Calcium Binding Protein S100A16 Expedites Proliferation, Invasion and EMT Process in Gastric Cancer

Abstract Background: Gastric cancer (GC) is one of the most common malignant tumors of the digestive system, which has been the second cause of cancer-related deaths worldwide. The distant metastasis is one of the main reasons for the high recurrence and mortality rate of GC patients. Hence, it is necessary to investigate the molecular mechanism underlying gastric carcinogenesis and progression, especially the key genes and signaling pathways that promote GC cells proliferation, invasion, and metastasis. Methods: Using bioinformatics and clinicopathological analysis, in vivo tumor formation assays, mass spectrometry and so on, we characterized the role and molecular mechanism of S100 Calcium Binding Protein A16 (S100A16) in promoting GC tumor growth, migration, invasion and epithelial-to-mesenchymal transition (EMT), and investigated how Zonula Occludens-2 (ZO-2) inhibition mediates S100A16-induced metastasis and progression in GC. Results: We analyzed S100A16 expression with the GEPIA database and the UALCAN cancer database, and the prognostic analysis was performed using 100 clinical GC samples. We found that S100A16 is significantly upregulated in GC tissues and closely correlated with poor prognosis in GC patients. Functional studies reveal that S100A16 overexpression triggers GC cells proliferation and migration both in vivo and in vitro ; by contrast, S100A16 knockdown restricts the speed of GC cells growth and mobility. Proteomic analysis results reveal a large S100A16 interactome, which includes ZO-2, a master regulator of cell-to-cell tight junctions. Mechanistic assay results indicate that excessive S100A16 instigates GC cell invasion, migration and EMT via ZO-2 inhibition, which arose from S100A16-mediated ZO-2 ubiquitination and degradation. Conclusions: Our results not only reveal that S100A16 is a promising candidate biomarker in GC early diagnosis and prediction of metastasis, but also establish the therapeutic importance of targeting S100A16 in order to prevent ZO-2 loss and suppress GC metastasis and progression.