A Null Mutation in Basigin, an Immunoglobulin Superfamily Member, Indicates Its Important Roles in Peri-implantation Development and Spermatogenesis

EMMPRIN is a transmembrane glycoprotein expressed at high levels by tumor cells. It has been identified as a tumor-derived factor that can stimulate matrix metalloproteinase expression in fibroblasts and hence facilitate tumor invasion and metastasis. Recent studies have shown that full-length EMMPRIN is released by tumor cells, but the mechanism of release remains unclear. Here, we show that EMMPRIN is released from the surface of NCI-H460 cells via microvesicle shedding. However, these vesicles are unstable and rapidly break down to release bioactive EMMPRIN. Although microvesicle shedding has been considered a constitutive process in tumor cells, our data show that it can be amplified upon cell exposure to PMA, elucidating at least one signalling cascade responsible for EMMPRIN release. This pathway is dependent on protein kinase C, calcium mobilization and mitogen-activated protein kinase kinase (MEK 1/2). Thus, the results outline a novel form of tumor-stromal interaction in which extracellular matrix degradation by fibroblasts is controlled through the microvesicular release of EMMPRIN from tumor cells.

The microvesicle as a vehicle for EMMPRIN in tumor-stromal interactions.

Basigin (Bsg) is a transmembrane glycoprotein with two immunoglobulin-like domains, and forms a family with embigin and neuroplastin In these proteins a conserved glutamic acid is present in the middle for the transmembrane domain Bsg is also called CD147 and EMMPRIN, and the symbol for the human basigin gene is BSG BSG is located in chromosome 19 band p13 3 Knockout mice deficient in the Bsg gene are sterile and show various neurological abnormalities Bsg-deficient embryos are also difficult to implant Bsg has been found to participate in the cell-surface orientation of monocarboxylic acid transporters (MCTs) to the plasma membrane Dysfunction of the retina in Bsg-deficient mice is ascribed to the failure of plasma membrane integration of MCTs in the tissue Bsg is also involved in inflammatory processes and is proposed to be a receptor of cyclophilin A; it is also likely to participate in HIV infection Bsg in tumor cells triggers the production or release of matrix metalloproteinases in the surrounding mesenchymal cells and tumor cells, thereby contributing to tumor invasion Furthermore, the association of Bsg with integrins might be important in signaling through Bsg

https://digitum.um.es/digitum/bitstream/10201/21468/1/Basigin%20CD147%20a%20multifunctional.pdf

Basigin (CD147): a multifunctional transmembrane protein involved in reproduction, neural function, inflammation and tumor invasion

Emmprin (basigin;CD147) is a widely distributed cell surface glycoprotein that belongs to the Ig superfamily and is highly enriched on the surface of malignant tumour cells. Emmprin is involved in numerous physiological and pathological systems and exhibits several molecular and cellular characteristics, but a major function of emmprin is stimulation of synthesis of several matrix metalloproteinases. In tumours, emmprin most likely stimulates matrix metalloproteinase production in stromal fibroblasts and endothelial cells as well as in tumour cells themselves by a mechanism involving homophilic interactions between emmprin molecules on apposing cells or on neighbouring cells after membrane vesicle shedding. Membrane-associated cofactors, including caveolin-1 and annexin II, regulate emmprin activity. Emmprin induces angiogenesis via stimulation of VEGF production, invasiveness via stimulation of matrix metalloproteinase production and multidrug resistance via hyaluronan-mediated up-regulation of ErbB2 signaling and cell survival pathway activities. Although the detailed mechanisms whereby it regulates these numerous phenomena are not yet known, it is clear that emmprin is a major mediator of malignant cell behavior.

Roles of the multifunctional glycoprotein, emmprin (basigin; CD147), in tumour progression.

