Research article

Transcription factors GATA-4 and GATA-6 in normal and neoplastic human gastrointestinal mucosa

Hanna Haveri^1,2 , Mia Westerholm-Ormio¹ , Katri Lindfors³ , Markku Mäki^3,4 , Erkki Savilahti¹ , Leif C Andersson⁵ and Markku Heikinheimo^1,2

¹Children's Hospital, University of Helsinki, Helsinki, Finland

²Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

³Pediatric Research Center, Medical School, University of Tampere, Tampere, Finland

⁴Department of Pediatrics, Tampere University Hospital, Tampere, Finland

⁵Department of Pathology, Haartman Institute, University of Helsinki, and HUSLAB, Helsinki University Hospital, Helsinki, Finland

author email corresponding author email

BMC Gastroenterology 2008, 8:9doi:10.1186/1471-230X-8-9

Published:	11 April 2008

Abstract

Background

Human gastrointestinal mucosa regenerates vigorously throughout life, but the factors controlling cell fate in mature mucosa are poorly understood. GATA transcription factors direct cell proliferation and differentiation in many organs, and are implicated in tumorigenesis. GATA-4 and GATA-6 are considered crucial for the formation of murine gastrointestinal mucosa, but their role in human gastrointestinal tract remains unexplored. We studied in detail the expression patterns of these two GATA factors and a GATA-6 down-stream target, Indian hedgehog (Ihh), in normal human gastrointestinal mucosa. Since these factors are considered important for proliferation and differentiation, we also explored the possible alterations in their expression in gastrointestinal neoplasias. The expression of the carcinogenesis-related protein Indian hedgehog was also investigated in comparison to GATA factors.

Methods

Samples of normal and neoplastic gastrointestinal tract from children and adults were subjected to RNA in situ hybridization with ³³P labelled probes and immunohistochemistry, using an avidin-biotin immunoperoxidase system. The pathological tissues examined included samples of chronic and atrophic gastritis as well as adenomas and adenocarcinomas of the colon and rectum.

Results

GATA-4 was abundant in the differentiated epithelial cells of the proximal parts of the gastrointestinal tract but was absent from the distal parts. In contrast, GATA-6 was expressed throughout the gastrointestinal epithelium, and in the distal gut its expression was most intense at the bottom of the crypts, i.e. cells with proliferative capacity. Both factors were also present in Barrett's esophagus and metaplasia of the stomach. GATA-6 expression was reduced in colon carcinoma. Ihh expression overlapped with that of GATA-6 especially in benign gastrointestinal neoplasias.

Conclusion

The results suggest differential but overlapping functions for GATA-4 and GATA-6 in the normal gastrointestinal mucosa. Furthermore, GATA-4, GATA-6 and Ihh expression is altered in premalignant dysplastic lesions and reduced in overt cancer.