Upregulation of KCNQ1OT1 promotes resistance to stereotactic body radiotherapy in lung adenocarcinoma by inducing ATG5/ATG12-mediated autophagy via miR-372-3p.
Upregulation of KCNQ1OT1 promotes resistance to stereotactic body radiotherapy in lung adenocarcinoma by inducing ATG5/ATG12-mediated autophagy via miR-372-3p.
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DOI：
10.1038/s41419-020-03083-8
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发表时间：
2020-10-20
影响因子：
9
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
He H;Song X;Yang Z;Mao Y;Zhang K;Wang Y;Su B;Li Q;Chen H;Li Y
立体定向放射治疗（SBRT）已成为非小细胞肺癌的标准治疗方法。然而，随着SBRT耐药性的发展，其治疗优势受到限制。用大剂量照射后建立耐SBRT细胞系A549/IR和H1975/IR。采用基因芯片技术筛选差异lncRNA，qPCR检测LUAD肿瘤组织和细胞株中lncRNA的表达。通过体外和体内试验评估对辐射反应的影响，并通过蛋白质印迹和透射电子显微镜评价自噬水平。生物信息学预测和拯救实验用于鉴定SBRT抗性的潜在途径。在LUAD SBRT耐药细胞和组织中发现了KCNQ 1 OT 1的高表达，与大肿瘤、晚期临床分期和对同期治疗的反应率较低呈正相关。KCNQ 1 OT 1耗竭通过抑制自噬显著地使A549/IR和H1975/IR细胞对辐射重新敏感，这可以通过miR-372- 3 p敲低来减弱。此外，自噬相关5（ATG 5）和自噬相关12（ATG 12）被证实为miR-372- 3 p的直接靶点。ATG 5或ATG 12的恢复消除了miR-372- 3 p介导的自噬抑制和放射敏感性。我们的数据描述了KCNQ 1 OT 1通过海绵状miR-372- 3 p诱导ATG 5和ATG 12依赖性自噬，负责LUAD中的SBRT抗性，这将是增强LUAD中放射治疗的抗肿瘤作用的潜在策略。
Stereotactic body radiotherapy (SBRT) has emerged as a standard treatment for non-small-cell lung cancer. However, its therapeutic advantages are limited with the development of SBRT resistance. The SBRT-resistant cell lines (A549/IR and H1975/IR) were established after exposure with hypofractionated irradiation. The differential lncRNAs were screened by microarray assay, then the expression was detected in LUAD tumor tissues and cell lines by qPCR. The influence on radiation response was assessed via in vitro and in vivo assays, and autophagy levels were evaluated by western blot and transmission electron microscopy. Bioinformatics prediction and rescue experiments were used to identify the pathways underlying SBRT resistance. High expression of KCNQ1OT1 was identified in LUAD SBRT-resistant cells and tissues, positively associated with a large tumor, advanced clinical stage, and a lower response rate to concurrent therapy. KCNQ1OT1 depletion significantly resensitized A549/IR and H1975/IR cells to radiation by inhibiting autophagy, which could be attenuated by miR-372-3p knockdown. Furthermore, autophagy-related 5 (ATG5) and autophagy-related 12 (ATG12) were confirmed as direct targets of miR-372-3p. Restoration of either ATG5 or ATG12 abrogated miR-372-3p-mediated autophagy inhibition and radiosensitivity. Our data describe that KCNQ1OT1 is responsible for SBRT resistance in LUAD through induction of ATG5- and ATG12-dependent autophagy via sponging miR-372-3p, which would be a potential strategy to enhance the antitumor effects of radiotherapy in LUAD.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
自噬反应的抑制使肺癌细胞对放射和化学疗法敏感。
影响因子：
8.8
作者：
Karagounis IV;Kalamida D;Mitrakas A;Pouliliou S;Liousia MV;Giatromanolaki A;Koukourakis MI
通讯作者：
Koukourakis MI
影响因子：
5.3
作者：
Gong W;Zheng J;Liu X;Liu Y;Guo J;Gao Y;Tao W;Chen J;Li Z;Ma J;Xue Y
通讯作者：
Xue Y
DOI：
10.18632/aging.101418
发表时间：
2018-04-17
期刊：
Aging
影响因子：
--
作者：
Guo B;Zhang Q;Wang H;Chang P;Tao K
通讯作者：
Tao K
长非编码 RNA KCNQ1OT1 通过作为 miR-504 的竞争性内源 RNA 介导肝细胞癌的生长。
影响因子：
5.2
作者：
Li, Chao;Miao, Runchen;Liu, Chang
通讯作者：
Liu, Chang