TLR4/ROS/miRNA-21 pathway underlies lipopolysaccharide instructed primary tumor outgrowth in lung cancer patients.
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.
Department of Thoracic Surgery, Qianfoshan Hospital, Shandong University, Shandong 250014, China.
Xianqi
X
Zhang
Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
Chunhong
C
Wang
Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
Shan
S
Shan
Department of Thoracic Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, China.
Xiyu
X
Liu
Department of Thoracic Surgery, Qianfoshan Hospital, Shandong University, Shandong 250014, China.
Zhongmin
Z
Jiang
Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
Tao
T
Ren
D000368:Aged; D000818:Animals; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008070:Lipopolysaccharides; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009368:Neoplasm Transplantation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D008070:Lipopolysaccharides; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D017382:Reactive Oxygen Species; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4
LPS; ROS; TLR4; lung cancer; miR-21