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  • Oncogenomics
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A candidate tumor suppressor HtrA1 is downregulated in ovarian cancer

Oncogene volume 23, pages 1636–1644 (2004)Cite this article

Abstract

We report here that HtrA1, a candidate tumor suppressor, is downregulated in ovarian cancer. Expression of HtrA1 is downregulated in five of seven ovarian cancer cell lines. In total, 59% of primary ovarian tumors have either a complete absence or markedly reduced levels of HtrA1 expression compared to the brushings of ovarian surface epithelium. Primary ovarian tumors show high frequencies of loss of an allele at microsatellite markers near htrA1 locus on 10q26. Downregulation of HtrA1 in SKOV3 by antisense transfection promotes anchorage-independent growth, while exogenous expression of HtrA1 in OV202 induces cell death. HtrA1-induced cell death is not inhibited by the broad caspase inhibitor, zVAD(OMe)fmk, but instead reflects serine protease activity associated with HtrA1. These observations raise the possibility of HtrA1 as a candidate tumor suppressor involved in promoting serine-protease-mediated cell death and that downregulation of HtrA1 in ovarian cancer may contribute to malignant phenotype.

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Abbreviations

DHPLC:

denaturing high-performance liquid chromatography

IGFBP:

insulin-like growth factor binding protein

PDZ:

postsynaptic density protein 95-Discs large-Zona occuldens 1

LOH:

loss of heterozygosity

OSE:

ovarian surface epithelium

XIAP:

X-linked inhibitor of apoptosis protein

H&E:

hematoxylin and eosin

zVAD(OMe)-fmk:

N-(Nα-benzyloxycarbonylvalinylalanyl) aspartic acid (O-methyl ester) fluoromethylketone

PE:

phycoerythrin

7-AAD:

7-amino-actinomycin

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Acknowledgements

We thank Kim R Kalli for providing us with short-term culture of ovarian surface epithelial cells. This work is supported in part by DOD Grnt DAMD17-99-1-9504 to VS, DIS, and SHK and a John W Anderson Foundation grant and Minnesota Ovarian Cancer Alliance grant to VS and the Mayo Foundation.

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Authors and Affiliations

  1. Mayo Clinic Cancer Center and Department of Experimental Pathology, Mayo Clinic, Rochester, 55905, MN, USA

    Jeremy Chien, Julie Staub, Michele R Erickson-Johnson, Fergus J Couch, David I Smith & Viji Shridhar

  2. Arthritis Biology Unit, Novartis Pharmaceuticals, E Hanover, 07936, NJ, USA

    Shou-Ih Hu & Robert M Crowl

  3. Department of Oncology, Mayo Clinic, Rochester, 55905, MN, USA

    Scott H Kaufmann

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  1. Jeremy Chien
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  2. Julie Staub
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Correspondence to Viji Shridhar.

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Chien, J., Staub, J., Hu, SI. et al. A candidate tumor suppressor HtrA1 is downregulated in ovarian cancer. Oncogene 23, 1636–1644 (2004). https://doi.org/10.1038/sj.onc.1207271

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