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Profiling follicle stimulating hormone-induced gene expression changes in normal and malignant human ovarian surface epithelial cells

Oncogene volume 22, pages 4243–4256 (2003)Cite this article

Abstract

Epidemiological data have implicated the pituitary gonadotropin follicle stimulating hormone (FSH) as both a risk factor for and a protective agent against epithelial ovarian cancer. Yet, little is known about how this hormone could play such opposing roles in ovarian carcinogenesis. Complementary DNA microarrays containing 2400 named genes were used to examine FSH-induced gene expression changes in ovarian cancer (OC) and immortalized normal human ovarian surface epithelial (HOSE) cell lines. Two-way t-statistics analyses of array data identified two distinct sets of FSH-regulated genes in HOSE and in established OC cell lines established from patients (OVCA cell lines). Among the HOSE cell lines, FSH increased expression of 57% of the 312 genes and downregulated 43%. In contrast, FSH diminished expression of 92% of the 177 genes in the OVCA cell lines. All but 18 of the genes affected by FSH in HOSE cell lines were different from those altered in OVCA cell lines. Among the 18 overlapping genes, nine genes exhibited the same direction of change following FSH challenge, while the other nine showed discordance in response between HOSE and OVCA cell lines. The FSH-induced differential expression of seven out of nine genes was confirmed by real-time RT–PCR. Gene-specific antisense oligonuleotides (ODNs) were used to inhibit the expression of genes encoding GTPase activating protein (rap1GAP), neogenin, and restin in HOSE and OVCA cells. Antisense ODNs to neogenin and restin, but not an antisense ODN to rap1GAP, were effective in inhibiting OVCA cell growth, diminishing proliferating cell nuclear antigen expression, and increasing caspase 3 activities. Furthermore, the ODN to rap1GAP was further shown to be ineffective in altering migration properties of OVCA cell lines. HOSE cell proliferation was not affected by treatment with any of the antisense ODNs. In summary, gene profiling data reveal for the first time that FSH may exert different biological actions on OVCA cells than on HOSE cells, by differential regulation of a set of putative oncogenes/tumor suppressors. Specifically, neogenin and restin were found to exhibit proproliferation/survival action on OC cells.

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Acknowledgements

We thank the editorial staff of Brigham and Women's Hospital, Harvard Medical School, Boston, for editorial help. This study was supported by NIH Grants CA091250 (to V. Syed) and CA94221 (to S-M Ho) and an Army Ovarian Cancer Research Program Grant DAMD17-99-1-9563 (to S-M Ho).

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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

    Shuk-Mei Ho, Kin-Mang Lau & Viqar Syed

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

    Shuk-Mei Ho

  3. Department of Obstetrics, Laboratory of Gynecologic Oncology, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

    Samuel Chi-ho Mok

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Correspondence to Viqar Syed.

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Ho, SM., Lau, KM., Mok, Sh. et al. Profiling follicle stimulating hormone-induced gene expression changes in normal and malignant human ovarian surface epithelial cells. Oncogene 22, 4243–4256 (2003). https://doi.org/10.1038/sj.onc.1206437

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