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Profiling estrogen-regulated gene expression changes in normal and malignant human ovarian surface epithelial cells

Oncogene volume 24, pages 8128–8143 (2005)Cite this article

Abstract

Estrogens regulate normal ovarian surface epithelium (OSE) cell functions but also affect epithelial ovarian cancer (OCa) development. Little is known about how estrogens play such opposing roles. Transcriptional profiling using a cDNA microarray containing 2400 named genes identified 155 genes whose expression was altered by estradiol-17β (E2) in three immortalized normal human ovarian surface epithelial (HOSE) cell lines and 315 genes whose expression was affected by the hormone in three established OCa (OVCA) cell lines. All but 19 of the genes in these two sets were different. Among the 19 overlapping genes, five were found to show discordant responses between HOSE and OVCA cell lines. The five genes are those that encode clone 5.1 RNA-binding protein (RNPS1), erythrocyte adducin α subunit (ADD1), plexin A3 (PLXNA3 or the SEX gene), nuclear protein SkiP (SKIIP), and Rap-2 (rap-2). RNPS1, ADD1, rap-2, and SKIIP were upregulated by E2 in HOSE cells but downregulated by estrogen in OVCA cells, whereas PLXNA3 showed the reverse pattern of regulation. The estrogen effects was observed within 6–18 h of treatment. In silicon analyses revealed presence of estrogen response elements in the proximal promoters of all five genes. RNPS1, ADD1, and PLXNA3 were underexpressed in OVCA cell lines compared to HOSE cell lines, while the opposite was true for rap-2 and SKIIP. Functional studies showed that RNPS1 and ADD1 exerted multiple antitumor actions in OVCA cells, while PLXNA3 only inhibited cell invasiveness. In contrast, rap-2 was found to cause significant oncogenic effects in OVCA cells, while SKIIP promotes only anchorage-independent growth. In sum, gene profiling data reveal that (1) E2 exerts different actions on HOSE cells than on OVCA cells by affecting two distinct transcriptomes with few overlapping genes and (2) among the overlapping genes, a set of putative oncogenes/tumor suppressors have been identified due to their differential responses to E2 between the two cell types. These findings may explain the paradoxical roles of estrogens in regulating normal and malignant OSE cell functions.

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Acknowledgements

We thank Dr Kun-Liang Guan at the Department of Biological Chemistry, University of Michigan for providing the Sex gene expression vector and Dr Samuel C Mok at the Laboratory of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Boston for providing the HOSE and OVCA cell lines. We thank the editorial staff of Brigham and Women's Hospital in Boston for their excellent editorial service. This study was supported, in part, by NIH Grants CA091250 (to VS) and CA94221 (to SMH).

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  1. Kin-Mang Lau

    Present address: Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China

Authors and Affiliations

  1. Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA

    Viqar Syed, Xiang Zhang, Kin-Mang Lau, Robert Cheng, Kasturi Mukherjee & Shuk-Mei Ho

  2. Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA

    Shuk-Mei Ho

  3. Department of Physiology, University of Massachusetts Medical School, Worcester, MA, USA

    Shuk-Mei Ho

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Syed, V., Zhang, X., Lau, KM. et al. Profiling estrogen-regulated gene expression changes in normal and malignant human ovarian surface epithelial cells. Oncogene 24, 8128–8143 (2005). https://doi.org/10.1038/sj.onc.1208959

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