LncRNA Uc003xsl.1-Mediated Activation of the NFKB/IL8 Axis Promotes Progression of Triple-Negative Breast Cancer

Aberrant activation of NF kappa B orchestrates a critical role in tumor carcinogenesis; however, the regulatory mechanisms underlying this activation are not fully understood. Here we report that a novel long noncoding RNA (lncRNA) Uc003xsl.1 is highly expressed in triple-negative breast cancer (TNBC) and correlates with poor outcomes in patients with TNBC. Uc003xsl.1 directly bound nuclear transcriptional factor NF kappa B-repressing factor (NKRF), subsequently preventing NKRF from binding to a specific negative regulatory element in the promoter of the NF kappa B-responsive gene IL8 and abolishing the negative regulation of NKRF on NF kappa B-mediated transcription of IL8. Activation of the NF kappa B/IL8 axis promoted the progression of TNBC. Trop2-based antibody-drug conjugates have been applied in clinical trials in TNBC. In this study, a Trop2-targeting, redox-responsive nano-particle was developed to systematically deliver Uc003xsl.1 siRNA to TNBC cells in vivo, which reduced Uc003xsl.1 expression and suppressed TNBC tumor growth and metastasis. Therefore, target-ing Uc003xsl.1 to suppress the NF kappa B/IL8 axis represents a prom-ising therapeutic strategy for TNBC treatment. Significance: These findings identify an epigenetic-driven NF kappa B/IL8 cascade initiated by a lncRNA, whose aberrant acti-vation contributes to tumor metastasis and poor survival in patients with triple-negative breast cancer.