Dickkopf-3 (DKK-3) obstructs VEGFR-2/Akt/mTOR signaling cascade by interacting of β2-microglobulin (β2M) in ovarian tumorigenesis.
In this study, we investigated a possible mechanism of β2-microglobulin (β2M) function in cancer metastases in vitro, using a human ovarian carcinoma cell line. β2M, a modulator acts as a cell growth-promoting and cellular signaling factors, was identified as a dickkopf-3 (DKK-3) interacting protein. We also observed that DKK-3 suppresses endothelial cell angiogenesis of β2M through vascular endothelial growth factor receptor-2 (VEGFR-2) in tumorigenesis. Luciferase activity was remarkably reduced by the transfection of DKK-3 in a dose-dependent manner. In addition, over-expression of β2M activates cell growth by suppressing DKK-3-induced apoptosis. The effect of β2M on cell cycle and apoptosis-regulatory components was also confirmed through the silencing of β2M expression. Furthermore, induction of β2M-mediated VEGFR-2/Akt/mTOR phosphorylation and tumor angiogenesis was significantly suppressed by over-expression of DKK-3. Taken together, our results suggest an underlying mechanism for an increase of β2M-related activity in ovarian tumor cells.
Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
Boh-Ram
BR
Kim
Department of Obstetrics and Gynecology, Chung-Ang University School of Medicine, Chung-Ang University Hospital, 224-1, Heuksuk-Dong, Dongjak-Gu, Seoul 156-755, Republic of Korea.
Eun-Ju
EJ
Lee
Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
Seung Hee
SH
Seo
Department of Life Science, Yong In University, 470, Samga-dong, Cheoin-gu, Yongin-si, Gyeonggi-do 449-714, Republic of Korea.
Seung-Hoon
SH
Lee
Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea. Electronic address: sbrho@ncc.re.kr.
Seung Bae
SB
Rho
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D018925:Chemokines; D005260:Female; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology; D010051:Ovarian Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D001613:beta 2-Microglobulin / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D001613:beta 2-Microglobulin; D008156:Luciferases; C546842:MTOR protein, human; C000588866:KDR protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
Anti-apoptotic effect; DKK-3; Ovarian tumor metastasis; Protein–protein interaction; β2M