title: Downregulation of Rap1GAP through epigenetic silencing and loss of heterozygosity promotes invasion and progression of thyroid tumors.
abstract: Thyroid cancer is the most common type of endocrine malignancy, encompassing tumors with various levels of invasive growth and aggressiveness. Rap1GAP, a Rap1 GTPase-activating protein, inhibits the RAS superfamily protein Rap1 by facilitating hydrolysis of GTP to GDP. In this study, we analyzed 197 thyroid tumor samples and showed that Rap1GAP was frequently lost or downregulated in various types of tumors, particularly in the most invasive and aggressive forms of thyroid cancer. The downregulation was due to promoter hypermethylation and/or loss of heterozygosity, found in the majority of thyroid tumors. Treatment with demethylating agent 5-aza-deoxycytidine and/or histone deacetylation inhibitor trichostatin A induced gene reexpression in thyroid cells. A genetic polymorphism, Y609C, was seen in 7% of thyroid tumors but was not related to gene downregulation. Loss of Rap1GAP expression correlated with tumor invasiveness but not with specific mutations activating the mitogen-activated protein kinase pathway. Rap1GAP downregulation was required in vitro for cell migration and Matrigel invasion. Recovery of Rap1GAP expression inhibited thyroid cell proliferation and colony formation. Overall, our findings indicate that epigenetic or genetic loss of Rap1GAP is very common in thyroid cancer, where these events are sufficient to promote cell proliferation and invasion.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zuo
authors.forename: Manoj
authors.initials: M
authors.lastname: Gandhi
authors.forename: Martin M
authors.initials: MM
authors.lastname: Edreira
authors.forename: Daniel
authors.initials: D
authors.lastname: Hochbaum
authors.forename: Vishwajit L
authors.initials: VL
authors.lastname: Nimgaonkar
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: James
authors.initials: J
authors.lastname: Dipaola
authors.forename: Viktoria
authors.initials: V
authors.lastname: Evdokimova
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Altschuler
authors.forename: Yuri E
authors.initials: YE
authors.lastname: Nikiforov
mesh_terms: D018265:Carcinoma, Papillary, Follicular / Q000235:genetics* / Q000473:pathology*; D002478:Cells, Cultured; D019175:DNA Methylation / Q000502:physiology; D018450:Disease Progression; D015536:Down-Regulation; D044127:Epigenesis, Genetic / Q000502:physiology; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D019656:Loss of Heterozygosity / Q000502:physiology*; D009361:Neoplasm Invasiveness; D020641:Polymorphism, Single Nucleotide; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology*; D016606:Thyroid Nodule / Q000235:genetics
chemical_list: D020690:GTPase-Activating Proteins; C484658:RAP1GAP protein, human