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

ABSTRACT: The signal transducer and activator of transcription (STAT) and transforming growth factor-? (TGF-?) signaling pathways play important roles in epithelial ovarian cancer (EOC). However, the mechanism of crosstalk between two pathways is not completely understood.The expression of STAT1 protein was detected by tissue microarray and immunoblotting (IB). The interaction of STAT1 isoforms with TGF-? receptors was confirmed by immunoprecipitation and IB. The effect of TGF-? signaling on STAT1 activation was examined in EOC and non-tumorous HOSEpiC cells treated with TGF-?1 in the presence or absence of the inhibitor of TGF-? type I receptor. The gain-of-function and loss-of-function approaches were applied for detecting the role of STAT1 on EOC cell behaviours.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-?1 activated the STAT1 pathway by inducing the phosphorylation of STAT1? on S727 residue. The full-length STAT1? and the truncated STAT1? directly interacted with TGF-? receptors (ALK1/ALK5 and T?RII), which was mediated by TGF-?1. STAT1? and STAT1? blocked the activation of the TGF-?1 signaling pathway in EOC cells by reducing Smad2 phosphorylation. STAT1 overexpression induced EOC cell proliferation, migration, and invasion; whereas its inhibition enhanced TGF-?1-induced phospho-Smad2 and suppressed EOC cell proliferation, migration, and invasion.Our data unveil a novel insight into the molecular mechanism of crosstalk between the STAT1 and TGF-? signaling pathways, which affected the cancer cell behavior. Suppression of STAT1 may be a potential therapeutic strategy for targeting ovarian cancer.

SUBMITTER: Tian X

PROVIDER: S-EPMC5948853 | biostudies-other | 2018 May

REPOSITORIES: biostudies-other

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

Tian Xiaoling X Guan Wencai W Zhang Lingyun L Sun Wenwen W Zhou Daibing D Lin Qunbo Q Ren Weimin W Nadeem Lubna L Xu Guoxiong G

Journal of experimental & clinical cancer research : CR 20180511 1

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 29751820

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Project description:Nrf2 and TGF-?1 both affect tumorigenesis in a dual fashion, either by preventing carcinogen induced carcinogenesis and suppressing tumor growth, respectively, or by conferring cytoprotection and invasiveness to tumor cells during malignant transformation. Given the involvement of Nrf2 and TGF-?1 in the adaptation of epithelial cells to persistent inflammatory stress, e.g. of the pancreatic duct epithelium during chronic pancreatitis, a crosstalk between Nrf2 and TGF-?1 can be envisaged. By using premalignant human pancreatic duct cells (HPDE) and the pancreatic ductal adenocarcinoma cell line Colo357, we could show that Nrf2 and TGF-?1 independently but additively conferred an invasive phenotype to HPDE cells, whereas acting synergistically in Colo357 cells. This was accompanied by differential regulation of EMT markers like vimentin, Slug, L1CAM and E-cadherin. Nrf2 activation suppressed E-cadherin expression through an as yet unidentified ARE related site in the E-cadherin promoter, attenuated TGF-?1 induced Smad2/3-activity and enhanced JNK-signaling. In Colo357 cells, TGF-?1 itself was capable of inducing Nrf2 whereas in HPDE cells TGF-?1 per-se did not affect Nrf2 activity, but enhanced Nrf2 induction by tBHQ. In Colo357, but not in HPDE cells, the effects of TGF-?1 on invasion were sensitive to Nrf2 knock-down. In both cell lines, E-cadherin re-expression inhibited the proinvasive effect of Nrf2. Thus, the increased invasion of both cell lines relates to the Nrf2-dependent downregulation of E-cadherin expression. In line, immunohistochemistry analysis of human pancreatic intraepithelial neoplasias in pancreatic tissues from chronic pancreatitis patients revealed strong Nrf2 activity already in premalignant epithelial duct cells, accompanied by partial loss of E-cadherin expression. Our findings indicate that Nrf2 and TGF-?1 both contribute to malignant transformation through distinct EMT related mechanisms accounting for an invasive phenotype. Provided a crosstalk between both pathways, Nrf2 and TGF-?1 mutually promote their tumorigenic potential, a condition manifesting already at an early stage during inflammation induced carcinogenesis of the pancreas.

Project description:BACKGROUND:Bulk tumor tissue samples are used for generating gene expression profiles in most research studies, making it difficult to decipher the stroma-cancer crosstalk networks. In the present study, we describe the use of microdissected transcriptome profiles for the identification of cancer-stroma crosstalk networks with prognostic value, which presents a unique opportunity for developing new treatment strategies for ovarian cancer. METHODS:Transcriptome profiles from microdissected ovarian cancer-associated fibroblasts (CAFs) and ovarian cancer cells from patients with high-grade serous ovarian cancer (n = 70) were used as input data for the computational systems biology program CCCExplorer to uncover crosstalk networks between various cell types within the tumor microenvironment. The crosstalk analysis results were subsequently used for discovery of new indications for old drugs in ovarian cancer by computational ranking of candidate agents. Survival analysis was performed on ovarian tumor-bearing Dicer/Pten double-knockout mice treated with calcitriol, a US Food and Drug Administration-approved agent that suppresses the Smad signaling cascade, or vehicle control (9-11 mice per group). All statistical tests were two-sided. RESULTS:Activation of TGF-?-dependent and TGF-?-independent Smad signaling was identified in a particular subtype of CAFs and was associated with poor patient survival (patients with higher levels of Smad-regulated gene expression by CAFs: median overall survival = 15 months, 95% confidence interval [CI] = 12.7 to 17.3 months; vs patients with lower levels of Smad-regulated gene expression: median overall survival = 26 months, 95% CI = 15.9 to 36.1 months, P = .02). In addition, the activated Smad signaling identified in CAFs was found to be targeted by repositioning calcitriol. Calcitriol suppressed Smad signaling in CAFs, inhibited tumor progression in mice, and prolonged the median survival duration of ovarian cancer-bearing mice from 36 to 48 weeks (P = .04). CONCLUSIONS:Our findings suggest the feasibility of using novel multicellular systems biology modeling to identify and repurpose known drugs targeting cancer-stroma crosstalk networks, potentially leading to faster and more effective cures for cancers.

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

Publications

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

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