| Objective:With the development of radiophysics,computer science,and medical imaging equipment,progress has been made in cancer radiotherapy.Although cancer radiotherapy is more precise with advances in science,normal tissues are still inevitably injured by radiation.In addition,the potential for radioactive nuclear accidents still exists.Compared with skin injury caused by other factors,radiation directly damages the skin and its deep tissue cells,which seriously impedes the cancer radiotherapy.Pathophysiological changes in radiation-induced skin injury include erythema and desquamation,which occur within hours or weeks,as well as dermal atrophy,ulceration,telangiectasia,and fibrosis,which occur over the long term.Although some progress has been made in the prevention and treatment of this disorder,there are still a various of difficulties.?-catenin signaling pathway is involved in the repair and regeneration of injured tissues.However,the role and regulatory mechanism of the ?-catenin pathway in radiation-induced skin injury have not been fully elucidated.In this study,we investigated the involvement of the P-catenin signaling pathway in radiation-induced acute injury of the skin.Methods:Immunofluorescence and Western blot were used to detect the effect of irradiation on expression and location of ?-catenin.The influence on activation of?-catenin pathway by radiation in skin cells was verified by a ?-catenin-responsive luciferase reporter.Immunohistochemistry was used to detect the expression of?-catenin in skin tissues obtained at different times after irradiation in rat.Flow cytometry,wound healing migration assay,and reactive oxygen species(ROS)assay kit were used to detect influence of activated or inhibited ?-catenin pathway on apoptosis,cell migration,and ROS.RNA-sequencing explored possible mechanism by which irradiated skin cells alleviated radiation-induced skin injury through activation of?-catenin pathway.Marvel D3-specific siRNAs were used to silence Marvel D3 expression in skin cells.Flow cytometry,wound healing migration assay,and ROS assay kit were used to explore the effects of Marvel D3-depleted on cellular behavior.The link between Marvel D3 and PI3K-MAPK signaling cascade was detected by Western blot.SP600125(an inhibitor of JNK)was used to investigate the effects of JNK pathway on skin cells.The model of full-thickness skin wounds combined total body irradiation was made on Balb/c mice.Corresponding drugs were topically applied to the wound site,respectively,to observe the progress of wound healing.Results:Irradiation resulted in increased ?-catenin expression in skin cells,while Wnt3a exacerbated this role.Results of luciferase assay indicated that irradiation led to activation of ?-catenin signaling pathway in skin cells.The expression of ?-catenin in the irradiated skin tissue gradually decreased with time,resulted in signaling pathway could not maintain a long-term activation state.Activated ?-catenin signaling pathway inhibited apoptosis and production of ROS in irradiated skin cells,promoted migration of cells.Activated ?-catenin signaling pathway by Wnt3a led to down-regulation of Marvel D3.Depletion of Marvel D3 inhibited apoptosis and ROS production caused by irradiation,accelerated skin cell migration.Depletion of Marvel D3 induced JNK phosphorylated and inhibition of JNK aggravated radiation-induced skin cell injury.At animal level,Wnt3a accelerated skin wounds healing.Conclusion:1.The activation of ?-catenin signaling pathway in skin is the body's stress response to irradiation stimulation,but the activation state of ?-catenin signaling pathway cannot be maintained sustainable.2.The activated ?-catenin signaling pathway mitigates radiation-induced injury at the cellular level and promotes wound healing at the animal level.3.The activated ?-catenin signaling pathway protects irradiated skin cells by down-regulated Marvel D3.4.Marvel D3 acts on the biological behavior of skin cells by regulating the phosphorylation of JNK.This study illustrates activated?-catenin promotes the activation of JNK by negative regulation of Marvel D3 to ameliorates radiation-induced skin injury. |
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