title: Increased expression of sonic hedgehog and altered methylation of its promoter region in gastric cancer and its related lesions.
abstract: The hedgehog (Hh) signaling pathway plays an important role in foregut development, and its activity is increased in various tumors, including those of the digestive tract. Our objective in the present study was to determine the pattern and extent of Sonic hedgehog (Shh) expression in gastric cancer and related lesions as well as the methylation status of its promoter region, in an attempt to clarify the regulatory mechanism of Shh expression. A total of 237 gastric cancers and related lesions (89 carcinomas, 22 high-grade dysplasia, 21 low-grade dysplasia, 47 intestinal metaplasia, 38 chronic gastritis, and 20 normal epithelia) were subjected to immunohistochemical analysis with the Shh monoclonal antibody. The methylation status of Shh was determined by methylation-specific PCR (MS PCR), involving bisulfate treatment of DNA from 150 tissues followed by amplification using specific primer pairs designed by our group. Shh was completely absent in the upper part of normal gastric epithelia (gastric pit cells), and no significant differences were observed among the lower parts of normal epithelia, chronic gastritis, and intestinal metaplasia. However, Shh expression was significantly elevated in neoplastic lesions, such as carcinoma and high low-grade dysplasia, compared to non-neoplastic lesions. In carcinomas, Shh expression was associated with clinical stage, direct tumor invasion, and differentiation of tumor cells. Methylation of the Shh promoter region was frequent in normal gastric pit cells (11/18, 61.1%), but very rare in gastritis (0/18), intestinal metaplasia (0/19), dysplasia (0/10), and carcinoma (1/63, 1.6%), and correlated significantly with expression (P<0.001). Our results suggested that the increased and constitutive Shh expression is implicated in gastric carcinogenesis, and that promoter methylation may be an important regulatory mechanism of Shh expression.
authors.affiliation: Department of Pharmacy, Seoul National University, College of Pharmacy, Seoul, Korea.
authors.forename: Li-Hui
authors.initials: LH
authors.lastname: Wang
authors.forename: Yoon-La
authors.initials: YL
authors.lastname: Choi
authors.forename: Xuan-Yan
authors.initials: XY
authors.lastname: Hua
authors.forename: Young-Kee
authors.initials: YK
authors.lastname: Shin
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Song
authors.forename: Sei-Jin
authors.initials: SJ
authors.lastname: Youn
authors.forename: Hyo-Young
authors.initials: HY
authors.lastname: Yun
authors.forename: Seon-Mee
authors.initials: SM
authors.lastname: Park
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Jong-Sun
authors.initials: JS
authors.lastname: Choi
authors.forename: Seok-Hyung
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D019175:DNA Methylation; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D053823:Hedgehog Proteins; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D013270:Stomach / Q000737:chemistry / Q000473:pathology; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D053823:Hedgehog Proteins; C509239:SHH protein, human; D015534:Trans-Activators