Intracellular matrix Gla protein promotes tumor progression by activating JAK2/STAT5 signaling in gastric cancer

Matrix Gla protein (MGP) has been widely reported as an extracellular matrix protein with abnormal expression in various types of cancer. However, the function of intracellular MGP in gastric cancer (GC) cells remains largely unknown. Here, we demonstrated aberrantly high expression of intracellular MGP in GC as compared to adjacent normal tissues by immunohistochemistry. Moreover, The Cancer Genome Atlas (TCGA) dataset analysis suggested a positive correlation between MGP overexpression and unfavorable prognosis. MGP silencing reduced cell proliferation, migration, invasion, and survival in GC cell lines. Gene set enrichment analysis of TCGA dataset indicated significant enrichment of the IL2–STAT5 signaling in MGP‐high GC patients. Immunofluorescence staining and immunoprecipitation showed that MGP binds to p‐STAT5 in the nuclei of GC cells. Furthermore, ChIP‐qPCR and luciferase reporter assays indicated that MGP acts as a transcriptional co‐activator through the enhancement of STAT5 binding to target gene promoters. Use of STAT5 inhibitor revealed that the oncogenic functions of intracellular MGP mainly depend on the JAK2/STAT5 signaling pathway. Taken together, our results indicate that intracellular MGP promotes proliferation and survival of GC cells by acting as a transcriptional co‐activator of STAT5. The detected aberrant, high MGP expression in GC tissues highlights MGP as a potential new prognostic biomarker in patients with GC.