High expression of Tbx15 in lung adenocarcinoma cells facilitates bone metastasis by suppressing IL-25 secretion and reducing MVP expression in osteoclasts.

Bone is a primary site for lung cancer metastasis, and T-box transcription factor 15 (Tbx15) is aberrantly expressed in multiple cancers. It aims to investigate the role of Tbx15 in lung cancer bone metastasis and its potential mechanisms. TCGA and cellular analyses revealed elevated Tbx15 lung adenocarcinoma tissues and cells (MLE-12, CMT64, LA795, LLC), while recombinant IL-25 (rIL-25) expression was low in supernatants and lysates. And Pearson analysis showed a negative correlation between Tbx15 and IL-25. The CCK-8 and EdU assays showed that Tbx15 knockdown inhibited LA795 cell proliferation, migration, and invasion. In vivo, simultaneous Tbx15 knockdown and rIL-25 administration promote tumor cell growth and accelerate bone metastasis in mice. Mechanistically, Tbx15 knockdown upregulates IL-25 expression, thereby promoting apoptosis of osteoclasts (OCs) and suppressing bone metastasis. Besides, OCs were treated with rIL-25 and the apoptosis inhibitor Z-VAD-FMK, and found that extracellular IL-25 protein promoted apoptosis of OCs by upregulating major vault protein (MVP) expression. In conclusion, our study demonstrates that knockdown of Tbx15 upregulates IL-25 expression to promote apoptosis of OCs, while exogenous supplementation of IL-25 promotes proliferation and bone metastasis of lung adenocarcinoma cells. The dual role of IL-25 in Tbx15-positive lung adenocarcinoma cells and its potential regulatory mechanism were elucidated.