Galectin-3 activates TLR4/NF-κB signaling to promote lung adenocarcinoma cell proliferation through activating lncRNA-NEAT1 expression

Lung cancer remains the top contributor to cancer-related mortality worldwide. Long non-coding RNAs (lncRNAs) have been reported to participate in normal development and tumorigenesis. LncRNA nuclear enriched abundant transcript 1 (NEAT1) is highly expressed in lung cancer and promotes lung cancer cell proliferation and migration. However, the upstream regulatory mechanism still needs investigation.

In the present study, we investigated the upstream regulators and mechanisms of NEAT1 expression disorders. We first examined NEAT1 expression in lung adenocarcinoma tissues and its correlation with clinic features in patient with lung adenocarcinoma; next, the detailed function of NEAT1 in lung cancer cell proliferation and migration was assessed. To investigate whether NF-κB acts as a transcription factor of NEAT1 to activate its expression, we validated the combination between NF-κB and NEAT1, and NF-κB regulation of NEAT1 upon LPS stimulation. Further, the effect of NF-κB upstream regulator, TLR4, on NEAT1 expression upon LPS stimulation was examined. Galectin-3 reportedly serves as a ligand of TLR4 and promotes TLR4, MyD88 and p-p65 expression; we investigated whether Galectin-3 could modulate lung adenocarcinoma cell proliferation and migration through TLR4/NF-κB/NEAT1. Finally, the expression and correlation of the above factors in lung adenocarcinoma tissues was validated.

NEAT1 is highly expressed in lung adenocarcinoma tissues and promotes lung cancer cell proliferation and migration. NF-κB binds to NEAT1 promoter to activate NEAT1 expression after LPS-stimulated p65 nucleus translocation. LPS stimulation activates TLR4 signaling, followed by downstream NF-κB activation, and ultimately NEAT1 expression activation. Galectin-3 activates TLR4 signaling thus affecting lung cancer cell proliferation and migration through TLR4/NF-κB/NEAT1. Galectin-3 and TLR4 expression are abnormally up-regulated in lung adenocarcinoma tissues, and positively correlated with NEAT1 expression.

We confirmed that Galectin-3 as a ligand of TLR4 induced TLR4 signaling activation in lung adenocarcinoma cells, thereby activating downstream p65 nucleus translocation, promoting NEAT1 expression, and finally affecting lung adenocarcinoma cell proliferation and migration. Inhibiting Galectin-3-induced TLR4 signaling activation, thus to reduce p65-activated NEAT1 expression might be a promising strategy of suppressing lung adenocarcinoma cell proliferation and migration.