LAMC2 promotes gallbladder carcinoma metastasis through the TGF-β pathway.

BACKGROUND: Gallbladder cancer (GBC) is an aggressive malignant tumor that seriously threatens the survival of GBC patients. Laminin-γ2 (LAMC2), an important component of laminins, has been reported to facilitate cancer development and chemoresistance in several cancers. However, the biological effect of LAMC2 on GBC is still unclear. METHODS: LAMC2 expression was assessed in GBC specimens through proteomics and RNA-seq data. To evaluate the biological effects of LAMC2, we performed colony formation, sphere formation, wound healing, and transwell and invasion assays, along with an in vivo metastasis model. Additionally, we also explored the role of LAMC2 in GBC organoid. Finally, Western blot and RT-qPCR were employed to identify the molecular mechanism underlying LAMC2-mediated regulation of aggressive behavior in GBC. RESULTS: Here, we revealed that LAMC2 was overexpressed in GBC tissues and was positively correlated with poor patient outcomes. Furthermore, the genetic silencing of LAMC2 significantly inhibited GBC cell colony formation, sphere formation, and organoid growth. Additionally, LAMC2 deficiency impaired GBC cell metastasis in vitro and in vivo, accompanied by a reversal of the epithelial-mesenchymal transition (EMT) phenotype. Mechanistically, LAMC2 expression was induced by the canonical TGF-β/SMAD2 signaling pathway, and in turn, LAMC2 feedback enhanced the activity of TGF-β signaling by binding to TGF-β receptor II (TGF-βRII). CONCLUSION: Our findings suggest that LAMC2 promotes GBC progression and metastasis, potentially by regulating the TGF-β signaling pathway. Therefore, LAMC2 could serve as a potential prognostic biomarker and therapeutic target for GBC.