Deleted in colorectal cancer (DCC) is a candidate tumorsuppressor 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 tumorsuppressor 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.

Deleted in colorectal cancer is a putative conditional tumor-suppressor gene inactivated by promoter hypermethylation in head and neck squamous cell carcinoma

FAZIO V. M.;
2006-01-01

Abstract

Deleted in colorectal cancer (DCC) is a candidate tumorsuppressor 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 tumorsuppressor 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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12610/12488
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