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1. Introduction
The radiation-induced bystander effect (RIBE) is an interesting biological event in which ionizing radiation can induce cellular damage, both in directly-exposed cells and in their neighboring, non-irradiated cells. Since it was first discovered by Nagasawa [1], RIBE has become the focus of research regarding tumor radiotherapy and radiobiological studies. A series of cellular responses in RIBE have been reported, including micronucleus formation, genomic instability, sister chromatid exchanges, carcinogenesis, and cell killing. Many bystander signal factors, such as NO, TGF-β1, ROS, p53, and IGF, play important roles in RIBE via direct communication or culture medium transmission [2,3].
RIBE has important implications in tumor radiotherapy. A variety of bystander effects have been found in bystander cells, co-cultured with irradiated tumor cells. The study of hepatoma cells showed that irradiated cells could induce bystander effects in co-cultured, non-irradiated cells via the p53 pathway [4,5]. On the other hand, evidence has shown that bystander normal human fibroblast cells reduced damage response in irradiated human melanoma cells through intercellular ROS level modulation [6]. In contrast, the radio-sensitivity of breast cancer cells could be enhanced by bystander fibroblast cells via the Akt pathway [7]. Hence, RIBE is significant to clinical tumor radiotherapy.
S-phase kinase protein 2 (SKP2) is the substrate recognition subunit of the SCFSKP2 ubiquitin ligase complex, and was originally identified as a protein that interacts with cyclin A [8,9]. This protein is implicated in ubiquitin-mediated degradation of the cyclin dependent kinase (CDK) inhibitor p27KIP1, and positively regulates G1/S transition. Targeted inactivation of the SKP2 gene results in the accumulation of p27 and cyclin E, and causes the cell cycle to be blocked in the G1 phase. SKP2 also plays an important role in regulating the cell cycle by controlling the expression of other target proteins, including p21, p57, p130, c-Myc, and E2F1, which are associated with the initiation, development, treatment, and prognosis of cancer [10]. SKP2 is an oncogene and is overexpressed in many human tumors in different organs; examples of such cancers are esophageal, prostate, breast, stomach, and colon [11,12,13,14]. However, until now, no reports regarding the effects of SKP2 on the bystander response of esophageal cancer (EC) have been found. In the present study, we found, for the first time, that overexpression...