Abstract
BackgroundInsulin-like growth factor binding protein 7 (IGFBP7) has been suggested to act as a tumour suppressor gene in various human cancers, yet its role in epithelial ovarian cancer (EOC) has not yet been investigated. We previously observed that IGFBP7 was one of several genes found significantly upregulated in an EOC cell line model rendered non-tumourigenic as consequence of genetic manipulation. The aim of the present study was to investigate the role of IGFBP7 in high-grade serous ovarian carcinomas (HGSC), the most common type of EOC.MethodsWe analysed IGFBP7 gene expression in 11 normal ovarian surface epithelial cells (NOSE), 79 high-grade serous ovarian carcinomas (HGSC), and seven EOC cell lines using a custom gene expression array platform. IGFBP7 mRNA expression profiles were also extracted from publicly available databases. Protein expression was assessed by immunohistochemistry of 175 HGSC and 10 normal fallopian tube samples using tissue microarray and related to disease outcome. We used EOC cells to investigate possible mechanisms of gene inactivation and describe various in vitro growth effects of exposing EOC cell lines to human recombinant IGFBP7 protein and conditioned media.ResultsAll HGSCs exhibited IGFBP7 expression levels that were significantly (p = 0.001) lower than the mean of the expression value of NOSE samples and that of a whole ovary sample. IGFBP7 gene and protein expression were lower in tumourigenic EOC cell lines relative to a non-tumourigenic EOC cell line. None of the EOC cell lines harboured a somatic mutation in IGFBP7, although loss of heterozygosity (LOH) of the IGFBP7 locus and epigenetic methylation silencing of the IGFBP7 promoter was observed in two of the cell lines exhibiting loss of gene/protein expression. In vitro functional assays revealed an alteration of the EOC cell migration capacity. Protein expression analysis of HGSC samples revealed that the large majority of tumour cores (72.6%) showed low or absence of IGFBP7 staining and revealed a significant correlation between IGFBP7 protein expression and a prolonged overall survival (p = 0.044).ConclusionThe low levels of IGFPB7 in HGSC relative to normal tissues, and association with survival are consistent with a purported role in tumour suppressor pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1138-8) contains supplementary material, which is available to authorized users.
Highlights
Insulin-like growth factor binding protein 7 (IGFBP7) has been suggested to act as a tumour suppressor gene in various human cancers, yet its role in epithelial ovarian cancer (EOC) has not yet been investigated
Insulin-like growth factor binding protein 7 (IGFBP7), a gene suspected to play a role in tumour suppressor pathways in various cancer types but not extensively studied in EOC, was among the list of genes which were reprogrammed as a consequence of tumour suppression in our OV90 cell line model [15,22,23,24,25,26,27]
EOC cell lines The EOC cell lines and their culture conditions have been described previously [19,46] Briefly, they were established from the malignant ovarian tumours (TOV) and ascites (OV) from patients who had not undergone radiation treatment or chemotherapy prior to surgery and represent different subtypes: undifferentiated adenocarcinoma (OV90), high-grade endometrioid carcinomas (HGEC) (TOV112D), a low-grade serous carcinoma (TOV81D), high-grade serous ovarian carcinomas (HGSC) (TOV1946, OV1946, and TOV2223), and a clear cell carcinoma (TOV21G), where TOV1946 and OV1946 were derived from malignant ovarian ascites (OV1946) or tumour (TOV1946) from the same patient
Summary
Insulin-like growth factor binding protein 7 (IGFBP7) has been suggested to act as a tumour suppressor gene in various human cancers, yet its role in epithelial ovarian cancer (EOC) has not yet been investigated. Our group has focused on investigating somatic molecular genetic events associated with tumour suppressor pathways affected in HGSC [15,16,17,18] Towards this goal, we have started characterizing the genes reprogrammed in the context of a tumourigenic OV90 EOC cell line rendered non-tumourigenic as a consequence of a unique complementation assay involving the transfer of normal chromosomal fragments [15,16,18]. Insulin-like growth factor binding protein 7 (IGFBP7), a gene suspected to play a role in tumour suppressor pathways in various cancer types but not extensively studied in EOC, was among the list of genes which were reprogrammed as a consequence of tumour suppression in our OV90 cell line model [15,22,23,24,25,26,27]
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