Abstract 736: HOXA5 induction by norepinephrine in precursor cells of ovarian cancer

Abstract

Abstract Chronic stress induced by repetitive activation of the sympathetic nervous system leads to rapid release of catecholamines like norepinephrine (NE). Several studies have shown that increased levels of NE can contribute to tumor progression by promoting tumor growth, migration and invasion of ovarian cancer cells. However, the role of NE in tumor initiation remains mostly unknown. The purpose of this study was to explore the acute and chronic effects of NE on immortalized normal fallopian tube and ovarian cell lines presumed to be the origin of epithelial ovarian cancers. Normal immortalized ovarian (iOSE11) and fallopian tube (iFTE283) surface epithelial cells were treated with 10µM NE for 15 min, 1h and 4h followed by whole-transcriptome RNA-Seq. 234 and 313 differentially expressed genes were identified at 1h and 4h time points in iFTE283 cells respectively; while 53 and 34 differentially expressed genes were identified at 1h and 4h time points in iOSE11 cells. Gene ontology analysis using Panther Statistical Overrepresentation Test was performed on these differentially expressed genes. Panther Protein Class analysis revealed ‘transcription factor' to be the most significantly overrepresented at both 1h and 4h time-points. Promoter enrichment analysis using oPOSSUM database identified transcription factor HOXA5 to be consistently enriched at both time points in both cell lines. Time course studies performed by qPCR and luciferase promoter assays for HOXA5 transcription factor in normal cells (iOSE11, iFTE283), partially transformed cells (iOSE11-p53R175H, iFTE283-p53R175H, iFTE282-p53R175H and iOSE4-cMyc) and cancer cells (OvCAR8, SkoV3) revealed that HOXA5 induction by NE occurred only in normal immortalized cells and partially transformed p53R175H overexpressing cells, but not in cancer cells. In contrast, chronic exposure to NE for 4 months followed by HOXA5 time course study by qPCR revealed attenuation of HOXA5 induction in normal as well as p53R175H overexpressing cells. Additionally, long term NE treatment lead to increased proliferation and colony forming capacity in iFTE283, iFTE283-p53R175H and iFTE282-p53R175H cells. p53R175H overexpressing iFTE283 cells also showed slight increase in chromosomal instability, as measured by karyotype, after 4 months of treatment with NE. These observations suggest that HOXA5 plays a central role in regulating the early response to NE in normal as well as p53R175H overexpressing ovarian epithelial and fallopian tube cells, but this induction is attenuated in cancer cells as well as in normal and partially transformed cells that are exposed to long term NE treatment. We will further assess the induction of HOXA5 by NE through promoter bashing experiments. Citation Format: Sweta Dash, Ling Cen, Sean Yoder, Tania Mesa, Andrew Smith, Chaomei Zhang, Jamie Teer, Guillermo Armaiz-Pena, Alvaro Monteiro. HOXA5 induction by norepinephrine in precursor cells of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 736.