Disturbance of the let-7/LIN28 double-negative feedback loop is associated with radio- and chemo-resistance in non-small cell lung cancer.
Disturbance of the let-7/LIN28 double-negative feedback loop is associated with radio- and chemo-resistance in non-small cell lung cancer.
复制标题
let-7/LIN28双负反馈环路的紊乱与非小细胞肺癌的放疗和化疗耐药相关
DOI：
10.1371/journal.pone.0172787
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Zhang S
中科院分区：
文献类型：
--
作者：
Yin J;Zhao J;Hu W;Yang G;Yu H;Wang R;Wang L;Zhang G;Fu W;Dai L;Li W;Liao B;Zhang S
放射和化学耐药性是非小细胞肺癌（NSCLC）治疗的主要障碍，其潜在的分子机制尚不清楚。在本研究中，在NSCLC细胞诱导放射或化学抗性的过程中，动态分析表明，放射线或顺铂诱导的let-7表达减少导致其靶基因LIN28表达增加，而LIN28表达增加则通过抑制let-7的成熟和生物发生进一步导致let-7表达减少。此外，我们发现let-7的下调和LIN28表达的上调通过调节NSCLC细胞的单细胞增殖能力来促进对放射或顺铂的抵抗。因此，在NSCLC细胞中，let-7和LIN28可以通过相互抑制形成双负反馈环，放疗或化疗药物引起的let-7/LIN28双负反馈环的紊乱可导致放疗和化疗耐药。此外，NSCLC患者中let-7的低表达和LIN28的高表达与放疗或化疗的抵抗显着相关。因此，我们的研究表明，let-7/LIN28双负反馈环路的紊乱参与了放疗和化疗耐药的调节，let-7和LIN28可以作为NSCLC患者放疗或化疗反应的预测生物标志物。
Radio- and chemo-resistance represent major obstacles in the therapy of non-small-cell lung cancer (NSCLC) and the underlying molecular mechanisms are not known. In the present study, during induction of radio- or chemo-resistance in NSCLC cells, dynamic analyses revealed that decreased expression of let-7 induced by irradiation or cisplatin resulted in increased expression of its target gene LIN28, and increased expression of LIN28 then contributed to further decreased expression of let-7 by inhibiting its maturation and biogenesis. Moreover, we showed that down-regulation of let-7 and up-regulation of LIN28 expression promoted resistance to irradiation or cisplatin by regulating the single-cell proliferative capability of NSCLC cells. Consequently, in NSCLC cells, let-7 and LIN28 can form a double-negative feedback loop through mutual inhibition, and disturbance of the let-7/LIN28 double-negative feedback loop induced by irradiation or chemotherapeutic drugs can result in radio- and chemo-resistance. In addition, low expression of let-7 and high expression of LIN28 in NSCLC patients was associated significantly with resistance to radiotherapy or chemotherapy. Therefore, our study demonstrated that disturbance of the let-7/LIN28 double-negative feedback loop is involved in the regulation of radio- and chemo-resistance, and that let-7 and LIN28 could be employed as predictive biomarkers of response to radiotherapy or chemotherapy in NSCLC patients.