| Popis: |
Background: Gastric cancer (GC) is a major cause of human deaths worldwide, and is notorious for its high incidence and mortality rates. Mesoderm Posterior Basic Helix-loop-helix (bHLH) transcription factor 2 (MESP2) acts as a transcription factor with a conserved bHLH domain. However, whether MESP2 contributes to tumorigenesis and its potential molecular mechanisms, remain unexplored.Methods: Immunohistochemistry was used to examine MESP2 expression in clinical gastric tissues. In vitro cell proliferation, migration, and invasion assays were used to investigate the effects of MESP2 on gastric cells progress. Expression microarray profiling，co-immunoprecipitation and chromatin immunoprecipitation were used to explore the potential molecular mechanisms of MESP2 on tumorigenesis. Subcutaneous tumor formation and orthotopic implantation assays were performed in NOD/SCID mice to confirm the effects of MESP2 on gastric growth and metastasis in vivo. Results: Noticeably, MESP2 expression levels are decreased in GC tissues and cell lines compared to those in normal tissue. Further, in vitro and in vivo experiments have confirmed that MESP2 overexpression suppresses GC cell growth, migration, and invasion, whereas MESP2 knockdown results in the exact opposite. In addition, MESP2 binds to transcription factor 7-like 2 (TCF7L2/TCF4) to inhibit the activation of the TCF4/beta-catenin transcriptional complex, decrease the occupancy of the complex on the S-phase kinase Associated Protein 2 (SKP2) promoter, and promote p27 accumulation. MESP2 knockdown facilitated tumorigenesis, which was partially suppressed by SKP2 knockdown. Conclusions: Our findings demonstrate that MESP2 binds competitively to TCF4 to suppress GC progression by regulating the SKP2/p27 axis, thus offering a potential therapeutic strategy for future treatment. |
