Stabilization of LTBP2 by SIRT1 promotes EMT and chemosensitivity in cardia gastric adenocarcinoma through TGF-β signaling

Cardia gastric adenocarcinoma (CGA) is an aggressive malignancy with rising incidence and poor prognosis, driven in part by significant molecular heterogeneity. Through integrated bioinformatics and clinical analyses, we identify Latent-Transforming Growth Factor Beta-Binding Protein 2 (LTBP2) as a key heterogeneously expressed protein markedly upregulated in CGA compared to non-cardia gastric adenocarcinoma (NCGA), correlating with advanced tumor stage and reduced survival. Mechanistically, we uncover a novel post-translational regulation of LTBP2 wherein SIRT1-mediated deacetylation stabilizes LTBP2 by attenuating its binding to the CUL3/SPOP E3 ubiquitin ligase complex, thereby reducing ubiquitination and proteasomal degradation. Functionally, stabilized LTBP2 activates the TGF-β/PI3K-AKT signaling axis, promoting tumor cell proliferation, epithelial-mesenchymal transition (EMT), and metastasis in vitro and in vivo. Genetic ablation of LTBP2 or SIRT1 impairs tumor growth and EMT, phenotypes rescued by LTBP2 reconstitution. Importantly, LTBP2 deficiency sensitizes tumors to 5-fluorouracil (5-FU) chemotherapy, both in cell models and murine xenografts. Collectively, our findings delineate a SIRT1-LTBP2-TGF-β regulatory axis critical for CGA progression and chemoresistance, nominating LTBP2 as a promising therapeutic target in this aggressive gastric cancer subtype.