Guojiang Xie, Xiulan Ao, Tianmiao Lin, Guixuan Zhou, Ming Wang, Hanwei Wang, Yuangui Chen, Xiaobo Li, Benhua Xu, Wangzhong He, Hao Han, Yuval Ramot, Ralf Paus, Zhicao Yue

Radiotherapy is a primary oncological treatment modality, which also damages normal tissue including the skin and causes radiation dermatitis (RD). Here, we explore the mechanism of acute epidermal damage in RD. Two distinctive phases in the damage response were identified: an early destructive phase where a burst of reactive oxygen species (ROS) induces loss of E-cadherin-mediated cell contact, followed by a regenerative phase where Wnt and Hippo signaling are activated. A blocking peptide, as well as a neutralizing antibody to E-cadherin, works synergistically with ionizing radiation to promote the epidermal damage. In addition, ROS disassembles adherens junctions (AJs) in epithelial cells via post-translational mechanisms, i.e. activation of Src/Abl kinases and degradation of β-catenin/E-cadherin. The key role of tyrosine kinases in this process is further substantiated by the rescue effect of the tyrosine kinase inhibitor genistein, and the more specific Src/Abl kinase inhibitor dasatinib: Both reduced ROS-induced degradation of β-catenin/E-cadherin in vitro, and ameliorated skin damages in rodent models. Finally, we confirm that the same key molecular events are also seen in human RD. Therefore, we propose that loss of cell contact in epidermal keratinocytes through ROS-mediated disassembly of AJs is pivotal for the acute epidermal damage in RD.