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STAT1 and STAT3 Signaling in Ovarian Cancer: Prognostic Biomarkers and Therapeutic Targets [RNA-seq]

ABSTRACT: 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 IFNγ 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293444 | GEO | 2026/02/16

REPOSITORIES: GEO

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

Project description: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 IFNγ 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.

2026-02-16 | GSE293317 | GEO

Multi-omics profiling reveals key signaling pathways in ovarian cancer controlled by STAT3

Project description:Inhibiting STAT3 signaling reduces tumor progression, metastases and chemoresistance, however the precise molecular mechanism has not been fully delineated in ovarian cancer. Methods: In this study, we generated STAT3 knockout (KO) ovarian cancer cell lines. Effect of STAT3 KO on cell proliferation, migration and spheroid formation was assessed in vitro and effect on in vivo tumor growth was tested using several tumor xenograft models. We used multi-omic genome-wide profiling to identify multi-level (Bru-Seq, RNA-Seq, and MS Proteomic) expression signatures of STAT3 KO ovarian cancer cells.

2019-07-17 | GSE134375 | GEO

Asymmetry of STAT action in driving IL-27 and IL-6 transcriptional outputs and cytokine specificity

Project description:IL-6 and IL-27 have antagonistic and overlapping functions, signal through a shared receptor subunit and employ the same downstream STAT proteins. To evaluate the degree of specificity and redundancy for these cytokines, we quantified global transcriptomic changes induced by the two cytokines and determined the relative contributions of STAT1 and STAT3 using genetic models and ChIP-seq. We found a high degree of overlap of the transcriptomes induced by IL-6 and IL-27 and extremely few examples in which the cytokines acted in opposition. Using STAT deficient cells and T cells from patients with gain-of-function STAT1 mutations, we show that STAT3 was responsible for the overall transcriptional output driven by both cytokines, whereas STAT1 was the driver of cytokine specificity. STAT1 did not compensate for the lack STAT3; on the contrary, much of STAT1 binding to chromatin was STAT3 dependent. Thus, STAT1 shapes the specific cytokine signature superimposed upon STAT3’s action. Integrated analysis of transcriptome and transcription factor binding data from cytokine treated CD4+T cells

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Opposing Roles of STAT1 and STAT3 in IL-21 Function in CD4+ T cells

Project description:Interleukin-21 (IL-21) is a type 1 cytokine essential for immune cell differentiation and function. Although IL-21 can activate several STAT family transcription factors, previous studies focused mainly on the role of STAT3 in IL-21 signaling. Here, we investigated the role of STAT1 and show that STAT1 and STAT3 have at least partially opposing roles in IL-21 signaling in CD4+ T cells. IL-21 induced STAT1 phosphorylation, and this was augmented in Stat3-deficient CD4+ T cells. RNA-Seq analysis of CD4+ T cells from Stat1- and Stat3-deficient mice revealed that both STAT1 and STAT3 are critical for IL-21-mediated gene regulation. Expression of some genes, including Tbx21 and Ifng, was differentially regulated by STAT1 and STAT3, and interestingly, ChIP-Seq analysis showed that STAT3 binding at Tbx21 and Ifng loci was attenuated in Stat1-deficient cells. Moreover, opposing actions of STAT1 and STAT3 on IFN- expression in CD4+ T cells were demonstrated in vivo during chronic lymphocytic choriomeningitis (LCMV) infection. Finally, IL-21-mediated induction of STAT1 phosphorylation, as well as IFNG and TBX21 expression, were higher in CD4+ T cells from patients with autosomal dominant hyper-IgE syndrome (AD-HIES), which is caused by STAT3 deficiency. These data indicate an interplay between STAT1 and STAT3 in fine-tuning IL-21 actions. Genome-wide transcription factors mapping and binding of STAT3 in mouse CD4+ T cells in both WT and Stat1-deficient mice. RNA-Seq is performed in mouse CD4+ T cells in WT, Stat1-deficient and Stat3-deficient mice.

