Physical interaction of STAT1 isoforms with TGF-β receptors leads to functional crosstalk between two signaling pathways in epithelial ovarian cancer

Abstract

BackgroundThe signal transducer and activator of transcription (STAT) and transforming growth factor-β (TGF-β) signaling pathways play important roles in epithelial ovarian cancer (EOC). However, the mechanism of crosstalk between two pathways is not completely understood.MethodsThe expression of STAT1 protein was detected by tissue microarray and immunoblotting (IB). The interaction of STAT1 isoforms with TGF-β receptors was confirmed by immunoprecipitation and IB. The effect of TGF-β signaling on STAT1 activation was examined in EOC and non-tumorous HOSEpiC cells treated with TGF-β1 in the presence or absence of the inhibitor of TGF-β type I receptor. The gain-of-function and loss-of-function approaches were applied for detecting the role of STAT1 on EOC cell behaviours.ResultsThe high level of STAT1 was observed in patients with high-grade serous EOC. STAT1 expression was higher in ovarian cancer cells than noncancerous cells. TGF-β1 activated the STAT1 pathway by inducing the phosphorylation of STAT1α on S727 residue. The full-length STAT1α and the truncated STAT1β directly interacted with TGF-β receptors (ALK1/ALK5 and TβRII), which was mediated by TGF-β1. STAT1α and STAT1β blocked the activation of the TGF-β1 signaling pathway in EOC cells by reducing Smad2 phosphorylation. STAT1 overexpression induced EOC cell proliferation, migration, and invasion; whereas its inhibition enhanced TGF-β1-induced phospho-Smad2 and suppressed EOC cell proliferation, migration, and invasion.ConclusionsOur data unveil a novel insight into the molecular mechanism of crosstalk between the STAT1 and TGF-β signaling pathways, which affected the cancer cell behavior. Suppression of STAT1 may be a potential therapeutic strategy for targeting ovarian cancer.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0773-8) contains supplementary material, which is available to authorized users.

Transforming growth factor‐β signaling: Tumorigenesis and targeting for cancer therapy

“…with TβRI/TβRII suppresses the inducible effects of TGF-β on Smad2 shown in ovarian cancer. STAT1 activation is induced by IFN-γ (Tian et al, 2018), and, as it was aforementioned, IFN-γ production is repressed by TGF-β (Y. Wang, Chu et al, 2018).…”

Highly expressed STAT1 contributes to the suppression of stemness properties in human paclitaxel-resistant ovarian cancer cells

“…High level of STAT1 is associated with improved chemotherapy response in high-grade serous OC, suggesting that STAT1 may be a biomarker of chemosensitivity [16]. Our previous study demonstrated the overexpression of STAT1 in high-grade serous OC and unveiled crosstalk between STAT1 and TGF-β signaling pathways in OC cells [17]. It has been shown that the TGF-β signaling pathway is one of the primary signaling pathways responsible for maintaining pluripotency and self-renewal abilities in embryonic and somatic stem cells [18,19].…”

“…The STAT1-overexpressing plasmid was generated in this laboratory as described in our previous report. [17] STAT1-siRNAs were synthesized from GenePharma (Shanghai, China) and the sequences were listed in Supplementary Table 1. Briefly, after seeding in 6-well plates for 24 h, cells were transfected with 5 nM siRNA or 2.5 μg STAT1 plasmid for 6 h. After removing transfection reagents, cells were further incubated for 48 h. The transfected cells were lysed for mRNA and protein extraction or further used for sphere or colony formation assays.…”

Prognostic Implications of Immune-Related Genes’ (IRGs) Signature Models in Cervical Cancer and Endometrial Cancer

“…The biological function of STAT1 is still controversial and unclear. Studies of breast (Hou et al, 2018) and ovarian cancer (Tian et al, 2018) found that STAT1 is overexpressed in malignant tumors and plays an oncogenic role. However, studies on colorectal cancer (Crncec et al, 2018) and other breast cancers (Varikuti et al, 2017) found that TAT1 may act as a tumor suppressor.…”