MMP28 belongs to the matrix metalloproteinases (MMPs) family and functions in tissue homeostasis and development. Although many other MMPs have been reported to regulate tumor progression, the roles of MMP28 in cancer remain largely elusive. In this study, we investigated the potential roles of MMP28 in hepatocellular carcinoma (HCC). The upregulation of MMP28 was first determined by the analysis on different public datasets. Further quantitative real-time PCR (qPCR) analysis, western blot (WB) assay and immunohistochemistry (IHC) assay on tumor and tumor-adjacent samples from HCC patients confirmed the aberrant elevation of MMP28 in HCC. Pathological analysis showed that increased MMP28 was associated with tumor size, vascular invasion, TNM stage and overall survival in HCC patients. Meanwhile, upregulated MMP28 was identified as an independent prognosis factor in multivariate analysis, and the incorporation of MMP28 expression with TNM staging system established a novel model to improve the accuracy of the predictions. In vivo and in vitro data revealed that MMP28 promoted migration and invasion of HCC cells, and enhanced epithelial-mesenchymal transition (EMT) via elevating zinc finger E-box binding homeobox (ZEB) homologues levels. Furthermore, we determined that Notch3 signaling was critical for the functions of MMP28 in HCC. In conclusion, upregulated MMP28 in HCC promoted migration and invasion and predicted poor prognosis for HCC patients, and the effects of MMP28 depended on Notch3 signaling.

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.

OGT-mediated O-GlcNAcylation on GLDC promotes metastasis in cervical cancer OGT-mediated O-GlcNAcylation on GLDC promotes metastasis in cervical cancer