Circ0006969-miR18a-mTOR通路轴调控乳腺肿瘤干细胞耐药的机制研究

Cancer stem cell play an important role in breast cancer metastasis and drug resistance. circRNA could regulate cell function by combined with miRNA in sponge.mTOR signal pathway involved tumor apoptosis and drug resisitance regulation. In previous study, we used circRNA microarray chip detected the cancer and adjacent normal tissue, and found that circ-0006969 was high expression in cancer tissue.Based on bioinformation analysis, we confirmed the miR-18a was the target gene of circ-0006969 which could influence the cells drug resisitance combined with mTOR signal pathway.So we hypothesis that there have a circc0006969-miR18a-mTOR signal axis in breast cancer cells, which could influence the cells metastasis and drug resistance.To further investigate the function of circ-0006969 and miR-18a, we planning construct circ-0006969 over expression vector and miR-18a inhibited vector, transfected the vector into breast cancer stem cells, treating the cells with chemotherapy Paclitaxel and detecting the gene and protein expression of circ-0006969,miR-18a and mTOR signal pathway.Then we make a mouse breast cancer model and study the influence of circ-0006969,miR-18a for the mouse model Paclitaxel resisitance.Based on the study, we hope to investigate the mechamnism of circc0006969-miR18a-mTOR signal axis in regulating breast cancer stem cells drug resisitance.

乳腺肿瘤干细胞在肿瘤增殖和化疗抵抗过程中起重要的作用，circRNA通过“海绵作用”吸附miRNA调控细胞功能，mTOR信号通路参与肿瘤细胞凋亡及耐药调控。前期通过芯片检测确定circ-0006969在乳腺癌组织中低表达，软件预测并验证确定miR-18a与之具有相互作用，紫杉醇处理后干细胞中circ-0006969、miR-18a、mTOR通路基因和蛋白的表达均有改变。由此假设存在circ0006969-miR18a-mTOR信号轴调控干细胞对紫杉醇的耐药。为研究该机制，计划通过构建circ0006969过表达和miR-18a干扰载体并转染肿瘤干细胞，紫杉醇处理后，检测细胞功能及相关基因和蛋白改变，动物水平验证circ-0006969与miR-18a对肿瘤耐药的影响。希望能阐明circ0006969-miR-18a-mTOR信号通路轴调控乳腺肿瘤干细胞对紫杉醇耐药的分子机制

乳腺肿瘤干细胞在肿瘤增殖和化疗抵抗过程中起重要的作用，circRNA通过“海绵作用”吸附miRNA调控细胞功能，mTOR信号通路参与肿瘤细胞凋亡及耐药调控。本项目主要探讨circ0006969在乳腺癌(breast cancer, BC)中的表达及其对乳腺肿瘤细胞增殖和凋亡的影响，研究circ0006969靶向miR-18a 通过mTOR信号通路调控乳腺肿瘤干细胞对紫杉醇耐药的分子机制。项目利用生物芯片技术， 结合PCR和WB以及细胞耐药实验等，分析了circ0006969在乳腺肿瘤患者组织和外周血中的表达情况， 评估了其临床诊断价值和生物学功能；研究了其对乳腺肿瘤细胞增殖转移的影响。探讨了circ0006969靶向miR-18a调控乳腺肿瘤干细胞对紫杉醇耐药的分子机制。结果证实circ0006969抑制MCF-7细胞增殖，增加其凋亡比率，circ0006969靶向miR-18a 经由PI3K/AKT/mTOR信号通路促进乳腺肿瘤干细胞对紫杉醇的耐药。circ-0006969被证明是BC诊断和治疗的新靶点。

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