A ROS/STAT3/HIF-1α signaling cascade mediates EGF-induced TWIST1 expression and prostate cancer cell invasion

Kyung Hwa Cho, Moon Jung Choi, Kang Jin Jeong, Jeong Jin Kim, Min Ha Hwang, Shang Cheul Shin, Chang Gyo Park, Hoi Young Lee
Prostate 2014, 74 (5): 528-36

BACKGROUND: Epidermal growth factor (EGF) has been known to induce epithelial-mesenchymal transition (EMT) and prostate cancer cell progression. However, a detailed underlying mechanism by which EGF induces EMT and prostate cancer cell progression remained to be answered. Hypoxia-inducible factor (HIF)-1α and TWIST1 are transcription factors implicated in EMT and cancer metastasis. The purpose of this study is to determine the underlying mechanism of EGF-induced TWIST1 expression and prostate cancer invasion.

METHODS: siRNAs were used to silence genes. Immunoblotting, quantitative RT-PCR and immunofluorescence analysis were used to examine protein or mRNA expression. Modified Boyden chamber and invasion assay kit with Matrigel-coated inserts were used to determine prostate cancer cell migration and invasion, respectively.

RESULTS: We observed that EGF induced HIF-1α expression and morphological change of prostate cancer epithelial cells to mesenchymal cells. Silencing HIF-1α expression dramatically reduced EGF-induced TWIST1 expression and prostate cancer cell EMT. Conversely, transfection of the cells with HIF-1α siRNA reversed the reduced E-cadherin expression by EGF. Pretreatment of the cells with pharmacological inhibitors of reactive oxygen species [ROS, N-acetylcysteine (NAC)] and STAT3 (WP1066) but not p38 MAPK (SB203580) significantly reduced EGF-induced HIF-1α mRNA and protein expression. Further, pretreatment of the cells with NAC attenuated EGF-induced STAT3 phosphorylation. In addition, we showed that TWIST1 mediated EGF-induced N-cadherin expression, leading to prostate cancer invasion.

CONCLUSIONS: We demonstrate a mechanism by which EGF promotes prostate cancer cell progression through a ROS/STAT3/HIF-1α/TWIST1/N-cadherin signaling cascade, providing novel biomarkers and promising therapeutic targets for prostate cancer cell progression.

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