Abstract
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.
Highlights
Lung cancer is the leading cause of cancer deaths worldwide [1]
To detect the potential role of Toll-like receptor 4 (TLR4) signaling in LPSmediated tumor outgrowth, primary human lung cancer cells were transfected with TLR4 shRNA or control and stimulated with LPS
We found that transfection of TLR4 shRNA reduced TLR4 expression at both mRNA and protein levels (Figure 1B, Supplementary Figure S1B), and limited LPS-induced tumor outgrowth (Figure 1C)
Summary
The outcome of lung cancer patients still remains poor, exploration of crucial effectors involved in cancer progression was urgently needed [2, 3]. Accumulating studies reported that pulmonary infection facilitated lung cancer progression [4]. Expression of Toll-like receptor 4 (TLR4), which recognizes LPS from Gram-negative bacteria, was increased and reflected disease progress of lung cancer patients [8, 9]. These findings regarded TLR4 activation by LPS as an important stimulus of lung cancer progression. Whether primary human lung cancer outgrowth respond to LPS and underlying mechanisms remain unclear
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