title: Downregulation of Filamin A interacting protein 1-like is associated with promoter methylation and induces an invasive phenotype in ovarian cancer.
abstract: Ovarian cancer is the most lethal gynecologic malignancy with a five-year survival rate below 25% for patients with stages III and IV disease. Identifying key mediators of ovarian cancer invasion and metastasis is critical to the development of more effective therapeutic interventions. We previously identified Filamin A interacting protein 1-like (FILIP1L) as an important mediator of cell proliferation and migration. In addition, targeted expression of FILIP1L in tumors inhibited tumor growth in vivo. In our present study, we confirmed that both mRNA and protein expression of FILIP1L were downregulated in ovarian cancer cells compared with normal ovarian epithelial cells. FILIP1L expression was inversely correlated with the invasive potential of ovarian cancer cell lines and clinical ovarian cancer specimens. We also provide evidence that DNA methylation is a mechanism by which FILIP1L is downregulated in ovarian cancer. The CpG island in the FILIP1L promoter was heavily methylated in ovarian cancer cells. Methylation status of the FILIP1L promoter was inversely correlated with FILIP1L expression in ovarian cell lines and clinical ovarian specimens. Reduced methylation in the FILIP1L promoter following treatment with a DNA demethylating agent was associated with restoration of FILIP1L expression in ovarian cancer cells. A transcription activator, cAMP-responsive element binding protein (CREB) was shown to bind to the CREB/ATF site in the CpG island of the FILIP1L promoter. Overall, these findings suggest that downregulation of FILIP1L associated with DNA methylation is related with the invasive phenotype in ovarian cancer and that modulation of FILIP1L expression has the potential to be a target for ovarian cancer therapy.
authors.affiliation: Department of Surgery, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Burton
authors.forename: Aneesa
authors.initials: A
authors.lastname: Gaffar
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Folashade
authors.initials: F
authors.lastname: Adeshuko
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Whitney
authors.forename: Joon-Yong
authors.initials: JY
authors.lastname: Chung
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.forename: Gloria S
authors.initials: GS
authors.lastname: Huang
authors.forename: Gary L
authors.initials: GL
authors.lastname: Goldberg
authors.forename: Steven K
authors.initials: SK
authors.lastname: Libutti
authors.forename: Mijung
authors.initials: M
authors.lastname: Kwon
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018899:CpG Islands / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic
chemical_list: C115163:CREB1 protein, human; D002352:Carrier Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D003598:Cytoskeletal Proteins; C464562:FILIP1 protein, human