RORγ drives non-small cell lung cancer progression by upregulating the NGF signaling.

[BACKGROUND] Lung cancer remains one of the most prevalent and lethal malignancies worldwide, with non-small cell lung cancer (NSCLC) representing the most common subtype-highlighting the critical need for novel therapeutic approaches. The retinoic acid receptor-related orphan receptor gamma (RORγ) has been implicated in various cancers, but its role and mechanism in NSCLC remain unclear.

[METHODS] RORγ expression and its correlation with patient prognosis in NSCLC were assessed by integrating public database bioinformatics analysis, immunohistochemistry, and Western blot. The functional roles of RORγ in NSCLC proliferation, migration, and invasion were determined in vitro through genetic overexpression, pharmacological inhibition, or genetic silencing of RORγ, assessed by cell counting, colony formation, wound healing, and transwell assays. The underlying mechanism was investigated using RNA sequencing, chromatin immunoprecipitation, and rescue experiments with exogenous nerve growth factor (NGF) supplementation or NGF overexpression. In vivo, the anti-tumor efficacy of RORγ inhibition was evaluated using subcutaneous xenograft and experimental metastasis models.

[RESULTS] We identify RORγ as a key driver of NSCLC progression. Integrative bioinformatics and immunohistochemical analysis revealed that RORγ is highly expressed in NSCLC tissues and that its expression correlates with poor patient prognosis. Functionally, elevated RORγ significantly enhanced the proliferation, migration, and invasion capabilities of NSCLC cells. Conversely, treatment with the RORγ antagonist or genetic silencing of RORγ potently suppressed these malignant phenotypes both in vitro and in vivo. Mechanistically, RORγ directly binds to the promoter region of NGF, stimulates NGF gene transcription, and thereby promotes NSCLC progression. RORγ antagonists suppress NGF expression and inhibit its downstream signaling pathways, whereas exogenous NGF supplementation or overexpression of NGF notably reverses the inhibitory effects of RORγ antagonists on NSCLC cells.

[CONCLUSION] Taken together, these results establish RORγ as a critical regulator of NSCLC and a promising therapeutic target for NSCLC treatment.