Liu Jinglei, Yao Lei, Zhang Mingyan, Jiang Ji, Yang Maopeng, Wang Yue
Harbin Medical University, Heilongjiang, China.
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Heilong Jiang, China.
Aging (Albany NY). 2019 Sep 25;11(18):7830-7846. doi: 10.18632/aging.102291.
LncRNA-XIST participated in the regulation of Non-small cell lung cancer (NSCLC) progression, but the underlying mechanisms are still unclear. This study showed that LncRNA-XIST aberrantly overexpressed in either NSCLC tissues or cell lines comparing to their paired control groups. Knock-down of LncRNA-XIST promoted NSCLC cell apoptosis and inhibited cell proliferation, which were reversed by synergistically treating cells with pyroptosis inhibitor Necrosulfonamide (NSA). In addition, knock-down of LncRNA-XIST also promoted reactive oxygen species (ROS) production and NLRP3 inflammasome activation. In parallel, ROS scavenger N-acetyl cysteine (NAC) abrogated the effects of downregulated LncRNA-XIST on NSCLC cell pyroptosis. Furthermore, miR-335 was the downstream target of LncRNA-XIST and overexpressed LncRNA-XIST increased SOD2 expression levels by sponging miR-335. Mechanistically, miR-335 inhibitor reversed the effects of downregulated LncRNA-XIST on ROS levels and cell pyroptosis, which were abrogated by synergistically knocking down SOD2. Taken together, knock-down of LncRNA-XIST inhibited NSCLC progression by triggering miR-335/SOD2/ROS signal pathway mediated pyroptotic cell death.
长链非编码RNA-XIST参与非小细胞肺癌（NSCLC）进展的调控，但其潜在机制仍不清楚。本研究表明，与配对的对照组相比，长链非编码RNA-XIST在NSCLC组织或细胞系中异常高表达。敲低长链非编码RNA-XIST可促进NSCLC细胞凋亡并抑制细胞增殖，而用焦亡抑制剂磺柳酸（NSA）协同处理细胞可逆转这些作用。此外，敲低长链非编码RNA-XIST还可促进活性氧（ROS）生成和NLRP3炎性小体激活。同时，ROS清除剂N-乙酰半胱氨酸（NAC）可消除下调长链非编码RNA-XIST对NSCLC细胞焦亡的影响。此外，miR-335是长链非编码RNA-XIST的下游靶点，过表达长链非编码RNA-XIST通过海绵吸附miR-335增加SOD2表达水平。机制上，miR-335抑制剂可逆转下调长链非编码RNA-XIST对ROS水平和细胞焦亡的影响，而协同敲低SOD2可消除这些影响。综上所述，敲低长链非编码RNA-XIST通过触发miR-335/SOD2/ROS信号通路介导的焦亡性细胞死亡抑制NSCLC进展。
