Mucinous colorectal cancers are characterized by abundant production of intestinal goblet cell mucin, MUC2 and frequent ectopic expression of gastric foveolar mucin, MUC5AC. SOX2, an HMG-box transcription factor expressed in gastric mucosa but not in intestine is thought to play an important role in regulating transcription and expression of gastric differentiation related genes. Herein, we investigated the possible role of SOX2 in MUC5AC transcription and in the development of mucinous cancers. We observed good correlation between SOX2 and MUC5AC message levels in most colon cancer cell lines. SOX2 expression significantly transactivated MUC5AC promoter/reporter constructs in 3 of 5 colon cancer cell lines. We also examined SOX2 expression in normal stomach and colon, nonmucinous and mucinous colorectal cancers, serrated polyps and conventional adenomas using immunohistochemistry and in situ hybridization. SOX2 was expressed in the nuclei of both gastric foveolar cells and fundic glands by immunohistochemistry and in the cytoplasm by in situ hybridization. SOX2 was not expressed in normal colon but was strongly expressed in serrated polyps, mucinous and signet ring cell carcinomas, but rarely in nonmucinous carcinomas and tubular adenomas. Concordant expression of SOX2 with MUC5AC was observed in these lesions. Our results suggest that SOX2 is important in the upregulation of gastric foveolar mucin, MUC5AC in colorectal mucinous and signet ring cell carcinomas. In addition, the expression of both SOX2 and MUC5AC in serrated polyps supports the hypothesis that these polyps may be predominant precursors of mucinous and signet ring cell carcinomas of the colorectum. © 2007 Wiley-Liss, Inc.