Studies On The Innate Immune Signal Molecules MAVS Involved In Radiation Response And Transduction Mechanism

Ionizing radiation affects the immune function of cells,but the report about the effects of immune molecules on the radiobiological effects in cells is less so far.In this study,MAVS,an innate immune signaling molecules,located on the surface of mitochondrial membrane,were used as the target to investigate the impact.Firstly,MAVS gene knockout plasmid was constructed by means of CRISPR/Cas9 technique,and then the stable MAVS gene knockout cell line was screened.Secondly,PIRES2-EGFP-MAVS was constructed and the MAVS overexpression cell line was screened.Finally,the role of MAVS in radiation-induced bystander effects,cytokines secretion,invasion and migration of tumor cells,and signal transduction mechanism after irradiation were investigated by means of the biological research methods.Our study may provide a new idea to improve the curative effect of radiotherapy by modulating the signal pathway involved in MAVS.Our results are listed that:(1)MAVS are involved in radiation-induced bystander effects(BIRE).After irradiation,donor cells with high MAVS expression produced the factorsof bystander effect such as ROS,which mediate the polymerization of MAVS and the increase of ROS in recipient cells with high MAVS expression,and induce more DNA damage than those with low expression of MAVS,showing higher RIBE.Inhibition of MAVS can reduce this RIBE and inhibit the production of some cytokines.(2)MAVS are involved in invasion and migration of tumor cells induced by low LET radiation.X-ray radiation could induce the upregulation of MAVS by producing ROS,and then activated the NF-?B/c-fos signaling pathway.And further,this path promoted the production and secretion of MMP9 protein then changed the intercellular adhesion ability.Finally,these phenomena attenuated E-cadherin and enhanced N-cadherin expression under irradiation.These cascade reflect that radiation can increase the invasion and migration ability of tumor cells after low LET X-ray radiation.(3)MAVS may be involved in the inhibition of invasion and migration of tumor cells with high LET radiation.Preliminary experiments showed that the heavy ion radiation could inhibit the expression of MAVS protein.The knockout of MAVS gene further intensified the inhibition of the production and secretion of MMP9 after heavy ions,which in turn,enhanced the inhibition of invasion and migration of tumor cells after heavy ion radiation.Our results suggest that MAVS are involved in RIBE.Radiation-induced ROS promoted the polymerization of MAVS in recipient cells,which is the key factor in the induction of RIBE.Low LET photon radiotherapy promotes the invasion and migration of tumor cells by inducing the upregulation of MAVS and increasing MMP9 production and secretion,which involves the MAVS/NF-?B/MMP9 signaling pathway.The relative inhibition of invasion and migration of tumor cells after heavy ion radiation may relate to the inhibition of MAVS expression and MMP9 production and secretion by heavy ion radiation.Our study can provide guidance for the prevention and control of secondary cancer by photon radiotherapy with low LET in clinical practice.And it also preliminarily demonstrated that heavy ion treatment of cancer can better inhibit the invasion and migration of tumor cells from the perspective of immune molecules MAVS.