Low levels of IGFBP7 expression in high-grade serous ovarian carcinoma is associated with patient outcome

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.

Antitumor activity of pan‐HER inhibitors in HER2‐positive gastric cancer

“…Actually, IGFBP7 reportedly plays a role as a tumor suppressor gene in breast cancer, colorectal cancer, and hepatocellular carcinoma . The association of HER family protein and IGF‐1R has also been well‐documented, and low expression of IGFBP7 is correlated with poor prognosis in high‐grade serous ovarian carcinoma . The activation of IGF‐1R might influence the sensitivity of pan‐HER inhibitors indirectly, as IGF‐1R reportedly forms a heterodimer with EGFR .…”

Cellular senescence is a central response to cytotoxic chemotherapy in high-grade serous ovarian cancer

“…RNA from HGSOC cultures were extracted and purified as previously described (Gambaro et al, 2015;Zietarska et al, 2007) U133A GeneChip arrays (Affymetrix®, Santa Clara, CA). Gene expression levels were calculated for each probe set from the scanned image by Affymetrix® GeneChip (MAS5) as previously described (Cody et al, 2007).…”

IGFBP7 acts as a negative regulator of RANKL‐induced osteoclastogenesis and oestrogen deficiency‐induced bone loss

“…The details of the establishment of the OVX murine model were consistent with previous studies . One week after the ovariectomy operation, mice in the OVX + IGFBP7 group were treated with tail vein injection of IGFBP7 (2 μg rIGFBP7 in a total volume of 100 μl PBS, once a week, based on previous studies), while mice in the Sham and OVX groups were treated with PBS. After 6 weeks, all mice were sacrificed in a CO 2 chamber.…”

“…Following 5 days of co-culture, the upper chamber was removed and osteoclastogenesis of the lower chamber was evaluated using TRAP staining. week, based on previous studies), 17,[30][31][32] Images were obtained for histomorphological analysis using a microscope (Leica).…”