demonstrate that human RCC tissues frequently have decreased levels of expression of BMP-RII and that the human RCC cell lines 117 and 181 are resistant to the growth-inhibitory effect of BMP-6 because they have decreased levels of expression of BMP-RII.
Kim
Isaac Yi
IY
Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA.
Lee
Dong-Hyeon
DH
Lee
Dug Keun
DK
Kim
Byung Chul
BC
Kim
Heung Tae
HT
Leach
Fredrick S
FS
Linehan
W Marston
WM
Morton
Ronald A
RA
Kim
Seong Jin
SJ
D015152:Blotting, Northern; D055418:Bone Morphogenetic Protein 6; D052006:Bone Morphogenetic Protein Receptors, Type II; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured
C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II