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

作者：Baojin Fu, Mingzhou Guo, Shelun Wang, Domenico Campagna, Mingde Luo, James Gordon Herman, Christine A. Iacobuzio–Donahue · 发表于：Cancer Biology & Therapy · 年份：2007 · DOI：10.4161/cbt.6.10.4708 · 被引用次数：42 · 研究领域：Epigenetics and DNA Methylation、Tracheal and airway disorders

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, i...