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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. MMP‐21 enhanced macrophage recruitment by upregulating CCL‐14 levels and promoted macrophage M2‐type polarization by increasing the expression of CSF‐1 and FGF‐1, and ultimately facilitated metastasis in HCC.

Fibroblast growth factor 1 (FGF-1) is a classical member of the FGF family and is produced by chondrocytes cultured from osteoarthritic patients. Also, this growth factor was shown to bind to CCN family protein 2 (CCN2), which regenerates damaged articular cartilage and counteracts osteoarthritis (OA) in an animal model. However, the pathophysiological role of FGF-1 in cartilage has not been well investigated. In this study, we evaluated the effects of FGF-1 in vitro and its production in vivo by use of an OA model. Treatment of human chondrocytic cells with FGF-1 resulted in marked repression of genes for cartilaginous extracellular matrix components, whereas it strongly induced matrix metalloproteinase 13 (MMP-13), representing its catabolic effects on cartilage. Interestingly, expression of the CCN2 gene was dramatically repressed by FGF-1, which repression eventually caused the reduced production of CCN2 protein from the chondrocytic cells. The results of a reporter gene assay revealed that this repression could be ascribed, at least in part, to transcriptional regulation. In contrast, the gene expression of FGF-1 was enhanced by exogenous FGF-1, indicating a positive feedback system in these cells. Of note, induction of FGF-1 was observed in the articular cartilage of a rat OA model. These results collectively indicate a pathological role of FGF-1 in OA development, which includes an insufficient cartilage regeneration response caused by CCN2 down regulation.

We studied the phenotypes in an oligodendrocyte genesis site at the acute stage of spinal cord injury, when we observed regenerated ascending neurites. Pan-oligodendrocyte marker OLIG2+ cells were more in fibroblast growth factor (FGF)-1-treated rats (F group) than in non-treated (T group) in this site, while the number of NG2+OX42− oligodendrocyte progenitor cell (OPC), CNPase+ OPC, Nkx2.2+ OPC, and APC+ remyelinating oligodendrocytes was less in the F group. Paradoxically, when we label the rats with pulsed bromodeoxyuridine (BrdU), we found that the mitotic NKX2.2+ OPC cells are more in the F group than in the T group. We tested the embryonic spinal cord mixed culture. FGF treatment resulted in more NG2(+) CNPase (+) than non-FGF-1-treated culture, while the more mature NG2(−) CNPase(+) cell numbers were reduced. When we block the FGF receptor in the injured rat model, the NG2+OX42− cell numbers were increased to be comparable to non-FGF-1 rats, while this failed to bring back the APC+ mature oligodendrocyte cell numbers. As migration of OPC toward injury is a major factor that was absent from the cell culture, we tested 8 mm away from the injury center, and found there were more NG2+ cells with FGF-1 treatment. We proposed that it was possibly a combination of migration and proliferation that resulted in a reduction in the NG2+ OPC population at the oligodendrocyte genesis site when FGF-1 was added to the spinal cord injury in vivo.

Immunotherapy mediated by recombinant antibodies is an effective therapeutic strategy for a variety of cancers. In a previous study, we demonstrated that the fibroblast growth factor 1 (FGF‐1)‐specific recombinant antibody scFv1C9 arrests the cell cycle at the G0/G1 transition by blocking the intracrine FGF‐1 pathway in breast cancer cells. Here, we further show that the overexpression of scFv1C9 in MCF‐7 and MDA‐MB‐231 breast cancer cells by lentiviral infection resulted in decreased tumourigenicity, tumour growth and lung metastasis through FGF‐1 neutralization. We found that scFv1C9 resulted in the up‐regulation of p21, which in turn inhibited the expression of CDK2 and blocked cell cycle progression. To explore the potential role of scFv1C9 in vivo, we delivered the gene into solid tumours by electroporation, which resulted in significant inhibition of tumour growth. In tumour tissue sections, immunohistochemical staining of the cellular proliferation marker Ki‐67 and the microvessel marker CD31 showed a reduction in the proliferative index and microvessel density, respectively, upon expression of scFv1C9 compared with the appropriate controls. Thus, our data indicate a central role for scFv1C9 in blocking the intracrine pathway of FGF‐1, therefore, scFv1C9 could be developed in an effective therapeutic for breast cancer.

In an attempt to find out a new molecular counterpart of CCN family protein 2 (CCN2), a matricellular protein with multiple functions, we performed an interactome analysis and found fibroblast growth factor (FGF) -1 as one of the candidates. Solid-phase binding assay indicated specific binding between CCN2 and FGF-1. This binding was also confirmed by surface plasmon resonance (SPR) analysis that revealed a dissociation constant (Kd) of 3.98 nM indicating strong molecular interaction between the two. RNA analysis suggested that both FGF-1 and CCN2 could be produced by chondrocytes and thus their interaction in the cartilage is possible. These findings for the first time indicate the direct interaction of CCN2 and FGF-1 and suggest the co-presence of these molecules in the cartilage microenvironment. CCN2 is a well-known promoter of cartilage development and regeneration, whereas the physiological and pathological role of FGF-1 in cartilage mostly remains unclear. Biological role of FGF-1 itself in cartilage is also suspected.

Fibroblast growth factor‐1 (FGF‐1) has both extra‐ and intracellular functions. To identify intracellular binding partners for FGF‐1, we isolated proteins from U2OS human osteosarcoma cells interacting specifically with FGF‐1. One of the isolated proteins was identified as protein kinase CK2 (CK2). We here provide evidence that FGF‐1 binds to both the catalytic α‐subunit and to the regulatory β‐subunit of CK2. The interaction between FGF‐1 and CK2α and β was characterized by surface plasmon resonance, giving K D values of 0.4 ± 0.3 and 1.2 ± 0.2 μM, respectively. By using a novel assay for intracellular protein interaction, FGF‐1 and CK2α are shown to interact in vivo. In vitro , FGF‐1 and FGF‐2 are phosphorylated by CK2, and the presence of FGF‐1 or FGF‐2 was found to enhance the autophosphorylation of CK2β. A correlation between the mitogenic potential of FGF‐1 mutants and their ability to bind to CK2α was observed. The possible involvement of CK2 in the FGF‐induced stimulation of DNA synthesis is discussed.

Externally added fibroblast growth factor‐1 (FGF‐1) is capable of crossing cellular membranes to reach the cytosol and the nucleus in a number of cell types. We have monitored the translocation of the growth factor by two methods: phosphorylation of FGF‐1, and prenylation of an FGF‐1 mutant that contains a C‐terminal prenylation signal. Inhibition of endosomal acidification by ammonium chloride or monensin did not block the translocation of FGF‐1, whereas bafilomycin A1, a specific inhibitor of vacuolar proton pumps, blocked translocation completely. A combination of ionophores expected to dissipate the vesicular membrane potential (valinomycin plus monensin) also fully inhibited the translocation. The inhibition of translocation by bafilomycin A1 was overcome in the presence of monensin or nigericin, while ouabain blocked translocation under these conditions. The data indicate that translocation of FGF‐1 to cytosol occurs from the lumen of intracellular vesicles possessing vacuolar proton pumps, and that a vesicular membrane potential is required. Apparently, activation of vesicular Na + /K + ‐ATPase by monensin or nigericin generates a membrane potential that can support translocation when the proton pump is blocked.