miR-193a-3p inhibition of the Slug activator PAK4 suppresses non-small cell lung cancer aggressiveness via the p53/Slug/L1CAM pathway

Abstract

L1 cell adhesion molecule (L1CAM) promotes invasiveness and metastasis in non-small cell lung cancer (NSCLC) cells and is upregulated by the p53-regulated transcription factor Slug. p21-activated kinase 4 (PAK4) directly phosphorylates Slug, resulting in pro-malignant Slug stabilization. We hypothesized that microRNA-based negative regulation of PAK4 would reduce L1CAM-induced NSCLC aggressiveness via destabilizing Slug. We found that elevated L1CAM expression was tightly correlated with p53 loss-of-function and reduced NSCLC patient survival. L1CAM suppression reduced NSCLC cell migration and invasiveness in vitro as well as tumor formation and distal metastasis in vivo. Mechanistically, p53 restricts L1CAM expression through the β-catenin/Slug pathway, with levels of β-catenin and Slug positively correlating with L1CAM expression in NSCLC tumors. The microRNA miR-193a-3p directly targets PAK4 and suppresses downstream p-Slug and L1CAM expression. Silencing PAK4, Slug, and L1CAM mirrored miR-193a-3p's effects upon the migration and invasiveness of NSCLC cells in vitro. Decreased miR-193a-3p levels correlated with elevated PAK4, p-Slug, and L1CAM levels in NSCLC tumors. Our findings support a model of miR-193a-3p as a suppressor of metastatic disease progression in NSCLC via modulation of the p53/Slug/L1CAM pathway.

Keywords: L1CAM; Lung cancer; NSCLC; PAK4; Slug.