Zhang Xianqi, Wang Chunhong, Shan Shan, Liu Xiyu, Jiang Zhongmin, Ren Tao
Department of Thoracic Surgery, Qianfoshan Hospital, Shandong University, Shandong 250014, China.
Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
Oncotarget. 2016 Jul 5;7(27):42172-42182. doi: 10.18632/oncotarget.9902.
Activation of Toll-like receptor 4 (TLR4) signaling in human lung cancer with lipopolysaccharide (LPS) enhances tumor progression. However, whether primary human lung cancer outgrowth could respond to LPS and underlying mechanisms are unclear. Here we determined that TLR4 activation with LPS promoted outgrowth of primary human lung cancer cells in vitro and in vivo. Mechanistically, LPS stimulation increased expression levels of microRNA-21 (miR-21) in primary human lung cancer cells. Inhibition of miR-21 blocked the enhanced lung cancer growth induced by LPS in vitro and in vivo. Up-regulation of miR-21 promoted outgrowth of primary human lung cancer. Down-regulation of miR-21 limited primary human lung cancer outgrowth. Further, TLR4 activation in primary human lung cancer cells increased their ROS levels. Scavenge of ROS abrogated the up-regulation of miR-21 in primary human lung cancer cells and attenuated LPS-induced outgrowth. For in vivo relevance, expression of TLR4 was correlated with miR-21 expression and ROS production in freshly isolated, untreated primary human lung cancer cells. These findings demonstrate an essential role of TLR4/ROS/miR-21 pathway in LPS-induced outgrowth of primary human lung cancer. Our study connected a framework of innate signaling, oxidative stress and microRNA in tumor immunity and provided clues for developing new therapeutics for lung cancer.
脂多糖（LPS）激活人肺癌中的Toll样受体4（TLR4）信号通路可促进肿瘤进展。然而，原发性人肺癌的生长是否会对LPS产生反应及其潜在机制尚不清楚。在此，我们确定LPS激活TLR4可在体外和体内促进原发性人肺癌细胞的生长。机制上，LPS刺激可增加原发性人肺癌细胞中微小RNA-21（miR-21）的表达水平。抑制miR-21可在体外和体内阻断LPS诱导的肺癌生长增强。miR-21的上调促进原发性人肺癌的生长。miR-21的下调限制原发性人肺癌的生长。此外，原发性人肺癌细胞中TLR4的激活会增加其活性氧（ROS）水平。清除ROS可消除原发性人肺癌细胞中miR-21的上调，并减弱LPS诱导的生长。在体内相关性方面，TLR4的表达与新鲜分离的未经处理的原发性人肺癌细胞中miR-21的表达和ROS的产生相关。这些发现证明了TLR4/ROS/miR-21通路在LPS诱导的原发性人肺癌生长中的重要作用。我们的研究在肿瘤免疫中建立了先天信号、氧化应激和微小RNA的框架，并为开发肺癌新疗法提供了线索。
