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.

Enhanced CD24 Expression in Colorectal Cancer Correlates with Prognostic Factors

BACKGROUND: CD24 was originally described as a B cell-specific marker, however its aberrant expression in various solid tumors has recently been reported. Our objective was to determine the pattern and extent of the CD24 expression in colorectal cancer and its related lesions, and to clarify its correlation with clinico-pathological parameters and especially those associated with patients' prognoses. METHODS: A total of 307 colorectal cancers and the related lesions (150 carcinomas, 30 high-grade adenomas, 49 low-grade adenomas, 41 hyperplastic polyps, and 37 normal colorectal epithelia) were immunohistochemically analyzed by treating CD24 monoclonal antibody onto tissue embedded paraffin blocks. RESULTS: CD24 expression was very rarely observed in the normal epithelia, hyperplastic polyps, and low-grade adenomas; however, in high-grade adenomas, the CD24 expression was shown to be mildly increased in the cytoplasm (13.3%). In carcinomas, the CD24 expression was increased substantially in both the membrane (38.0%) and the cytoplasm (44.7%). The expression of CD24 in the membrane was positively correlated with tumor size (p<0.01). The CD24 expression in the cytoplasm was positively correlated with several unfavorable parameters, including a larger tumor size (p<0.01), a higher tumor grade (p<0.01), a higher rate of tumor invasion (p<0.05), and a higher pTNM stage (p<0.05). CONCLUSION: High levels of CD24 expression in the membrane and cytoplasm were characteristic in colorectal cancer, and the cytoplasmic CD24 expression was correlated with several unfavorable clinical parameters.