title: Deleted in colorectal cancer is a putative conditional tumor-suppressor gene inactivated by promoter hypermethylation in head and neck squamous cell carcinoma.
abstract: Deleted in colorectal cancer (DCC) is a candidate tumor-suppressor gene located at chromosome 18q21. However, DCC gene was found to have few somatic mutations and the heterozygous mice (DCC(+/-)) showed a similar frequency of tumor formation compared with the wild-type mice (DCC(+/+)). Recently, DCC came back to the spotlight as a better understating of its function and relationship with its ligand (netrin-1) had shown that DCC may act as a conditional tumor-suppressor gene. We evaluated hypermethylation as a mechanism for DCC inactivation in head and neck squamous cell carcinoma (HNSCC). DCC promoter region hypermethylation was found in 75% of primary HNSCC. There was a significant correlation between DCC promoter region hypermethylation and DCC expression (assessed by immunohistochemistry; P = 0.021). DCC nonexpressing HNSCC cell lines JHU-O12 and JHU-O19 with baseline hypermethylation of the DCC promoter were treated with 5-aza-2'-deoxycytidine (a demethylating agent) and reexpression of DCC was noted. Transfection of DCC into DCC-negative HNSCC cell lines resulted in complete abrogation of growth in all cell lines, whereas additional cotransfection of netrin-1 resulted in rescue of DCC-mediated growth inhibition. These results suggest that DCC is a putative conditional tumor-suppressor gene that is epigenetically inactivated by promoter hypermethylation in a majority of HNSCC.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD 21287-0910, USA.
authors.forename: André Lopes
authors.initials: AL
authors.lastname: Carvalho
authors.forename: Alice
authors.initials: A
authors.lastname: Chuang
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Jiang
authors.forename: Juna
authors.initials: J
authors.lastname: Lee
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Begum
authors.forename: Luana
authors.initials: L
authors.lastname: Poeta
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Carmen
authors.initials: C
authors.lastname: Jerónimo
authors.forename: Rui
authors.initials: R
authors.lastname: Henrique
authors.forename: Chetan S
authors.initials: CS
authors.lastname: Nayak
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Park
authors.forename: Mariana R O
authors.initials: MR
authors.lastname: Brait
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liu
authors.forename: Shaoyu
authors.initials: S
authors.lastname: Zhou
authors.forename: Wayne
authors.initials: W
authors.lastname: Koch
authors.forename: Vito Michele
authors.initials: VM
authors.lastname: Fazio
authors.forename: Edward
authors.initials: E
authors.lastname: Ratovitski
authors.forename: Barry
authors.initials: B
authors.lastname: Trink
authors.forename: William
authors.initials: W
authors.lastname: Westra
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.forename: Chul-so
authors.initials: CS
authors.lastname: Moon
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Califano
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D000075389:DCC Receptor; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016163:Genes, DCC; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D019656:Loss of Heterozygosity; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009414:Nerve Growth Factors / Q000235:genetics / Q000502:physiology; D000075388:Netrin-1; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D000075389:DCC Receptor; C501909:DCC protein, human; D004273:DNA, Neoplasm; C000617351:NTN1 protein, human; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1