lncCRLA Enhanced Chemoresistance in Lung Adenocarcinoma That Underwent EpithelialMesenchymal Transition.
lncCRLA Enhanced Chemoresistance in Lung Adenocarcinoma That Underwent EpithelialMesenchymal Transition.
复制标题
lncCRLA增强肺腺癌上皮间质转化的化疗耐药性
DOI：
10.3727/096504021x16203818567367
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发表时间：
2022-01-31
影响因子：
3.1
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Min W;Sun L;Li B;Gao X;Zhang S;Zhao Y
EMT增加了癌细胞的转移潜力和对化疗的抵抗力。然而，emt相关化疗耐药的确切机制尚不清楚。肺腺癌细胞系中EMT必需的c- src介导的caspase 8磷酸化优先发生在具有间充质表型的细胞中，导致可切除肺腺癌患者对顺铂加紫杉醇的化疗耐药，并且5年PFS明显恶化。不管caspase 8是否存在，顺铂均能杀死肺腺癌细胞。紫杉醇引发的肺腺癌细胞坏死坏死依赖于caspase 8的磷酸化或缺失，在此过程中，FADD与RIPK1相互作用，激活RIPK1/RIPK3/MLKL信号轴。伴随着c- src介导的caspase 8磷酸化触发EMT，一种名为lncrla的新型lncRNA被显著上调，并通过与RIPK1中间结构域的结合，损害RIPK1- ripk3的相互作用，从而抑制RIPK1诱导的坏死坏死。达沙替尼减轻了c- src介导的caspase 8诱导的EMT磷酸化，并增强了紫杉醇处理的间充质样肺腺癌细胞的坏死坏死，而c-FLIP敲低主要使间充质样肺腺癌细胞对紫杉醇+达沙替尼敏感。c-Src-caspase 8相互作用通过caspase 8磷酸化和lncrla表达启动EMT和化疗耐药，达沙替尼/紫杉醇脂质体+ siFLIP方案是致命的。
EMT confers increased metastatic potential and the resistance to chemotherapies to cancer cells. However, the precise mechanisms of EMT-related chemotherapy resistance remain unclear. c-Src-mediated caspase 8 phosphorylation essential for EMT in lung adenocarcinoma cell lines preferentially occurs in cells with the mesenchymal phenotype, resulting in chemoresistance to cisplatin plus paclitaxel in patients with resectable lung adenocarcinoma and a significantly worse 5-year PFS. Cisplatin killed lung adenocarcinoma cells regardless of caspase 8. Paclitaxel-triggered necroptosis in lung adenocarcinoma cells was dependent on the phosphorylation or deficiency of caspase 8, during which FADD interacted with RIPK1 to activate the RIPK1/RIPK3/MLKL signaling axis. Accompanied with c-Src-mediated caspase 8 phosphorylation to trigger EMT, a novel lncRNA named lncCRLA was markedly upregulated and inhibited RIPK1-induced necroptosis by impairing RIPK1–RIPK3 interaction via binding to the intermediate domain of RIPK1. Dasatinib mitigated c-Src-mediated phosphorylation of caspase 8-induced EMT and enhanced necroptosis in mesenchymal-like lung adenocarcinoma cells treated with paclitaxel, while c-FLIP knockdown predominantly sensitized the mesenchymal-like lung adenocarcinoma cells to paclitaxel + dasatinib. c-Src–caspase 8 interaction initiates EMT and chemoresistance via caspase 8 phosphorylation and lncCRLA expression, to which the dasatinib/paclitaxel liposome + siFLIP regimen was lethal.