The role of Reg IV gene and its encoding product in gastric carcinogenesis☆

Although the biologic function of Reg IV is poorly understood, it has been reported that Reg IV is a potent activator of the epidermal growth factor receptor/Akt/AP-1 signaling pathway in colon cancer cells and closely linked with the inhibition of apoptosis. To clarify the role of Reg IV in gastric carcinogenesis and subsequent progression, we examined its expression by immunohistochemistry and in situ hybridization on tissue microarray containing gastric carcinoma, adjacent nonneoplastic mucosa, adenoma, intestinal metaplasia, or gastritis. Gastric carcinoma cell lines (MKN28, AGS, MKN45, KATO-III, and HGC-27) were studied for Reg IV expression by Western blot and reverse transcriptase–polymerase chain reaction followed by sequencing. Frozen samples of gastric carcinoma and adjacent nonneoplastic mucosa were subjected to Western blot, and patient serum, to enzyme-linked immunosorbent assay for Reg IV. Gastric carcinoma cell lines showed different levels of Reg IV mRNA and its encoding protein. The Reg IV protein expression was gradually decreased from intestinal metaplasia, adenoma, and carcinoma to gastritis (P < .05). The positive rate of its mRNA was higher in intestinal metaplasia than carcinoma or nonneoplastic mucosa (P < .05). Elevated serum Reg IV level in gastric carcinoma patients was detected in comparison with that in health individuals (P < .05). Reg IV expression was significantly correlated with the MUC-2 and MUC-5AC expression (P < .05). Among histologic subtypes of the World Health Organization, signet ring cell carcinoma more frequently expressed Reg IV than the others (P < .05), whereas it is the converse for the poorly differentiated group (P < .05). Our study indicated that Reg IV expression experienced up-regulation in gastric intestinal metaplasia and adenoma and then down-regulation with malignant transformation of gastric epithelial cells. It was suggested that Reg IV expression should be considered as a good biomarker for gastric precancerous lesions and was especially related to the histogenic pathway of signet ring cell carcinoma.