Epithelial ovarian cancer continues to be a highly fatal female reproductive malignancy despite treatment with aggressive chemotherapy, anti-angiogenic agents, PARP inhibitors, and surgical debulking strategies. JAK/STAT signaling is reported to be oncogenic in ovarian cancer and constitutively active in a proportion of chemotherapy-resistant ovarian cancer cell lines and human tumors. However, the individual contributions of specific JAK/STAT pathway components, in particular STAT1 and STAT3, in mediating oncogenic activity are not well understood. To delineate the precise molecular functions of STAT1 and STAT3 in the two most common ovarian cancer subtypes, high-grade serous and endometrioid, OVSAHO and MDAH-2774 cell lines were treated with IFNγ or IL6, to activate canonical STAT1 and STAT3 signaling respectively, with and without STAT1 and STAT3 knockdown. RNA-sequencing and ChIP-sequencing were utilized to globally define STAT1 and STAT3 specific transcriptomes and cistromes. STAT1 and STAT3 specific gene signatures were derived and applied to publicly available datasets to evaluate their predictive/prognostic value. Through these global and unbiased assessments, unique and overlapping STAT1 and STAT3 transcriptional profiles, and their associated pathways, were identified. From these data, STAT1 and STAT3 gene signatures were developed that are representative of transcriptionally active STAT1 and STAT3. STAT1 specific gene signatures were found to be more lowly expressed in ovarian tumors compared to normal ovarian tissue while STAT3 specific signatures were higher in malignant tissue. Elevated levels of STAT1 and STAT3 signaling were associated with non-responsiveness to initial chemotherapy treatment. Finally, STAT1 and STAT3 signatures were associated with worse progression free survival for ovarian cancer patients, while only STAT1 signatures were associated with worse overall survival. Importantly, these results were specific to the gene signatures indicative of STAT activity and differed from assessment of STAT1 and STAT3 gene expression alone. These studies further inform the precise mechanisms of STAT1 and STAT3 action in ovarian cancer and have defined gene signatures that have both prognostic and predictive value. Additionally, these results can be leveraged for the identification and development of pharmacologic approaches that elicit specific effects on the JAK/STAT signaling pathway and/or selectively alter the functions of individual STAT transcription factors.
Rodman et al. (Mon,) studied this question.