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

Abstract

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.

Prognostic and Immune Landscape Analysis of Ubiquitination-related Genes in Hepatocellular Carcinoma: Based on Bulk and Single-cell RNA Sequencing Data

“…The correlation analysis between immune cells, expression of hub UbRGs, and risk scores revealed a strong positive correlation between macrophages and ubiquitination genes (Figure 7 F). M2 macrophages are recognized as crucial contributors to tumor progression and have been associated with poor prognoses 38 . Ubiquitin promotes macrophage M2 polarization and activates the CXCR4/ERK signaling pathway, thereby facilitating the invasion of HCC 39 .…”

Comprehensive analysis and immune landscape of chemokines- and chemokine receptors-based signature in hepatocellular carcinoma

“…It has been shown that the overexpression of CCL14 inhibits cancer cell proliferation and promotes apoptosis and that its low expression is associated with poor prognosis in HCC patients (23). MMP-21 promotes macrophage recruitment by increasing CCL-14 levels and M2 macrophage polarization by increasing CSF-1 and FGF-1 expressions, thereby regulating the immune microenvironment and metastasis of HCC (24). The CCL20-CCR6 axis has been reported to be associated with a variety of cancers, including HCC, colorectal cancer, breast cancer, pancreatic cancer, cervical cancer and renal cancer (25).…”

Role of exosomes in hepatocellular carcinoma and the regulation of traditional Chinese medicine

“…Additionally, the exosomes can further reduce the efficacy of chemotherapy for HCC ( Giallombardo et al, 2016 ). Evidences show that exosome-mediated cellular communication is involved in drug resistance ( Li Y et al, 2021 ; Lu et al, 2021 ; Zhou J et al, 2022 ). It was reported that circZFR was highly expressed in CAFs and cisplatin-resistant HCC cells ( Zhou Y et al, 2022 ).…”

“…In the TEM, the M2 TAMs are the major cell types of macrophages and associate with a poor clinical outcome in HCC. It is well known that M2 TAMs usually promote tumor growth, malignance, and metastasis ( Deng et al, 2021 ; Zhou J et al, 2022 ). In the TME of HCC, tumor-derived exosomes can promote the M2 polarization of macrophages ( Kwon et al, 2020 ).…”