Neuroendocrine differentiation contributes to radioresistance development and metastatic potential increase in non-small cell lung cancer (Retracted Article)
Neuroendocrine differentiation contributes to radioresistance development and metastatic potential increase in non-small cell lung cancer (Retracted Article)
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DOI：
10.1016/j.bbamcr.2018.09.005
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发表时间：
2018-12-01
影响因子：
5.1
通讯作者：
Chen, Yuhchyau
中科院分区：
文献类型：
--
作者：
Zhu, Rongying;Yang, Xiaodong;Chen, Yuhchyau
放射治疗诱导非小细胞肺癌（NSCLC）A549和H157细胞的神经内分泌分化（NED），因此在放射抗性A549（A549 R26 -1）和H157（H157 R24 -1）细胞中观察到比亲本细胞更高的NE样特征。我们检测到A549 R26 -1细胞来源的肿瘤中NED标记物的表达高于A549细胞来源的肿瘤。在机制研究中，我们发现NED在A549 R26 -1和H157 R24 -1细胞中的诱导伴随着细胞内cAMP和IL-6水平的增加。用腺苷酸环化酶（AC）抑制剂（SQ 22536）或IL-6中和抗体（Ab）处理放射抵抗性肺癌细胞，导致放射抵抗性肺癌细胞中NE样特征减少。此外，我们发现MEK/Erk是触发cAMP和IL-6介导的辐射抗性肺癌细胞NED诱导的信号通路。此外，我们发现MEK/Erk信号通路抑制降低辐射抗性细胞的NED。具有高NE样特征的放射抗性肺癌细胞也显示出比亲本细胞更高的放射抗性和更高的转移潜力。当我们抑制cAMP或IL-6介导的通路或下游MEK/Erk信号通路时，放射抗性肺癌细胞的放射敏感性显著增加，其转移潜力显著降低。在体内小鼠研究中，通过用MEK/Erk抑制剂治疗小鼠来减少NED增加了放射敏感性。当用MEK/Erk抑制剂处理小鼠时，肿瘤组织的免疫组织化学染色降低了NED/上皮-间质转化（EMT）/转移标志物的表达。
Radiation treatment induces neuroendocrine differentiation (NED) in non-small cell lung cancer (NSCLC) A549 and H157 cells, so higher NE-like features in radioresistant A549 (A549R26-1) and H157 (H157R24-1) cells are observed than in parental cells. We detected higher NED marker expressions in A549R26-1 cell-derived tumors than in A549 cell-derived tumors. In mechanism studies, we found that NED induction in A549R26-1 and H157R24-1 cells was accompanied by increased intracellular cAMP and IL-6 levels. Treatment of radioresistant lung cancer cells with the inhibitor (SQ22536) of adenylate cyclase (AC) which is the enzyme responsible for the cAMP production, or the neutralizing antibody (Ab) of IL-6, resulted in decreased NE-like features in radioresistant lung cancer cells. In addition, we found MEK/Erk is the signaling pathway that triggers the cAMP- and IL-6-mediated NED induction in radioresistant lung cancer cells. Also, we found that MEK/Erk signaling pathway inhibition decreased NED in radioresistant cells. Radioresistant lung cancer cells exhibiting high NE-like features also showed higher radioresistance and higher metastatic potential than parental cells. When we inhibited cAMP-, or IL-6-mediated pathways, or the downstream MEK/Erk signaling pathway, radiosensitivity of radioresistant lung cancer cells was significantly increased and their metastatic potential was significantly reduced. In in vivo mouse studies, reducing NED by treating mice with the MEK/Erk inhibitor increased radiosensitivity. Immunohistochemical staining of tumor tissues lowered expressions of the NED/epithelial-mesenchymal transition (EMT)/metastatic markers when mice were treated with the MEK/Erk inhibitor.