PLS3-AS1 promotes colorectal cancer progression and radioresistance by sustaining NF-κB signaling

Radioresistance is a key challenge in colorectal cancer (CRC) therapy. Through integrative analysis of TCGA datasets and RNA-seq of irradiated CRC cells, we identified PLS3-AS1 as a radiation-inducible lncRNA upregulated in recurrent tumors and post-irradiation. Functional assays revealed that PLS3-AS1 promotes CRC cell proliferation, survival, and radioresistance in vitro and in vivo. Mechanistically, PLS3-AS1 enhances NF-κB signaling by directly binding to p65 and IκBα, disrupting their interaction and facilitating p65 nuclear translocation. Moreover, PLS3-AS1 expression is itself induced by NF-κB activation, forming a positive feedback loop. Inhibition of NF-κB with BAY 11-7082 suppressed PLS3-AS1 expression and reversed its pro-tumorigenic effects. These findings identify PLS3-AS1 as a critical mediator of NF-κB-driven radioresistance in CRC and a potential therapeutic target to improve radiotherapy efficacy.