The ZEB1/LAYN cascade promotes cancer cell malignant phenotypes and macrophage M2 polarization in gastric cancer

Background M2-polarized macrophages in the tumor microenvironment contribute to tumor development, angiogenesis, and immune suppression. Layilin (LAYN) is linked to macrophage infiltration and patient outcomes in gastric cancer (GC). Here, we characterized the role of LAYN in malignant progression and macrophage M2 polarization in GC. Methods Protein levels were assessed using immunoblotting and immunohistochemistry (IHC), and mRNA levels were detected through quantitative PCR (qPCR). The impact on GC cell functions was determined by assessing cell invasion, migration, apoptosis, proliferation, and colony formation ability. The effect on macrophage M2 polarization was evaluated by analyzing the expression of M2 markers and the percentage of CD163 ⁺ macrophages. Xenograft models were generated to determine the role in vivo . The ZEB1-LAYN relationship was confirmed by chromatin immunoprecipitation (ChIP) and luciferase assays. Results LAYN and ZEB1 were up-regulated in GC samples and cell lines. LAYN deficiency weakened cancer cell malignant phenotypes and induced their apoptosis in vitro , as well as diminished MKN-45 xenograft growth in vivo . Moreover, LAYN deficiency attenuated the migration and M2 polarization of GC-related macrophages. Mechanistically, ZEB1 transcriptionally enhanced LAYN expression. LAYN restoration enhanced malignant phenotypes in ZEB1-deficient GC cells and reduced the suppressive effects of ZEB1 depletion on the migration and M2 polarization of macrophages. Conclusion Our study demonstrates that the ZEB1/LAYN cascade contributes to the development of GC by enhancing cancer cell malignant phenotypes and macrophage M2 polarization. LAYN or ZEB1 could be a new target for GC intervention.