RIPK2/STAT3 signaling axis drives lung cancer metastasis through SNAIL activation: Molecular mechanisms and clinical implications.

BACKGROUND

Lung adenocarcinoma is the most common histological subtype of lung cancer with high metastatic propensity. Epithelial-mesenchymal transition (EMT) plays a crucial role in tumor metastasis, but the molecular mechanisms remain incompletely elucidated. This study investigates the role of RIPK2 in EMT and metastasis of lung adenocarcinoma.

METHODS

TCGA database analysis determined RIPK2 expression and clinical significance. RNA interference, overexpression, qRT-PCR, Western blot, co-immunoprecipitation, and immunofluorescence were employed in A549 and PC-9 cell lines. Transwell, EdU, colony formation assays, and cytoskeletal staining assessed cell invasion, proliferation, and EMT changes. Nuclear localization signal (NLS) and nuclear export signal (NES) fusion proteins investigated subcellular localization effects. Tail vein injection in nude mice validated in vivo effects.

RESULTS

RIPK2 was highly expressed in lung adenocarcinoma tissues and associated with poor prognosis. RIPK2 knockdown inhibited while overexpression promoted EMT, invasion, and metastasis. Co-immunoprecipitation and immunofluorescence confirmed direct RIPK2-STAT3 interaction. RIPK2 specifically upregulated EMT transcription factor SNAIL expression. Co-expression of RIPK2 and SNAIL correlated with shorter patient survival. STAT3 or SNAIL knockdown inhibited RIPK2-induced EMT and metastasis. Nuclear-localized RIPK2 completely restored cellular EMT, invasion, and metastatic capabilities while enhancing cisplatin resistance.

CONCLUSION

RIPK2 translocates to the nucleus, interacts with STAT3, and synergistically upregulates SNAIL expression, promoting EMT, invasion, metastasis, and chemotherapy resistance in lung adenocarcinoma. The RIPK2-STAT3-SNAIL signaling axis represents a potential therapeutic target.