Proinvasive activity of BMP-7 through SMAD4/src-independent and ERK/Rac/JNK-dependent signaling pathways in colon cancer cells.
Recent data indicate that the Bone Morphogenetic Protein BMP-7 exhibits mucosal protection against experimental colitis in rats, suggesting that this cytokine exerts direct actions in intestinal epithelial cells during inflammatory bowel diseases and other precancerous lesions of the colon. In this study, we investigated the functional expression of BMP-7 and its receptors in normal human colon crypts, aberrant crypt foci (ACF) in sigmoiditis and colorectal tumors, and their derived cancer cell lines. Transcripts encoding BMP-7 receptors type II (BMPRII, ActRII, ActRIIB) and type I (ALK-2) were clearly detected by RT-PCR in several premalignant and carcinoma cell lines. The cytokine was identified by immunohistochemistry in surface epithelial cells and crypts in the normal colon mucosa, ACF in sigmoiditis, sporadic high grade dysplastic adenoma, and in 9 of 16 colon carcinomas (56.2%). In addition, the conditioned medium collected from the adenoma PC/AA/C1 and carcinoma HCT8/S11 and SW48 cell lines in culture contained significant levels of BMP-7 ranging from 0.17 to 0.38 ng/ml. We found that BMP-7 induced scattering and proinvasive responses (EC50=1 ng/ml) in kidney and colon cancer cell lines through SMAD4 and src -independent pathways and signaling cascades using FAK phosphorylation at Y925 and activation of ERK1/2, Rac1 and JNK. This phosphorylation of FAK on Y925 was also induced by the proinvasive agent EGF. Taken together, our findings suggest that BMP-7 exerts divergent effects in the colon mucosa, one counteracting transient inflammatory situations and the other linked to pejorative functions during chronic ulcerative diseases and the neoplastic progression.
Grijelmo
Clara
C
INSERM U673 and Université Pierre et Marie Curie-Paris 6, Molecular and Clinical Oncology of Solid Tumors, Hôpital Saint-Antoine, 75571 Paris Cedex 12, France.
Rodrigue
Christelle
C
Svrcek
Magalie
M
Bruyneel
Erik
E
Hendrix
An
A
de Wever
Olivier
O
Gespach
Christian
C
D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D012189:Retrospective Studies; D051901:Smad4 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
C525819:BMP7 protein, human; C525821:Bmp7 protein, rat; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins