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Differential and divergent activity of Insulin-like Growth Factor Binding Protein 6 (IGFBP6) in platinum-sensitive versus platinum-resistant high-grade serous ovarian carcinoma cell lines.

ABSTRACT: IGFBP6 is a secreted protein with a controversial role in human malignancies, being downregulated in the majority of human cancers, but upregulated in selected tumors. Ovarian carcinoma (OC) is a human malignancy characterized by IGFBP6 downregulation, even though the significance of its low expression during ovarian carcinogenesis is still poorly understood. IGFBP6 expression levels and the activation of its signaling pathway were evaluated in two matched OC cell lines derived from a high-grade serous ovarian cancer 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 by Illumina technology. IGFBP6 gene expression in human OCs data were obtained from public datasets. Gene expression data from public datasets confirmed the downregulation of IGFBP6 from normal ovarian tissues to primary and metastatic OCs. The comparative analysis of platinum-sensitive (PEA1) and platinum-resistant (PEA2) cell lines showed quantitative and qualitative differences in the activation of IGFBP6 signaling. Indeed, IGFBP6 enhanced ERK1/2 phosphorylation only in PEA1 cells and induced a more evident and significant gene expression reprogramming in PEA1 compared to PEA2 cells. Furthermore, the analysis of selected genes modulated by IGFBP6 (i.e., FOS, JUN, TNF, IL6, IL8, and EGR1) showed an inverse regulation in PEA1 versus PEA2 cells, as well as selected hallmarks and IL-6 signaling were ositively regulated in PEA1, while inhibited in PEA2 cells.These data suggest that loss of IGFBP6 signaling may play a role in ovarian cancer progression, being likely associated to the development of platinum resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189717 | GEO | 2022/03/23

REPOSITORIES: GEO

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Project description:Purpose: Despite advances in radical surgery and chemotherapy delivery, ovarian cancer is the most lethal gynecologic malignancy. Most of these patients are treated with platinum-based chemotherapies, but there is no biomarker model to guide their responses to these therapeutic agents. We have developed and independently tested our novel multivariate molecular predictors for forecasting patients' responses to individual drugs on a cohort of 58 ovarian cancer patients. Experimental Design: We adapted and applied the previously-published COXEN algorithm to develop molecular predictors for therapeutic responses of patients' tumors based on expression signatures derived from the NCI-60 in vitro drug activities and genomic expression data. Genome-wide candidate biomarkers were first triaged by examining expression patterns of frozen and formalin-fixed paraffin embedded (FFPE) tissue samples. We then identify initial drug sensitivity biomarkers for carboplatin and paclitaxel, respectively. These biomarkers were further narrowed by examining concordant expression patterns between cell lines and a historical set of ovarian cancer patients. Multivariate predictors were obtained from the NCI-60 cell lines and refined using historical patient cohorts. To independent validate these molecular predictors, we performed genome-wide profiling on FFPE samples of 58 ovarian cancer patients obtained prior to adjuvant chemotherapy. Results: Carboplatin predictor significantly stratified platinum sensitive and resistant patients (p = 0.019) with sensitivity = 93%, specificity = 33%, PPV = 65%, and NPV = 78%. Paclitaxel predictor also significantly stratified patients' responses (p = 0.033) with sensitivity = 96%, specificity = 26%, PPV = 61%, and NPV = 86%. The combination predictor for platinum-taxane combination demonstrated a significant survival difference between the predicted responders and nonresponders with median survival of 12.9 months vs. 8.1 months (p = 0.045). Conclusions: COXEN predictors successfully stratified platinum resistance and taxane response in this retrospective cohort, especially based on their FFPE tumor samples. Accurate prediction of chemotherapeutic response, especially to platinum agents is highly clinically relevant and could alter primary management of ovarian cancer. Gene expression data from 58 stage III-IV ovarian cancer patients treated with Carboplatin and Taxol agents

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Differential and divergent activity of Insulin-like Growth Factor Binding Protein 6 (IGFBP6) in platinum-sensitive versus platinum-resistant high-grade serous ovarian carcinoma cell lines.

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