Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer, accounting for more than 80% of all lung cancers.

While NF-kappa-B-activating protein-like (NKAPL) has been positively correlated with prognosis in various cancer types, its specific role in the progression of NSCLC remains undetermined.

This research published in the Genes & Diseases journal by a team from Chongqing Medical University, Suining Central Hospital, Chongqing University and Sichuan University investigates the potential mechanisms underlying NSCLC growth.

Using AI-based machine learning, the team found that NKAPL had a high importance score of 0.9027 in patients with NSCLC.

The expression of NKAPL was examined in NSCLC cell lines and matched primary NSCLC tissues.

The results revealed significant downregulation of NKAPL in NSCLC, which correlated with clinicopathological parameters.

Notably, methylation-specific PCR analysis of primary NSCLC tissues revealed that 99.38% of NKAPL promoters were hypermethylated.

These findings confirm that NKAPL downregulation was due to promoter methylation, which was associated with poor prognosis in NSCLC patients.

Subsequent in vitro experiments demonstrated that increased NKAPL expression in NSCLC cell lines inhibited cell proliferation, decreased migration and invasion, induced cell cycle arrest at the G2/M phase, and promoted apoptosis.

In vivo, NKAPL overexpression substantially inhibited tumour growth and metastasis in metastatic mouse models, firmly establishing its role as a tumour suppressor in NSCLC.

Bioinformatics analysis revealed that the tripartite motif-containing 21 (TRIM21) protein is strongly correlated with NKAPL expression.

Furthermore, NKAPL overexpression prolonged the half-life of TRIM21, indicating that NKAPL enhances TRIM21 expression by stabilising the protein.

Moreover, knockdown of TRIM21 induced partial restoration of p65 phosphorylation by NKAPL overexpression, highlighting NKAPL’s ability to suppress the NF-κB signalling pathway via TRIM21.

Interestingly, TRIM21 knockdown reversed the inhibitory effect of NKAPL on NSCLC cells.

In conclusion, this study reveals that low expression of NKAPL, primarily due to hypermethylation, serves as a potential indicator of poor prognosis in NSCLC.

Overall, the findings of this research could pave the way for the development of NKAPL methylation inhibitors and NKAPL-targeted delivery systems as part of combination therapies for NSCLC.

Source: Compuscript Ltd