A hepatocyte growth factor/MET-induced antiapoptotic pathway protects against radiation-induced salivary gland dysfunction.

Abstract

Hepatocyte growth factor (HGF) and its receptor MET are expressed in the salivary glands during developmental stages and tumor formation; however, the function of HGF in injured salivary gland tissues remains unclear. The present study investigated the role of HGF in protecting the salivary glands against radiation-induced injury using an organotypic culture method. Acinar-like organoids were formed by means of a three-dimensional (3D) human parotid tissue-derived spheroids (hPTS) culture method. Radioprotective effects of HGF on irradiated hPTS and signaling pathways on radioprotection were investigated. We detected MET expression in hPTS grown in a 3D culture. Treatment of irradiated hPTS with recombinant human HGF (rhHGF) restored salivary marker expression and secretory function of hPTS. Changes in the phosphorylation levels of apoptosis-related proteins through HGF-MET axis inhibited radiation-induced apoptosis. Treatment with PHA665752, a MET inhibitor, blocked MET-PI3K-AKT pathway, increased apoptosis, and suppressed the radioprotective effect of rhHGF against IR-induced damage of hPTS. These results suggest that HGF is a key effector of radioprotection and that HGF-MET-PI3K-AKT axis is involved in protecting the salivary glands from radiation-induced apoptosis.