title: FHIT expression and hypermethylation in esophageal squamous cell carcinoma.
abstract: The expression of the fragile histidine triad (FHIT) gene has been proposed to play an important role in early events of carcinogenesis and to be correlated with the progression or clinical outcomes of various cancers. Attention has focused recently on the regulation of FHIT expression, and loss of heterozygosity or hypermethylation of the CpG island in the promoter region has been suggested as clues to a possible mechanism. Methylation status and FHIT expression were investigated in the present study to clarify the clinicopathologic impact of FHIT in vivo. One hundred and five patients with esophageal cancer were admitted to the study. Cancer tissues were immunohistochemically stained for FHIT, and FHIT methylation status was examined in 36 patients by the methylation-specific polymerase chain reaction. FHIT methylation and expression were analyzed with respect to both clinicopathologic parameters and their interactions. Tissue specimens from 35 of the 105 patients (33.3%) stained positively for FHIT. In contrast, the CpG island in the FHIT promoter region was hypermethylated in 25 of the 36 (69.4%) analyzed cases of esophageal cancer. Hypermethylation was significantly correlated with the deletion of FHIT protein expression (P<0.001). FHIT hypermethylation was not associated with any clinicopathologic parameters. In contrast, deletion of FHIT expression significantly promoted tumor invasion (P<0.05) and lymphatic vessel invasion (P<0.01). Lymph node metastasis also appeared higher in the absence of FHIT protein expression, but the result was not significant (P=0.069). Patients with a preserved FHIT gene expression possibly exhibited an improved prognosis compared with those with deleted FHIT expression (P=0.093). Hypermethylation of the FHIT promoter region may be a mechanism for regulating FHIT expression. FHIT gene expression was closely correlated with cancer progression, as indicated by tumor invasion and lymphatic spread, and it may provide insight into the mechanism of progression of esophageal cancer.
authors.affiliation: Surgery, Department of Oncological Science, Oita Medical University, Oita, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Noguchi
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Takeno
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kimura
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Uchida
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Daa
authors.forename: Shigeo
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Helmut E
authors.initials: HE
authors.lastname: Gabbert
authors.forename: Wolfram
authors.initials: W
authors.lastname: Mueller
mesh_terms: D017766:Acid Anhydride Hydrolases; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000503:physiopathology; D018899:CpG Islands; D019175:DNA Methylation; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase