GSTP1 negatively regulates Stat3 activation in epidermal growth factor signaling

Kou,Xianjuan; Chen,Ning; Feng,Zhiyong; Luo,Lan; Yin,Zhimin

doi:10.3892/ol.2012.1098

GSTP1 negatively regulates Stat3 activation in epidermal growth factor signaling

Authors:
- Xianjuan Kou
- Ning Chen
- Zhiyong Feng
- Lan Luo
- Zhimin Yin
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Affiliations: College of Health Science, Wuhan Institute of Physical Education, Wuhan 430079, P.R. China, Jiangsu Province Key Laboratory for Molecular and Medicine Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210046, P.R. China, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, P.R. China
Published online on: December 28, 2012 https://doi.org/10.3892/ol.2012.1098
Pages: 1053-1057

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Abstract

Glutathione S-transferases (GSTs) are the enzymes that defend cells against the damage mediated by oxidant and electrophilic carcinogens. GSTπ (GSTP1) is a member of the GST family and the hypermethylation GSTP1 CpG island DNA is detected in human hepatocellular carcinoma (HCC) tissues, which contributes to the negative expression of GSTP1 mRNA and protein. GSTP1 expression is considered to be an early event in HCC. Stat3, a member of the signal transduction and activator of transcription (Stat) family, is important for promoting the proliferation, survival and other biological processes of cells triggered by cytokines and growth factors. Activated Stat3 may participate in oncogenesis. Previous studies have demonstrated that overexpression of phosphorylated Stat3 is important in the proliferation of HCC cells, suggesting that disturbance of the Stat3 pathway may be an early event. We hypothesize that the suppression of GSTP1 expression in HCC cells increases Stat3 activation. In order to test this hypothesis, HepG2 cells were genetically modified to transiently express high levels of GSTP1. The transient expression of GSTP1 specifically downregulated epidermal growth factor (EGF)-mediated tyrosine phosphorylation of Stat3, and subsequently suppressed the transcriptional activity of Stat3. By contrast, GSTP1 RNAi was able to lead to an increase in the phosphorylation of Stat3. In addition, overexpression of GSTP1 was capable of reducing the survival of HepG2 cells and inducing cell cycle arrest. This inhibition was mediated by a direct interaction between GSTP1 and Stat3. Overall, our results suggest that GSTP1 is important in the regulation of the transcriptional activity of Stat3, and that it is also a regulator of the cell cycle via EGF signaling.

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