5-Hydroxytryptamine promotes non-small cell lung cancer metastasis via the SNRPG/WT1/CDK14 Axis

Tumor metastasis severely compromises the prognosis of patients with non-small cell lung cancer (NSCLC), yet the underlying mechanisms remain unclear. The biogenic amine 5-hydroxytryptamine (5-HT), derived from tryptophan (Trp), has been reported to promote tumor growth, but its role in NSCLC metastasis has not been fully elucitated. In this study, fecal metabolomic profiling revealed significant enrichment of Trp metabolism and serotonergic synapse pathways in patients with NSCLC metastasis. Notably, the levels of 5-HT in peripheral blood showed a positive correlation with fecal Trp concentrations in NSCLC patients. Functional experiments demonstrated that 5-HT promoted NSCLC cell migration, invasion, epithelial-mesenchymal transition (EMT), and metastasis by inhibiting the expression of small nuclear ribonucleoprotein polypeptide G (SNRPG). RNA sequencing (RNA-seq) further identified cyclin-dependent kinase 14 (CDK14) as a critical downstream target of SNRPG. SNRPG downregulated CDK14 expression, thereby restraining malignant phenotypes in NSCLC cells. Furthermore, SNRPG negatively regulated the protein levels of Wilms tumor 1 (WT1) by directly binding to it. Loss of SNRPG led to WT1 accumulation, which in turn bound to the CDK14 promoter and activated transcription, ultimately driving NSCLC metastasis. These findings collectively suggest that the 5-HT/SNRPG/WT1/CDK14 axis plays a pivotal role in promoting NSCLC metastasis and highlight 5-HT and SNRPG as potential therapeutic targets for NSCLC metastasis.