Differential and divergent activity of insulin-like growth factor binding protein 6 in platinum-sensitive versus platinum-resistant high-grade serous ovarian carcinoma cell lines

Annamaria Piscazzi; Valentina Condelli; Fabiana Crispo; Anna Rita Daniela Coda; Giovanni Calice; Giuseppina Bruno; Santina Venuto; Daniele Tibullo; Guido Giordano; Michele Pietrafesa; Arcangelo Liso; Matteo Landriscina

doi:10.3892/ol.2022.13305

Differential and divergent activity of insulin-like growth factor binding protein 6 in platinum-sensitive versus platinum-resistant high-grade serous ovarian carcinoma cell lines

Oncol Lett. 2022 Jun;23(6):185. doi: 10.3892/ol.2022.13305. Epub 2022 Apr 21.

Affiliations

¹ Department of Medical and Surgical Sciences, University of Foggia, I-71122 Foggia, Italy.
² Laboratory of Pre-Clinical and Translational Research, Scientific Institute for Research, Hospitalization and Healthcare-Referral Cancer Center of Basilicata (IRCCS-CROB), I-85028 Potenza, Italy.
³ Department of Biomedical and Biotechnological Sciences, Section of Biochemistry, University of Catania, I-95123 Catania, Italy.

Abstract

Insulin-like growth factor binding protein 6 (IGFBP6) is a secreted protein with a controversial role in human malignancies, being downregulated in most types of human cancer, but upregulated in selected tumors. Ovarian cancer (OC) is a human malignancy characterized by IGFBP6 downregulation; however, the significance of its low expression during ovarian carcinogenesis is still poorly understood. In the present study, IGFBP6 expression and activation of its associated signaling pathway were evaluated in two matched OC cell lines derived from a high-grade serous OC before and after platinum resistance (PEA1 and PEA2 cells, respectively). A whole genome gene expression analysis was comparatively performed in both cell lines upon IGFBP6 stimulation using Illumina technology. IGFBP6 gene expression data from human OC cases were obtained from public datasets. Gene expression data from public datasets confirmed the downregulation of IGFBP6 in primary and metastatic OC tissues compared with in normal ovarian tissues. The comparative analysis of platinum-sensitive (PEA1) and platinum-resistant (PEA2) cell lines showed quantitative and qualitative differences in the activation of IGFBP6 signaling. Notably, IGFBP6 enhanced ERK1/2 phosphorylation only in PEA1 cells, and induced more evident and significant gene expression reprogramming in PEA1 cells compared with in PEA2 cells. Furthermore, the analysis of selected genes modulated by IGFBP6 (i.e., FOS, JUN, TNF, IL6, IL8 and EGR1) exhibited an inverse regulation in PEA1 versus PEA2 cells. In addition, selected hallmarks (TNFA_signaling_via_NFKB, TGF_beta_signaling, P53_pathway) and IL-6 signaling were positively regulated in PEA1 cells, whereas they were inhibited in PEA2 cells in response to IGFBP6. These data suggested that dysregulation of IGFBP6 signaling may serve a role in the progression of OC, and is likely associated with the development of platinum resistance.

Keywords: IGFBP6; IL6 pathway; gene expression; ovarian serous carcinoma; platinum resistance.

Grants and funding

The present study was supported by the LILT grant 5×1000-2020 (grant no. CUP D79J21003680005) to ML. SV was supported by PON AIM R&I (National Operational Programme-Attraction and International Mobility-Research&Innovation) 2014-2020-1879351-3 (grant no. CUP D74I18000160006) and GB was supported by PON AIM R&I (National Operational Programme-Attraction and International Mobility-Research&Innovation) 2014-2020-1879351-2 (grant no. CUP D74I18000140006). This manuscript has been published with the financial support of the Dept. of Medical and Surgical Sciences of the University of Foggia.