MEX3A activates the JAK-STAT pathway to suppress NK cell cytotoxicity and accelerate lung adenocarcinoma progression.

BACKGROUND

Therapeutic potential of natural killer (NK) cells is recognized in treating lung adenocarcinoma (LUAD), but impairment of NK cell functions in various cancers weakens anti-tumor capabilities. Uncovering molecular mechanisms is imperative for fortifying NK cells against degradation and for enhancing their cancer-inhibiting functions.

METHODS

TCGA-LUAD database complemented by qRT-PCR presented MEX3A expression in LUAD. TIMER was employed to explore relationship between MEX3A levels and NK cell infiltration. In the co-culture system of LUAD and activated NK92 cells, CytoTox 96® assay was applied to gauge NK cell cytotoxicity. ELISA was used to quantify IFN-γ, Perforin, and Granzyme B in the supernatant. Flow cytometry assessed LUAD cell apoptosis. Single-gene enrichment analysis of MEX3A was performed with KEGG database. Western blot examined protein expression in JAK-STAT signaling. In vivo studies validated the role of MEX3A expression on tumorigenesis.

RESULTS

MEX3A was upregulated in LUAD tissue and cells, negatively linked to NK cell infiltration levels. Gene set enrichment analysis pointed to influences of MEX3A expression on dynamics of JAK-STAT signaling. MEX3A overexpression in LUAD cells impaired NK cell cytotoxicity and cell apoptosis, and these effects were reversible by a JAK pathway inhibitor. Mouse studies illustrated that LUAD progression was curbed by MEX3A suppression, alongside an enhanced presence of NK cells within tumor microenvironment.

CONCLUSION

To synthesize our results, this study identified that MEX3A in LUAD promoted malignancy of the disease by enhancing JAK-STAT signaling, which in turn inhibited cytotoxic capabilities of NK cells, thus providing novel insights for LUAD immunotherapy.