Matrix metalloproteinase‐21 promotes metastasis via increasing the recruitment and M2 polarization of macrophages in HCC

MMP‐21 is a newly identified member of the matrix metalloproteinase family and has been reported to regulate both embryonic development and tumor progression. However, the roles of MMP‐21 in hemofiltrate C–C chemokine (HCC) remain largely unclear. In this study, we used western blot, qPCR and immunohistochemistry (IHC) to determine the upregulation of MMP‐21 in HCC tissues, and showed that the increase in MMP‐21 was associated with vascular invasion and poor prognosis. Although changing levels of MMP‐21 in HCC cell lines had no significant effect on cell migration or invasion abilities in in vitro transwell tests, both IHC analysis and in vivo mouse models proved that upregulated MMP‐21 promoted metastasis. Functional enrichments of MMP‐21 using The Cancer Genome Atlas (TCGA) data suggested that MMP‐21 might regulate metastasis via macrophages. Further experiments proved that MMP‐21 enhanced macrophage recruitment by increasing CCL‐14 levels and promoted M2‐type polarization of macrophage by elevating the expression of CSF‐1 and FGF‐1. Taken together, this study revealed that MMP‐21 controlled the tumor microenvironment remodeling and functional regulation of macrophages to regulate HCC metastasis.