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Open Access Research article

Secreted frizzled-related protein 4 expression is positively associated with responsiveness to Cisplatin of ovarian cancer cell lines in vitro and with lower tumour grade in mucinous ovarian cancers

Uttara Saran1, Frank Arfuso1*, Nikolajs Zeps234 and Arunasalam Dharmarajan15

Author Affiliations

1 School of Anatomy and Human Biology, Faculty of Life and Physical Sciences, The University of Western Australia, 35 Stirling Highway, Perth, Crawley 6009, Western Australia

2 St John of God HealthCare, Subiaco, 6008, Western Australia

3 School of Surgery, The University of Western Australia, 35 Stirling Highway, Crawley, 6009, Western Australia

4 School of Pathology and Laboratory Medicine, The University of Western Australia, 35 Stirling Highway, Crawley, 6009, Western Australia

5 School of Biomedical Sciences, Faculty of Health Sciences, Curtin University and Curtin Health Innovation Research Institute (CHIRI), GPO Box U1987, Perth, 6845, Western Australia

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BMC Cell Biology 2012, 13:25  doi:10.1186/1471-2121-13-25

Published: 8 October 2012

Abstract

Background

Ovarian cancer is one of the most lethal malignancies in women, as it is frequently detected at an advanced stage, and cancers often become refractory to chemotherapy. Evidence suggests that dysregulation of pro-apoptotic genes plays a key role in the onset of chemoresistance. The secreted Frizzled-Related Protein (sFRP) family is pro-apoptotic and also a negative modulator of the Wnt signalling cascade. Studies have demonstrated that the re-expression of sFRPs, in particular sFRP4, is associated with a better prognosis, and that experimentally induced expression results in cell death.

Results

In vitro experimental models determined that sFRP4 was differentially expressed in chemosensitive (A2780) and chemoresistant (A2780 ADR and A2780 Cis) ovarian cell lines, with chemosensitive cells expressing significantly higher levels of sFRP4. Transfection of the chemoresistant cell lines with sFRP4 significantly increased their sensitivity to chemotherapy. Conversely, silencing of sFRP4 expression in the chemosensitive cell line resulted in a corresponding increase in chemoresistance. Comparison of sFRP4 expression in tumour biopsies revealed a positive trend between sFRP4 expression and tumour grade, with mucinous cyst adenocarcinomas exhibiting significantly decreased sFRP4 levels compared to mucinous borderline tumours.

Conclusions

This study indicates a role for sFRP4 as a predictive marker of chemosensitivity in ovarian cancer and suggests that this pathway may be worth exploiting for novel therapies.

Keywords:
Secreted frizzled-related protein 4; Ovarian cancer; Cisplatin; Chemoresistance; Chemosensitivity; Tumour biopsy