甘氨胆酸对肺腺癌移植瘤小鼠放射治疗敏感性的影响及其机制OA

Objective:To investigate the effects and mechanisms of glycocholic acid(GCA)on the radiosensitivity of mice with lung adenocarcinoma A549 cell transplantation tumors.Methods:A lung adenocarcinoma A549 cell xenograft nude mouse model was established and randomized into four groups:the transplanted tumor control group(the control group),the GCA group,the radiotherapy(RT)group,and the GCA+RT group.The RT group and the GCA+RT group received a single 10 Gy irradiation;the GCA group and the GCA+RT group were gavaged with GCA at 280 mg/kg once daily for 7 consecutive days.Tumor volumes were monitored with two days between two measurements.After the last treatment mice were sacrificed and transplanted tumor tissues were collected.Superoxide dismutase(SOD)and glutathione peroxidase(GSH-Px)activities in transplantation tumor tissues were detected.qPCR and Western blot(WB)were used to detect the mRNA and protein expression levels of key radiation-related genes(MCM6,ITGA6,CASP3,etc.)respectively.Histomorphology was examined by H-E staining.External validation of candidate genes was performed using GEO datasets(GSE276500,GSE294906,and GSE218171)and TCGA.Results:GCA alone showed modest inhibition effect on tumor growth,whereas the GCA+RT group with combined radioactive therapy exhibited reduced radiosensitivity compared to the RT group with RT alone(P<0.05).GCA treatment significantly increased SOD activity(P<0.01)and decreased GSH-Px activity(P<0.01)in transplanted tumor tissues,indicating that GCA might change antioxidant enzyme balance and reduce radiation-induced oxidative stress in transplanted tumors.GCA interference upregulated the mRNA expressions of MCM6 and ITGA6 and downregulated the mRNA expression of CASP3 in transplanted tumors(all P<0.05).The expression of MCM6 protein was significantly higher in the transplanted tumor tissues of the GCA+RT group than that of the control group(P<0.05).H-E staining showed partial tumor necrosis in the GCA group,while the necrotic area in the GCA+RT group grew smaller than that in the RT group.GEO and TCGA database analyses supported the association of high MCM6/ITGA6 expressions with radioresistance and poorer prognosis.Conclusion:GCA reduces the radiosensitivity of A549 xenografts by changing oxidative stress and key signaling network,such as enhancing SOD,lowering GSH-Px,and upregulating ITGA6 or MCM6.