Reversible interconversion and maintenance of mammary epithelial cell characteristics by the ligand-regulated EGFR system

Scientific Reports - Tập 6 Số 1
Shinji Fukuda1,2, Hisayo Nishida‐Fukuda1, Daisuke Nanba1,3,2, Koh‐ichi Nakashiro4, Haruhiko Nakayama1,2, Hiroyuki Kubota5,6, Shigeki Higashiyama1,2
1Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Japan
2Division of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Ehime University, Toon, Japan
3Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
4Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Japan
5Division of Integrated Omics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
6PRESTO, Japan Science and Technology Corporation, Fukuoka, Japan

Tóm tắt

AbstractEpithelial cell plasticity is controlled by extracellular cues, but the underlying mechanisms remain to be fully understood. Epidermal growth factor (EGF) and amphiregulin (AREG) are high- and low-affinity ligands for EGF receptor (EGFR), respectively. EGFR signaling is known to promote epithelial-mesenchymal transition (EMT) by the activation of ERK and the induction of an EMT transcription factor, ZEB1. Here, we demonstrate that ligand-switching between EGF and AREG at equivalent molarity reversibly interconverts epithelial and mesenchymal-like states of EGFR signal-dependent mammary epithelial cells. The EGF- and AREG-cultured cells also differ in their epithelial characteristics, including the expression of cell surface markers, the mode of migration and the ability for acinus-formation. The ligand-switching between EGF and AREG temporally alters strength of the shared EGFR-ERK signaling. This alteration inverts relative expression levels of ZEB1 and its antagonizing microRNAs, miR-205 and miR-200c, those are critical determinants of the epithelial phenotype. Further, AREG-induced EGFR accumulation on the plasma membrane compensates for the weak association between AREG and EGFR. The EGFR dynamics enables AREG to support proliferation as efficiently as EGF at equivalent molarity and to maintain epithelial characteristics. Our findings reveal a role of EGFR ligands-generated signal strength in the regulation of mammary epithelial cell plasticity.

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