Abstract 2669: A role for HOXA5 in the transcriptional response of ovarian and fallopian tube surface epithelial cells to norepinephrine

Abstract

Abstract Chronic stress has been suggested to play a role in tumor initiation, progression and patient survival. Studies have shown that activation of the sympathetic nervous system and increased levels of stress-associated hormones such as norepinephrine can enhance migration, invasion and growth of ovarian cancer cells. However, the extent to which stress contributes to tumor initiation remains unknown. The purpose of this study was to explore the effects of norepinephrine on the transcriptional program of immortalized normal cell lines presumed to be the origin of epithelial ovarian cancers. We treated normal immortalized ovarian (iOSE) and fallopian tube (iFTE) surface epithelial cells with 10uM norepinephrine for 15 min, 1h and 4h and generated global transcriptomic profile of treated vs untreated cells by RNA-Seq. The most significant gene expression changes (P(adj) < 0.05) were observed at the 1h time point; with an overlap of 45 differentially expressed genes in both iOSE and iFTE cells. Genes in immune-related and developmental pathways were found to be highly enriched in the norepinephrine treated samples set. By the 4h time point, the number of differentially expressed genes had increased to 313 genes from 234 at 1h in iFTE cells, while it reduced to 34 genes from 53 in iOSE cells. Additionally, the number of differentially expressed genes common to iOSE and iFTE cells had reduced to 14. Gene ontology analysis of the differentially expressed genes revealed ‘transcription factor’ to be the most significantly overrepresented class (based on FDR value) at both 1h and 4h time-points. Promoter enrichment analysis identified HOXA5, GFI1 and FOXI1 transcription factor binding sites to be highly enriched (based on Z-score and Fisher-Score) at both time points. HOXA5 ranked consistently at the top in both cell lines and at both 1h and 4h time points. These observations suggest that HOXA5 may play a central role in regulating the early response to norepinephrine in normal ovarian and fallopian tube cells. We will further assess the function of HOXA5 through ChIP-Seq and shRNA- mediated silencing. Citation Format: Sweta Dash, Anxhela Gjyshi, Ling Cen, Chia-Ho Cheng, Chaomei Zhang, Sean J. Yoder, Jamie K. Teer, Guillermo N. Armaiz-Pena, Alvaro N. Monteiro. A role for HOXA5 in the transcriptional response of ovarian and fallopian tube surface epithelial cells to norepinephrine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2669.