Matrix Gla Protein Promotes Colon Cancer Proliferation by Activating NF-κB Pathway Through Upregulating Calcium Signaling Pathway

Abstract Matrix Gla Protein (MGP), an extracellular matrix protein, is mainly associated with the inhibition of calcification in skeleton, coronary artery, and kidney, more recently also implicated in cancer. However, the biological function of MGP inside cancer cells and its role in colon cancer (CC) remain largely unknown. MGP expression and its association with clinicopathologic characteristics in CC were analyzed by immunohistochemistry and verified by GEO and TCGA datasets. Effects of MGP on CC cells proliferation were evaluated via knockdown and overexpression experiments in vitro. Mechanisms of MGP in CC were explored by western blots, quantitative RT-PCR, Fluo-3 AM staining, Rhod-2 AM staining, immunofluorescence and etc. Our study confirmed that MGP was upregulated in different stages of CC and associated with a worse prognosis. MGP could enrich intracellular free Ca2+ concentration and promote NF-κB/P65 phosphorylation, activating the expression of c-MYC, ICAM-1 and VEGFA. Furthermore, the reduction of intracellular free Ca2+ concentration and subsequent growth inhibition effect on CC cells induced by siMGP could be rescued by a higher calcium concentration environment. Therefore, MGP promotes the growth and proliferation of CC cells by enriching intracellular calcium concentration and activating NF-κB pathway, and could serve as a potential prognostic biomarker in CC patients.