Canonical vs non-canonical NF kappaB signalling in lung carcinogenesis

Non-small cell lung cancer (NSCLC), with adenocarcinoma being the major histopathologic subtype, develops in distinct steps involving the progressive accumulation of genetic alterations. These include somatic oncogenic K-Ras and EGFR mutually exclusive mutations and inactivating mutations in the p53 tumour suppressor, leading to activation of IKKbeta/canonical (RelA/p65-p50) NF-kappaB signalling.

However, the mechanism(s) by which canonical NF-kappaB contributes to NSCLC development or progression is still under investigation. Further, the impact and mechanism of action of IKKbeta/noncanoncal (RelB-p52) NF-kappaB signalling on NSCLC remains elusive.

To better define the impact of IKKbeta/canonical versus IKKbeta/noncanoncal NF-kappaB signalling, we developed independent in vivo mouse and human lung cancer models and showed that while IKKbeta-RelA/p65 act as NSCLC tumour promoters, CHUK/IKKbeta but not p52 acts as a major NSCLC tumour suppressor.

Using high-throughput molecular analysis (RNA-seq, Nanostring miRNA) in conjunction with bioinformatics analysis, and several biochemical, cell and molecular biology assays, we defined mechanisms by which these two major NF-kappaB signalling pathways contribute to NSCLC development and progression.