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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.

SUBMITTER: Zhou J

PROVIDER: S-EPMC9899621 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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

Zhou Jiangfan J Liu Li L Hu Xudong X Feng Rong R Zhao Niannian N Zhang Li L Hu Wenhao W Zhang Jian J Huang Shiyong S Liu Lin L Li Wei W Shan Yunfeng Y Jin Jing J

Cancer science 20220428 2

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 o ...[more]

PMID: 35398966

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Project description:Pulsatilla saponins (PS) extracts from Pulsatilla chinensis (Bge.) Regel, are a commonly used traditional Chinese medicine. In the previous study, we found Pulsatilla saponins displayed anti-tumor activity without side effects such as bone marrow suppression. However, the mechanism of the anti-tumor effect was not illustrated well. Since M2-like tumor-associated macrophages (TAMs) that required activation of the signal transducer and activator of transcription 6 (STAT6) for polarization are the important immune cells in the tumor microenvironment and play a key role in tumor progress and metastasis, this study aimed to confirm whether Pulsatilla saponins could inhibit the development and metastasis of tumors by inhibiting the polarization of M2 macrophages. We investigated the relevance of M2 macrophage polarization and the anti-tumor effects of Pulsatilla saponins in vitro and in vivo. In vitro, Pulsatilla saponins could decrease the mRNA level of M2 marker genes Arg1, Fizz1, Ym1, and CD206, and the down-regulation effect of phosphorylated STAT6 induced by IL-4; moreover, the conditioned medium (CM) from bone marrow-derived macrophages (BMDM) treated with Pulsatilla saponins could inhibit the proliferation and migration of B16-F0 cells. In vivo, Pulsatilla saponins could reduce the number of lung metastasis loci, down-regulate the expression of M2 marker genes, and suppress the expression of phosphorylated STAT6 in tumor tissues. Furthermore, we used AS1517499 (AS), a STAT6 inhibitor, to verify the role of PS on M2 macrophage polarization both in vitro and in vivo. We found that Pulsatilla saponins failed to further inhibit STAT6 activation; the mRNA level of Arg1, Fizz1, Ym1, and CD206; and the proliferation and migration of B16-F0 cells after AS1517499 intervention in vitro. Similar results were obtained in vivo. These results illustrated that Pulsatilla saponins could effectively suppress tumor progress by inhibiting the polarization of M2 macrophages via the STAT6 signaling pathway; this revealed a novel mechanism for its anti-tumor activity.

Project description:BackgroundThe endoplasmic reticulum (ER) regulates critical processes, including lipid synthesis, which are affected by transmembrane proteins localized in the ER membrane. One such protein, transmembrane protein 147 (TMEM147), has recently been implicated for its role in hepatocellular carcinoma (HCC) tumorigenesis; however, the mechanisms remain unclear. We investigated the role of TMEM147 in HCC and the underlying mechanisms.MethodsTMEM147 expression was examined in human HCC cells and adjacent non-tumorous tissues using quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. In vitro and in vivo studies were conducted to investigate the impact of TMEM147 on the progression of HCC. Proteins interacting with TMEM147 were identified via RNA-seq, immunoprecipitation, and mass spectrometry analyses. Lipidomic analysis and enzyme-linked immunosorbent assay (ELISA) were employed to determine and analyze cholesterol and 27-hydroxycholesterol (27HC) contents. Extensive experimental techniques were used to study ferroptosis in HCC cells. The fatty acid content of macrophages affected by TMEM147 was quantified using ELISA. Macrophage phenotypes were determined using immunofluorescence assay and flow cytometric analysis.ResultsTMEM147 mRNA and protein levels were increased in HCC cells, and the increased TMEM147 expression was associated with a poor survival. TMEM147 promoted tumor cell proliferation and metastases in vitro and in vivo. The protein was found to interact with the key enzyme 7-dehydrocholesterol reductase (DHCR7), which affected cellular cholesterol homeostasis and increased the extracellular levels of 27HC in HCC cells. TMEM147 also promoted the expression of DHCR7 by enhancing the activity of signal transducer and activator of transcription 2. 27HC expression upregulated glutathione peroxidase 4 in HCC, leading to ferroptosis resistance and promotion of HCC proliferation. HCC cell-derived 27HC expression increased the lipid metabolism in macrophages and activated peroxisome proliferator-activated receptor-γ signaling, thereby activating M2 macrophage polarization and promoting HCC cell invasion and migration.ConclusionsOur results indicate that TMEM147 confers ferroptosis resistance and M2 macrophage polarization, which are primarily dependent on the upregulation of cellular cholesterol homeostasis and 27HC secretion, leading to cancer growth and metastasis. These findings suggest that the TMEM147/STAT2/DHCR7/27HC axis in the tumor microenvironment may serve as a promising therapeutic target for HCC.

Dataset Information

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

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

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