The small GTP-binding protein Rab25 is associated with tumor formation and progression. However, recent studies have shown discordant effects of Rab25 on cancer cell progression depending on cell lineage. In the present study, we elucidate the underlying mechanisms by which Rab25 induces cellular invasion. We demonstrate that Rab25 increases β1 integrin levels and subsequent activation of EGFR and upregulation of VEGF-A expression, leading to increased Snail expression, epithelial-to-mesenchymal transition and cancer cell invasiveness. Strikingly, we identify that Snail mediates Rab25-induced cancer cell invasiveness through fascin expression and that ectopic expression of Rab25 aggravates metastasis of ovarian cancer cells to the lung. We thus demonstrate a novel role of a β1 integrin/EGFR/VEGF-A/Snail signaling cascade in Rab25-induced cancer cell aggressiveness through induction of fascin expression, thus providing novel biomarkers and potential therapeutic targets for Rab25-expressing cancer cells.
Bibliographical noteFunding Information:
We thank Professor Jong In Yook (Yonsei University, Seoul, Korea) for the plasmid containing Snail, Dr. Machesky Laura M. (Beatson Institute for Cancer Research, University of Glasgow, Glasgow, UK) for the luciferase vector of fascin. This study was supported by the Konyang University Research Fund in 2016 (HYL) and a Basic Science Research Program through the National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF-2016-Fostering Core Leaders of the Future Basic Science Program/Global PhD Fellowship Program (BYJ)).
© The Author(s) 2018.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Clinical Biochemistry