STAT1 and STAT3 Signaling in Ovarian Cancer: Prognostic Biomarkers and Therapeutic Targets

Epithelial ovarian cancer is the 7th most common cancer in women worldwide and is the most fatal of all female reproductive cancers. JAK/STAT signaling is oncogenic in ovarian cancer and has been reported to be constitutively active in a proportion of chemotherapy resistant ovarian cancer cell lines and tumors. However, the precise molecular mechanisms by which STAT1 and STAT3 function in ovarian cancer are not well understood and the consequences of their specific inhibition have yet to be determined. Methods: To delineate the specific functions of STAT1 and STAT3 in high grade serous and endometrioid ovarian cancer cell lines, we treated OVSAHO and MDAH cells with IFN? or IL6, canonical STAT1 and STAT3 activators respectively, with and without STAT1 or STAT3 specific siRNAs. We conducted RNA-sequencing and ChIP-sequencing following treatment to delineate direct and indirect target genes for STAT1 and STAT3. We generated a STAT1 and STAT3 specific gene signature and applied them to publicly available datasets to test their predictive and prognostic ability. Results: Using these global and unbiased datasets, we identified STAT1 and STAT3 specific pathways, developed STAT1 and STAT3 specific gene signatures, and applied these signatures to publicly available ovarian cancer patient data. We determined the STAT1 and STAT3 signature's associations with tumor development, chemotherapy responsiveness and long-term patient outcomes. Conclusions: Our studies have further informed the precise mechanisms of STAT1 and STAT3 action in the two most common subtypes of ovarian cancer and have defined gene signatures that are both prognostic and predictive. Overall design: MDAH and OVSAHO (OVS) cells treated with vehicle (Veh), 10ng/µl IFN?, or 30ng/µl of IL6 in triplicate for 30 minutes. ChIP was performed with STAT1 (#SC417, Santa Cruz Biotechnology, Dallas, TX) and STAT3 (#CST9139, Cell Signaling, Danvers, MA).