Down-regulation of a Gastric Transcription Factor, Sox2, and Ectopic Expression of Intestinal Homeobox Genes, Cdx1 and Cdx2: Inverse Correlation During Progression from Gastric/intestinal-mixed to Complete Intestinal Metaplasia

Overview

Journal J Cancer Res Clin Oncol

Specialty Oncology

Date 2003 Dec 5

PMID 14655050

Citations 45

Authors

Tetsuya Tsukamoto

Kenichi Inada

Harunari Tanaka

Tsutomu Mizoshita

Mami Mihara

Toshikazu Ushijima

Yoshitaka Yamamura

Shigeo Nakamura

Masae Tatematsu

Affiliations

Soon will be listed here.

Abstract

Purpose: The molecular mechanisms underlying the development of intestinal metaplasia (IM) of the human stomach have yet to be clarified in detail. Besides ectopic expression of intestinal transcription factors, Cdx1 and Cdx2, little information is available regarding other regulatory factors. Hence, we here analyzed Sox2, a human homolog of a chicken gastric transcription factor, with reference to our new classification for gastric/intestinal (GI)-mixed type IM.

Methods: Twenty specimens of surgically resected antral mucosa were subjected to a gland isolation technique. Isolated glands were classified into gastric (G), GI-mixed, and solely intestinal (I) types according to Alcian blue and paradoxical concanavalin A staining and were quantified for mRNA levels of gastrointestinal markers.

Results: MUC5AC and MUC6 transcripts decreased with the progression of IM, while MUC2 and villin-1 were inversely correlated. Sox2 showed a gradual decrease from G, through GI, to the I type (G vs GI and GI vs I, P<0.01 and P<0.005, respectively). On the other hand, Cdx1 (G vs GI and GI vs I, P<0.0001 and P=0.337, respectively) and Cdx2 (G vs GI and GI vs I, P<0.0001 and P<0.05, respectively) appeared in IM. Immunohistochemical study confirmed decreased expression of Sox2 and ectopic emergence of Cdx2 protein in IM glands.

Conclusion: Down-regulation of Sox2, besides ectopic expression of Cdx genes, may be important factors for the development of IM.

Citing Articles

Exploration of gastric carcinogenesis from the relationship between bile acids and intestinal metaplasia and intragastric microorganisms (H. pylori and non-H. pylori).

Lei X, Cui Z, Huang X J Cancer Res Clin Oncol. 2023; 149(18):16947-16956.

PMID: 37707577 DOI: 10.1007/s00432-023-05407-5.

Characterization of Schistosome Sox Genes and Identification of a Flatworm Class of Sox Regulators.

Wood S, Ishida K, Hagerty J, Karahodza A, Dennis J, Jolly E Pathogens. 2023; 12(5).

PMID: 37242360 PMC: 10222431. DOI: 10.3390/pathogens12050690.

Roles and action mechanisms of bile acid-induced gastric intestinal metaplasia: a review.

He Q, Liu L, Wei J, Jiang J, Rong Z, Chen X Cell Death Discov. 2022; 8(1):158.

PMID: 35379788 PMC: 8979943. DOI: 10.1038/s41420-022-00962-1.

Decitabine and Cisplatin are Synergistic to Exert Anti-Tumor Effect on Gastric Cancer via Inducing Sox2 DNA Demethylation.

Zhu Z, Lin S, Wu X, Xu J, Li L, Ye W Onco Targets Ther. 2021; 14:623-636.

PMID: 33519210 PMC: 7837578. DOI: 10.2147/OTT.S276168.

Gastric Stem Cells: Physiological and Pathological Perspectives.

Xiao S, Zhou L Front Cell Dev Biol. 2020; 8:571536.

PMID: 33043003 PMC: 7527738. DOI: 10.3389/fcell.2020.571536.

References

Inada K, Nakanishi H, Fujimitsu Y, Shimizu N, Ichinose M, Miki K . Gastric and intestinal mixed and solely intestinal types of intestinal metaplasia in the human stomach. Pathol Int. 1998; 47(12):831-41. DOI: 10.1111/j.1440-1827.1997.tb03714.x. View

Soubeyran P, Andre F, Lissitzky J, Mallo G, Moucadel V, Roccabianca M . Cdx1 promotes differentiation in a rat intestinal epithelial cell line. Gastroenterology. 1999; 117(6):1326-38. DOI: 10.1016/s0016-5085(99)70283-0. View

Tatematsu M, Katsuyama T, Furihata C, Fukushima S, Shirai T, Kato T . Cellular differentiation and histogenesis of rat glandular stomach cancers. Jpn J Cancer Res. 1990; 81(8):760-7. PMC: 5918080. DOI: 10.1111/j.1349-7006.1990.tb02642.x. View

