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

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

  • J Exp Clin Cancer Res. 2018 May 11;37(1):103. doi: 10.1186/s13046-018-0773-8.
Xiaoling Tian 1,  Wencai Guan 1,  Lingyun Zhang 1 2,  Wenwen Sun 1,  Daibing Zhou 1 2,  Qunbo Lin 1 2,  Weimin Ren 1 2,  Lubna Nadeem 3,  Guoxiong Xu 4 5
Affiliations

Affiliations

  • 1 Center Laboratory, Jinshan Hospital, Fudan University, 1508 Longhang Road, Shanghai, 201508, People's Republic of China.
  • 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 3 Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
  • 4 Center Laboratory, Jinshan Hospital, Fudan University, 1508 Longhang Road, Shanghai, 201508, People's Republic of China. [email protected].
  • 5 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
PMID: 29751820 DOI: 10.1186/s13046-018-0773-8
Abstract

Background: The 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.

Methods: The 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.

Results: The 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.

Conclusions: Our 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.

Keywords

Activin receptor-like kinase; Cell proliferation; Crosstalk; Cytokine; Growth factor; Receptor; Signal transduction; Smad; Tumorigenesis; TβRII.

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