The EGFR Pathway as a Potential Therapeutic Target for Modulation of Radiation-induced Liver Injury.

Abstract

Radiation exposure can result in various complications influenced by factors such as dose, the amount of tissue exposed, and the type of tissue exposed. Radiation-induced liver injury (RILI) is a concern in cancer patients receiving thoracic and upper abdominal radiation, but it can also be a risk for civilians exposed to radiation in a nuclear event. RILI can lead to organ dysfunction or death; a deeper understanding of how radiation causes damage to normal tissue could pave the way for new treatments. In our study, we focused on the effects of radiation on the two main liver cell types: liver sinusoidal endothelial cells (LSECs) and hepatocytes. We exposed these cells to different doses of radiation (2, 4 or 8 Gy) as well as a sham irradiation (0 Gy) control. Proteins were extracted at 30 min, 6 h and 24 h postirradiation and analyzed using reverse phase protein array (RPPA). We observed changes to the Hepatic fibrosis signaling pathway, IL-8 signaling, and S100 family signaling pathways across multiple doses and time points in LSECs. In hepatocytes, radiation affected different pathways; we see changes in the Th1 and Th2 signaling pathways and the IL-10 signaling pathway. These pathways are critical in mediating the immune response, with Th1 being associated with pro-inflammatory responses and Th2 with anti-inflammatory responses. Hub proteins from protein-protein interaction (PPI) networks across all time points for both LSECs and hepatocytes highlighted EGFR as a top-ranked protein, indicating the potential role in mitigating radiation damage in liver cells. Herein, we showed alterations in protein expression after RILI using RPPA at early time points (hours to days) to determine potentially targetable molecular pathways. We further highlighted potential therapeutic protein markers, including EGFR, as an example of the potential utility of RPPA in target discovery.