REG Ia activates c-Jun through MAPK pathways to enhance the radiosensitivity of squamous esophageal cancer cells

Identification of the key molecules that mediate susceptibility to anticancer treatments would be highly desirable. Based on clinical and cell biological studies, we recently proposed that regenerating gene (REG) I alpha may be such a molecule. In the present study, we hypothesized that REG I alpha increases radiosensitivity through activation of mitogen-activated protein kinase (MAPK) pathways. To test that idea, we transfected TE-5 and TE-9 squamous esophageal cancer cells with REG I alpha and examined its involvement in MAPK signaling and its effect on susceptibility to radiotherapy. We found that REG I alpha-expressing cells showed increased expression of c-Jun messenger RNA (mRNA) and phospho-c-Jun protein mediated via the c-Jun N-terminal kinase (JNK) pathway and extracellular signal-regulated kinase (ERK) pathway, as well as increased radiosensitivity. Immunohistochemical analysis confirmed the activation of c-Jun in tumors expressing REG I alpha. Collectively, these findings suggest that REG I alpha activates c-Jun via the JNK and ERK pathway, thereby enhancing radiosensitivity.