2015-07-01 | E-GEOD-63204 | biostudies-arrayexpress

Epigenomic remodeling of the PAX8 cistrome in high grade serous ovarian cancer [RNA-Seq]

Project description:We report mapping of the PAX8 cistrome in three high grade serous ovarian cancer cell lines (KURAMOCHI, OVSAHO, and JHOS4) compared to three benign immortalized fallopian tube cell lines (FT33, FT194, and FT246). We identified a highly conserved PAX8 binding pattern common across benign fallopian tube cell lines that was distinct from the unique PAX8 binding patterns seen in each cancer cell line.

2016-08-08 | GSE83100 | GEO

Epigenomic remodeling of the PAX8 cistrome in high grade serous ovarian cancer [ChIP-Seq]

2016-08-08 | GSE79893 | GEO

Epigenomic remodeling of the PAX8 cistrome in high grade serous ovarian cancer [ChIP-Seq]

2016-08-08 | E-GEOD-79893 | biostudies-arrayexpress

Lestaurtinib inhibits therapy resistant ovarian cancer

Project description:Ovarian cancer is the deadliest gynecological malignancy, owing to its late-stage diagnosis and high rates of recurrence and resistance following standard-of-care treatment, highlighting the need for novel treatment approaches. Through an unbiased drug screen, we identified the kinase inhibitor, lestaurtinib, as a potent antineoplastic agent for chemotherapy- and PARP-inhibitor (PARPi)-sensitive and -resistant ovarian cancer cells and patient derived xenografts (PDXs). RNA-sequencing revealed that lestaurtinib potently suppressed JAK/STAT signaling and lestaurtinib efficacy was shown to be directly related to JAK/STAT pathway activity in cell lines and PDX models. Most ovarian cancer cells exhibited constitutive JAK/STAT pathway activation and genetic loss of STAT1 and STAT3 resulted in growth inhibition. Lestaurtinib also displayed synergy when combined with cisplatin and olaparib, including in a model of PARPi resistance. In contrast, the most well-known JAK/STAT inhibitor, ruxolitinib, lacked antineoplastic activity against all ovarian cancer cell lines and PDX models tested. This divergent behavior was reflected in the ability of lestaurtinib to block both Y701/705 and S727 phosphorylation of STAT1 and STAT3, whereas ruxolitinib failed to block S727. Consistent with these findings, lestaurtinib additionally inhibited the serine/threonine kinases, JNK and ERK, leading to more complete suppression of STAT phosphorylation. Concordantly, combinatorial treatment with ruxolitinib and a JNK or ERK inhibitor resulted in synergistic antineoplastic effects at dose levels where the single agents were ineffective. Taken together, these findings indicate that lestaurtinib, and other treatments that converge on JAK/STAT signaling, are worthy of further pre-clinical and clinical exploration for the treatment of highly aggressive and advanced forms of ovarian cancer.

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Asymmetry of STAT action in driving IL-27 and IL-6 transcriptional outputs and cytokine specificity

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Targeting USP8 Causes Synthetic Lethality through Degradation of FGFR2 in ARID1A-Deficient Ovarian Clear Cell Carcinoma

Project description:Over half of ovarian clear cell carcinoma (OCCC) cases exhibit deficiencies in the ARID1A gene, a chromatin remodeling complex component. OCCC is resistant to chemotherapy and challenging to treat, necessitating new drug treatment strategies. This study used a publicly available dependency factor database to identify synthetic lethal targets for ARID1A-deficient cancer. The DepMap portal was used to identify genes on which ARID1A-deficient cancer cell lines are highly dependent. Our analysis limited to ovarian cancer cell lines only identified the deubiquitinating enzyme USP8 as a synthetic lethal target in ARID1A-deficient OCCC cancer cell lines and mouse xenograft models. In addition, USP8 inhibitors were more selective for ARID1A-deficient cells than existing candidate drugs used in promising clinical trials for ARID1A-deficient cancers. Suppression of USP8 in ARID1A-deficient cells led to degradation of FGFR2 via the proteasome. Deficiency of ARID1A causes abnormalities in the STAT3 pathway, which is one of the downstream pathways of FGFR2, but suppression of USP8 attenuates phosphorylation of STAT3 pT705 and induces apoptosis. Taken together, the data suggest that USP8 is a novel therapeutic target for ARID1A-deficient OCCC and that it suppresses FGFR2-STAT3 signaling.

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