title: Rap1GAP regulates renal cell carcinoma invasion.
abstract: Although patients with localized and regional kidney tumors have a high survival rate, incidence of mortality significantly increases for patients with metastatic disease. It is imperative to decipher the molecular mechanisms of kidney tumor migration and invasion in order to develop effective therapies for patients with advanced cancer. Rap1, a small GTPase protein, has been implicated in cancer cell growth and invasion. Here, we profile migratory and invasive properties of commonly used renal cell carcinoma (RCC) cell lines and correlate that with expression and function of the Rap inactivator Rap1GAP. We report that levels of Rap1GAP inversely correlate with invasion but not migration. We also report that forced over-expression of Rap1GAP decreases invasion of RCC cells but does not impact their rate of proliferation. Low expression levels of Rap1GAP in RCC cells are due, at least in part, to promoter hypermethylation. Rescued expression of Rap1GAP with a demethylating drug, decitabine (5-azadC), decreases the RCC SN12C cell invasion of collagen, fibronectin, and Matrigel matrices. RCC cell lines express distinct levels of cell adhesion proteins and the forced over-expression of Rap1GAP attenuated levels of both cadherins and integrins that are known to regulate the cancer cells invasion. These results demonstrate that targeted restoration of Rap1GAP expression may serve as a potential therapeutic approach to reduce metastasis of kidney cancers.
authors.affiliation: Department of Urology, Prostate Disease Center, University of Florida College of Medicine, Gainesville, FL, United States.
authors.forename: Wan-Ju
authors.initials: WJ
authors.lastname: Kim
authors.forename: Zachary
authors.initials: Z
authors.lastname: Gersey
authors.forename: Yehia
authors.initials: Y
authors.lastname: Daaka
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D019175:DNA Methylation; D000077209:Decitabine; D020690:GTPase-Activating Proteins / Q000096:biosynthesis* / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016023:Integrins / Q000096:biosynthesis / Q000235:genetics; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection
chemical_list: D015820:Cadherins; D020690:GTPase-Activating Proteins; D016023:Integrins; C484658:RAP1GAP protein, human; D034741:RNA, Small Interfering; D000077209:Decitabine; D001374:Azacitidine