The DDR Gene Expression Profile In Cervical Cancer Xenografted Tumors With Different Fractionated Doses Of Irradiation

Objective:Genomic-adjusted radiation dose has been proposed to guide the radiation dose to match a specific tumor's radiosensitivity.Radiation-induced DNA damage and repair is controlled by expression and activation of the DNA damage response(DDR)genes.We evaluated the expression profiles of 12 related DDR genes and their relationship with radiation dose fractionation in cervical cancer.Methods:Cervical cancer HeLa and CasKi cells were subcutaneously implanted into female BALB/c nude mice;The xenografted tumors(volume?150mm~3)received different irradiation a total dose of EQD2=16Gy with 1.5Gy bid×10fx,2Gy×8fx,6Gy×2fx and 10Gy×1fx,respectively.Expresson profile of12 DDR genes including ARTEMIS,ATM,ATR,BRCA1,BRCA2,MRE11,NBN,PRKDC,RAD50,RAD51,53BP1 and TP53 were determined using RT-qPCR in xenografted tumors at 6hours after irradiation.The genes with a fold change?3.0 vs.the control were identified as the aberrant expressed genes.Results:Comparison to control group,we found seven genes were up-regulated and BRCA1,BRCA2 were down-regulated in the tumors underwent radiation of 1.5Gy bid×10fx in HeLa xenografted tumors.Moreover,9 genes were down-regulated in the tumors underwent 2Gy×8fx,6Gy×2fx and10Gy×1fx radiation and the expression of DDR gene was not significantly changed in HeLa xenografted tumors.Ask for CasKi xenografted tumors,DDR gene were down-regulated in the tumors underwent radiation of 1.5Gy bid×10fx and 2Gy×8fx.Artemis were up-regulated underwent radiation of6Gy×2fx.NBS1 and RAD50 were up-regulated underwent radiation of10Gy×1fx.Only in Post-irradiation with 2Gy×8fx and 6Gy×2fx obviously delayed the tumor growth as compared to post-irradiation with 1.5Gy bid×10fx.However,none difference of the expression of three genes of the DDR kinases,ATM?ATR and PRKDC were found between the irradiated and unirradiated tumors.Conclusions:Differential expression of the DDR related genes was radiation dose dependent.Fractionated high-dose but not fractionated low-dose irradiation is significantly associated with reduced expression of DDR genes and the tumor growth delay in cervical cancer.