Evaluation of GATA-4 and GATA-5 methylation profiles in human pancreatic cancers indicate promoter methylation patterns distinct from other human tumor types

Baojin Fu, Mingzhou Guo, Shelun Wang, Domenico Campagna, Mingde Luo, James G. Herman, Christine A. Iacobuzio-Donahue

Research output: Contribution to journalArticle

Abstract

The GATA-4 and GATA-5 transcription factors are increasingly recognized as playing a role in carcinogenesis of human tumors derived of endodermal and mesodermal origin. The pancreas is derived from endodermal tissues suggesting GATA-4 and GATA-5 gene methylation may play a critical role in the biology of human pancreatic cancer as well. We investigated GATA-4 and -5 by methylation-specific PCR (MSP) in normal and neoplastic pancreatic tissues, including isogenic xenografts or cultured cell lines derived from the coexistent primary cancer and/or metastases in patients with pancreatic carcinoma. The relationship of promoter methylation was correlated with mRNA expression for each gene, and methylation patterns were correlated with known clinicopathologic features of patients. GATA-4 demonstrated a significantly lower methylation frequency than GATA-5 in low passage pancreatic cancer xenografts or cell lines (1/34 versus 21/34, p <0.001). GATA-4 and -5 were also evaluated in microdissected samples of normal duct epithelium and cancer from pancreas cancer tissues which confirmed infrequent GATA-4 methylation in pancreatic cancers as well as in normal duct epithelium. GATA-4 was frequently overexpressed at the mRNA level with 27 of 30 (90%) pancreatic cancers showing >5.0-fold overexpression compared to normal duct epithelial cells. By contrast, high frequency methylation of GATA-5 was confirmed in pancreatic cancers tissues, but was rarely methylated in normal duct epithelium, indicating hypermethylation of this gene during pancreatic cancer development. GATA-5 mRNA expression did not correlate with its promoter hypermethylation, and treatment with the demethylating agent 5-aza-2′-deoxycytidine only partially restored mRNA expression suggesting additional regulatory mechanisms of GATA-5 expression. The presence of GATA-5 methylation showed a trend towards worse long-term survival (14.0 ± 9.2 months versus 19.5 ± 3.9 months, p = 0.06). While hypermethylation of GATA-5 seems to be a universal feature among human tumors, infrequent methylation of GATA-4, and its corresponding overexpression, appears unique to pancreatic cancer from other tumor types reported thus far.

Original languageEnglish (US)
Pages (from-to)1546-1552
Number of pages7
JournalCancer Biology and Therapy
Volume6
Issue number10
StatePublished - Oct 2007

Fingerprint

Pancreatic Neoplasms
Methylation
Neoplasms
decitabine
Heterografts
Messenger RNA
GATA4 Transcription Factor
Cell Line
Genes
Pancreas
Cultured Cells
Carcinogenesis
Epithelium
Epithelial Cells
Neoplasm Metastasis
Gene Expression
Polymerase Chain Reaction
Survival

Keywords

  • Desmoplasia
  • Differentiation
  • Epigenetic
  • Pancreas
  • Xenograft

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Fu, B., Guo, M., Wang, S., Campagna, D., Luo, M., Herman, J. G., & Iacobuzio-Donahue, C. A. (2007). Evaluation of GATA-4 and GATA-5 methylation profiles in human pancreatic cancers indicate promoter methylation patterns distinct from other human tumor types. Cancer Biology and Therapy, 6(10), 1546-1552.

Evaluation of GATA-4 and GATA-5 methylation profiles in human pancreatic cancers indicate promoter methylation patterns distinct from other human tumor types. / Fu, Baojin; Guo, Mingzhou; Wang, Shelun; Campagna, Domenico; Luo, Mingde; Herman, James G.; Iacobuzio-Donahue, Christine A.

In: Cancer Biology and Therapy, Vol. 6, No. 10, 10.2007, p. 1546-1552.

Research output: Contribution to journalArticle

Fu, B, Guo, M, Wang, S, Campagna, D, Luo, M, Herman, JG & Iacobuzio-Donahue, CA 2007, 'Evaluation of GATA-4 and GATA-5 methylation profiles in human pancreatic cancers indicate promoter methylation patterns distinct from other human tumor types', Cancer Biology and Therapy, vol. 6, no. 10, pp. 1546-1552.
Fu, Baojin ; Guo, Mingzhou ; Wang, Shelun ; Campagna, Domenico ; Luo, Mingde ; Herman, James G. ; Iacobuzio-Donahue, Christine A. / Evaluation of GATA-4 and GATA-5 methylation profiles in human pancreatic cancers indicate promoter methylation patterns distinct from other human tumor types. In: Cancer Biology and Therapy. 2007 ; Vol. 6, No. 10. pp. 1546-1552.
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