Wood H, Episkopou V . Comparative expression of the mouse Sox1, Sox2 and Sox3 genes from pre-gastrulation to early somite stages. Mech Dev. 1999; 86(1-2):197-201. DOI: 10.1016/s0925-4773(99)00116-1. View

Escande F, Aubert J, Porchet N, Buisine M . Human mucin gene MUC5AC: organization of its 5'-region and central repetitive region. Biochem J. 2001; 358(Pt 3):763-72. PMC: 1222110. DOI: 10.1042/0264-6021:3580763. View

Walker M . Is intestinal metaplasia of the stomach reversible?. Gut. 2002; 52(1):1-4. PMC: 1773527. DOI: 10.1136/gut.52.1.1. View

Stevanovic M, Zuffardi O, Collignon J, Lovell-Badge R, Goodfellow P . The cDNA sequence and chromosomal location of the human SOX2 gene. Mamm Genome. 1994; 5(10):640-2. DOI: 10.1007/BF00411460. View

Toribara N, Roberton A, Ho S, Kuo W, Gum E, Hicks J . Human gastric mucin. Identification of a unique species by expression cloning. J Biol Chem. 1993; 268(8):5879-85. View

Silva S, FILIPE M . Intestinal metaplasia and its variants in the gastric mucosa of Portuguese subjects: a comparative analysis of biopsy and gastrectomy material. Hum Pathol. 1986; 17(10):988-95. DOI: 10.1016/s0046-8177(86)80082-x. View

10.

Yamamoto H, Bai Y, Yuasa Y . Homeodomain protein CDX2 regulates goblet-specific MUC2 gene expression. Biochem Biophys Res Commun. 2003; 300(4):813-8. DOI: 10.1016/s0006-291x(02)02935-2. View

11.

Silberg D, Sullivan J, Kang E, Swain G, Moffett J, Sund N . Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice. Gastroenterology. 2002; 122(3):689-96. DOI: 10.1053/gast.2002.31902. View

12.

Satoh K, Mutoh H, Eda A, Yanaka I, Osawa H, Honda S . Aberrant expression of CDX2 in the gastric mucosa with and without intestinal metaplasia: effect of eradication of Helicobacter pylori. Helicobacter. 2002; 7(3):192-8. DOI: 10.1046/j.1523-5378.2002.00080.x. View

13.

STEMMERMANN G . Intestinal metaplasia of the stomach. A status report. Cancer. 1994; 74(2):556-64. DOI: 10.1002/1097-0142(19940715)74:2<556::aid-cncr2820740205>3.0.co;2-j. View

14.

Segura D, Montero C . Histochemical characterization of different types of intestinal metaplasia in gastric mucosa. Cancer. 1983; 52(3):498-503. DOI: 10.1002/1097-0142(19830801)52:3<498::aid-cncr2820520320>3.0.co;2-8. View

15.

Yamamoto M, Furihata C, Ogiu T, Tsukamoto T, Inada K, Hirano K . Independent variation in susceptibilities of six different mouse strains to induction of pepsinogen-altered pyloric glands and gastric tumor intestinalization by N-methyl-N-nitrosourea. Cancer Lett. 2002; 179(2):121-32. DOI: 10.1016/s0304-3835(02)00013-7. View

16.

Kato Y, Kitagawa T, Yanagisawa A, Kubo K, Utsude T, Hiratsuka H . Site-dependent development of complete and incomplete intestinal metaplasia types in the human stomach. Jpn J Cancer Res. 1992; 83(2):178-83. PMC: 5918776. DOI: 10.1111/j.1349-7006.1992.tb00084.x. View

17.

Eda A, Osawa H, Yanaka I, Satoh K, Mutoh H, Kihira K . Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia. J Gastroenterol. 2002; 37(2):94-100. DOI: 10.1007/s005350200002. View

18.

Mutoh H, Hakamata Y, Sato K, Eda A, Yanaka I, Honda S . Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice. Biochem Biophys Res Commun. 2002; 294(2):470-9. DOI: 10.1016/S0006-291X(02)00480-1. View

19.

Sakamoto N, Fukuda K, Watanuki K, Sakai D, Komano T, Scotting P . Role for cGATA-5 in transcriptional regulation of the embryonic chicken pepsinogen gene by epithelial-mesenchymal interactions in the developing chicken stomach. Dev Biol. 2000; 223(1):103-13. DOI: 10.1006/dbio.2000.9731. View

20.

Teglbjaerg P, Nielsen H . "Small intestinal type" and "colonic type" intestinal metaplasia of the human stomach, and their relationship to the histogenetic types of gastric adenocarcinoma. Acta Pathol Microbiol Scand A. 1978; 86A(5):351-5. DOI: 10.1111/j.1699-0463.1978.tb02055.x. View