Increased expression of sonic hedgehog and altered methylation of its promoter region in gastric cancer and its related lesions.
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.
Wang
Li-Hui
LH
Department of Pharmacy, Seoul National University, College of Pharmacy, Seoul, Korea.
Choi
Yoon-La
YL
Hua
Xuan-Yan
XY
Shin
Young-Kee
YK
Song
Young-Jin
YJ
Youn
Sei-Jin
SJ
Yun
Hyo-Young
HY
Park
Seon-Mee
SM
Kim
Wun-Jae
WJ
Kim
Hee-Jin
HJ
Choi
Jong-Sun
JS
Kim
Seok-Hyung
SH
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
D053823:Hedgehog Proteins; C509239:SHH protein, human; D015534:Trans-Activators