Anomalous expression of epithelial differentiation-determining GATA factors in ovarian tumorigenesis

Callinice D. Capo-Chichi, Isabelle H. Roland, Lisa Vanderveer, Rudi Bao, Tetsuya Yamagata, Hisamaru Hirai, Cynthia Cohen, Thomas C. Hamilton, Andrew K. Godwin, Xiang Xi Xu

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Tumor cells often appear in a deviant differentiated stage, and dedifferentiation is a hallmark of malignancy; however, the causative mechanism of the global changes in dedifferentiation is not understood. The GATA transcription factors function in cell lineage specification during embryonic development and organ formation. The transcriptional targets of the GATA factors in early embryonic development include Disabled-2 and collagen IV, markers for epithelial lineages. GATA-4 and GATA-6 are expressed strongly and are localized in the nucleus in ovarian surface epithelial cells in tissues or primary cell cultures. By immunohistochemistry, we found that 82% of the 50 tumors analyzed had lost GATA-6 function, either by a complete absence of expression or by cytoplasmic mislocalization. The frequent loss of GATA-6 was also confirmed in a panel of ovarian surface epithelial and tumor cell lines. Although GATA-4 is absent only in a small percentage (14%) of ovarian tumors, it is lost in the majority of established cell lines in culture. The loss of GATA-6 correlates with the loss of Disabled-2, collagen IV, and laminin, markers for epithelial cell types. Loss of GATA factors was also found in an in vitro model for spontaneous transformation of rat ovarian epithelial cells. Repression of GATA-6 by small interfering (si)RNA approach in cultured cells leads to dedifferentiation as indicated by the loss of Disabled-2 and laminin expression. Restoration of GATA factors expression by ectopic transfection suppresses cell growth and is incompatible with the maintenance of the cells in culture. However, restoration of GATA-4 and GATA-6 expression is not able to induce expression of endogenous Disabled-2 in tumor cells, suggesting that the loss of GATA factors and dedifferentiation are irreversible processes. In conclusion, we observed the inappropriate expression and cellular localization of the GATA transcription factors in ovarian tumor tissues and cancer cell lines, and we have demonstrated that down-regulation of GATA factor expression leads to dedifferentiation. We propose that alterations of GATA transcription factor expression and aberrant nucleocytoplasmic localization may contribute to the anomalous epithelial dedifferentiation of the ovarian tumor cells.

Original languageEnglish (US)
Pages (from-to)4967-4977
Number of pages11
JournalCancer Research
Volume63
Issue number16
StatePublished - Aug 15 2003
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Capo-Chichi, C. D., Roland, I. H., Vanderveer, L., Bao, R., Yamagata, T., Hirai, H., Cohen, C., Hamilton, T. C., Godwin, A. K., & Xu, X. X. (2003). Anomalous expression of epithelial differentiation-determining GATA factors in ovarian tumorigenesis. Cancer Research, 63(16), 4967-4977.