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Identification of ATF-3, caveolin-1, DLC-1, and NM23-H2 as putative antitumorigenic, progesterone-regulated genes for ovarian cancer cells by gene profiling

Oncogene volume 24, pages 1774–1787 (2005)Cite this article

Abstract

Although progesterone (P4) has been implicated to offer protection against ovarian cancer (OCa), little is known of its mechanism of action. The goal of this study was to identify P4-regulated genes that have anti-OCa action. Three immortalized nontumorigenic human ovarian surface epithelial (HOSE) cell lines and three OCa (OVCA) cell lines were subjected to 5 days of P4 treatment. Transcriptional profiling with a cDNA microarray containing ≈2400 known genes was used to identify genes (1) whose expression was consistently downregulated in OVCA cell lines compared to HOSE cell lines, and (2) whose expression was restored in OCa cell lines by P4 treatment. From the candidates selected, activating transcription factor-3 (ATF-3), caveolin-1, deleted in liver cancer-1 (DLC-1), and nonmetastatic clone 23 (NM23-H2) were chosen for post hoc functional studies based on their previously reported action as tumor suppressors or apoptosis inducers. Semiquantitative RT–PCR analyses confirmed loss of or reduced transcription of these genes in OVCA cells when compared to HOSE cells and their upregulation following P4 treatment. Hormonal specificity was demonstrated by blockade experiments with a progestin antagonist RU 38486. Ectopic expression of caveolin-1, DLC-1, and NM23-H2 caused growth inhibition in OVCA cell cultures, but not in HOSE cell cultures, while forced expression of ATF-3 suppressed growth in both. Overexpression of AFT-3 also enhanced caspase-3 activity in both HOSE and OVCA cells, whereas ectopic expression of caveolin-1 and DLC-1 only activated this enzyme in OCa cells. In contrast, NM23-H2 overexpression was ineffective in activating caspase-3. Overexpression of any of the four genes in OCa cells reduced soft-agar colony formation and cell invasiveness. Taken together, we have identified four new P4-regulated, antitumor genes for OCa. However, their modes of action differ significantly; ATF-3 primarily functions as an apoptosis inducer, NM23-H2 as a suppressor of cell motility, and caveolin-1 and DLC-1 exhibiting features of classical tumor suppressors. To the best of our knowledge, except for NM23-H2, this is the first report linking P4 to the regulation of these tumor suppressor/proapoptotic genes, which could serve as future therapeutic targets.

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Acknowledgements

We thank Dr Irene Ng, University of Hong Kong, China for providing DLC-1 expression vector, Dr Christine Sers, Charite, Humboldt University, Berlin, Germany for kindly providing caveolin-1 expression vector, Dr Carl V Hamby, New York Medical College Valhalla, New York, USA for providing NM23-H2 expression vector, and Dr Samuel C Mok, Laboratory of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston for providing HOSE and OVCA cell lines. We thank Mr Bhavesh Patel for technical assistance and the editorial staff of Brigham and Women's Hospital, Harvard Medical School, Boston, for editorial help. This study was supported in part by NIH Grants CA091250 (to V Syed) and CA94221 (to S-M Ho).

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Authors and Affiliations

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

    Viqar Syed, Kasturi Mukherjee & Shuk-mei Ho

  2. Department of Pathology/Center for Pathology Informatics/Benedum Center for Oncology Informatics, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15232, USA

    James Lyons-Weiler

  3. Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Shatin, Hong Kong, China

    Kin-Mang Lau

  4. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

    Tetsuo Mashima & Takashi Tsuruo

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

    Shuk-mei Ho

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

    Shuk-mei Ho

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Syed, V., Mukherjee, K., Lyons-Weiler, J. et al. Identification of ATF-3, caveolin-1, DLC-1, and NM23-H2 as putative antitumorigenic, progesterone-regulated genes for ovarian cancer cells by gene profiling. Oncogene 24, 1774–1787 (2005). https://doi.org/10.1038/sj.onc.1207991

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