TGFβ1 induces endometrial cancer cell adhesion and migration by up-regulating integrin αvβ3 via SMAD-independent MEK-ERK1/2 signaling.
Endometrial cancer is the most common, and second most lethal, gynecological malignancy, and its rates of incidence and death are growing. This is likely attributable to increased numbers of high-risk type II endometrial cancers which account for ~30% of cases but ~75% of deaths due to their aggressive and metastatic behaviour. Histopathological and in vitro functional studies suggest that aberrant TGFβ1 signaling may contribute to endometrial cancer development and the acquisition of invasive/metastatic characteristics. However, little is known about the cellular and molecular mechanisms of TGFβ1 in high-risk endometrial cancers. In the present study, we examined the roles and mechanisms of TGFβ1 on cell adhesion and motility in type II endometrial cancer cell lines, KLE and HEC-1B. We show that treatment with TGFβ1 increases cell adhesion to vitronectin and transwell cell migration. We also demonstrate that TGFβ1 treatment increases integrin β3 and αv mRNA and protein levels via SMAD-independent MEK-ERK1/2 signaling. Importantly, siRNA depletion or antibody-mediated blocking of integrin αvβ3 reversed the effects of TGFβ1 on cell adhesion and migration. Our results suggest that TGFβ1-MEK-ERK1/2-integrin αvβ3 signaling could contribute to the invasive behaviour of high-risk endometrial cancer by promoting cell adhesion and migration.
Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
Siyuan
S
Xiong
Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
Christian
C
Klausen
Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
Jung-Chien
JC
Cheng
Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada. Electronic address: peter.leung@ubc.ca.
Peter C K
PCK
Leung
D002070:Butadienes / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
D002070:Butadienes; D039302:Integrin alphaVbeta3; D009570:Nitriles; D034741:RNA, Small Interfering; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; C113580:U 0126; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases
Integrin αv; Integrin β3; Serous endometrial cancer; TGFβ1; Type II endometrial cancer; Vitronectin