CD147 immunoglobulin superfamily receptor function and role in pathology

Granulocyte and monocyte adsorptive apheresis (GMA) using a column filled with cellulose acetate (CA) beads (carriers) has been associated with a significant clinical efficacy in patients with rheumatoid arthritis and ulcerative colitis. To obtain further understanding on the mechanisms of disease modification by cellulose acetate-carrier-based GMA, in the present study, we investigated the mechanisms of granulocyte and monocyte adhesion to CA beads following exposure of human peripheral blood to the carriers at 37 degrees C for up to 60 min under controlled conditions. Cellulose acetate beads selectively adsorbed granulocytes, monocytes. CD19+ (B cells) and CD56+ (NK cells) lymphocyte subpopulations. The granulocyte and monocyte adsorption was inhibited by heat-inactivated plasma and EDTA, indicating that the adsorption was plasma protein (immunoglobulin, complement) and calcium dependent. Accordingly, granulocyte and monocyte adsorption was markedly enhanced by coating the carriers with IgG. Similarly, C3b was adsorbed onto the CA beads as a marker of complement activation. The results indicated that IgG and active complement fragments mediated leukocyte adhesion to CA beads via the FcgammaR and/or leukocyte complement receptor like CR3. Additionally, CA beads induced loss of expression of TNF receptors on CD16- granulocytes and CD14+ monocytes, but not on CD3+ lymphocytes In conclusion, CA beads might be an appropriate biomaterial for inducing extracorporeal immunomodulation as a treatment for auto-immune diseases which are associated with pathological leukocyte activity.

Studies on the mechanisms of leukocyte adhesion to cellulose acetate beads : an in vitro model to assess the efficacy of cellulose acetate carrier-based granulocyte and monocyte adsorptive apheresis

Basigin is a membrane glycoprotein belonging to the immunoglobulin superfamily. The mouse basigin gene was isolated from a genomic DNA library of the BALB/c mouse, and the structure of the gene and its flanking region (11.8 kb) was completely determined. The mouse basigin gene consists of seven exons and six introns spanning 7.5 kb. The distance between the first and second exons is 5.1 kb. The first immunoglobulin-like domain of the basigin molecule is encoded by the second and third exons, and the second immunoglobulin-like domain by the fourth and fifth exons. The fifth exon encodes not only the C proximal portion of the second immunoglobulin-like domain, but also the transmembrane domain and a small portion of the cytoplasmic domain. Thus, the organization of the basigin gene is unique. The 5' upstream sequence of the basigin gene contains no TATA box or CAAT box, but has a CpG-rich island. The BALB/c genomic sequence of all seven exons is consistent with the cDNA sequences of the 129/SV and Swiss mice except several minor substitutions in the 3'-terminal sequence of the 3'-noncoding region. No protein polymorphism has so far been found in basigin of different mouse strains.

Structure of the Mouse Basigin Gene, a Unique Member of the Immunoglobulin Superfamily

The Japanese apricot “Prunus mume,” which is also known as the Ume fruit in Japan, is a centuries-old traditional Japanese medicine, and it is a commonly consumed food. MK615, a compound extract from Ume fruits, has been shown to have anti-tumor and anti-inflammatory effects. In this study, we assessed the effects of MK615 on the in vitro growth of nine non-small cell lung cancer (NSCLC) cell lines and the HBEC4 immortalized bronchial epithelial cell line. While MK615 inhibited the in vitro cell growth of the majority of the NSCLC cell lines, the growthinhibitory effects varied among the cell lines, and some cell lines exhibited MK615 resistance. In the H1299 and H157 NSCLC cell lines that are highly sensitive to MK615, the induction of autophagy was observed after MK615 treatment. In addition, cell-cycle analysis showed that MK615 increased the proportion of cells in the G0-G1 phase in H1299 and H157 cells. In H1792 cells that overexpress IL-8, MK615 down-regulated IL-8 expression at the mRNA and protein levels in a dose-dependent manner. These results suggest that MK615 has multiple anti-tumor activities including the inhibition of cell proliferation, autophagy induction, G0-G1 cell cycle arrest and the downregulation of IL-8 expression in NSCLC cells.

https://www.hilarispublisher.com/open-access/mk615-compound-extract-from-japanese-apricot-prunus-mume-inhibits-in-vitro-cell-growth-and-interleukin-8-1948-5956.S11-002.pdf

MK615, A Compound Extract from the Japanese Apricot "Prunus mume" Inhibits In vitro Cell Growth and Interleukin-8 Expression in Non-small Cell Lung Cancer Cells

The complement system has been proposed to play a significant role in the regulation of T-cell responses. However, the precise mechanism underlying C4-induced immune tolerance remains to be clarified. We recently reported that monomeric C4b inhibits CXCL10 production from blood cells. The purpose of this study was to verify the active site of monomeric C4b. We investigated the in vitro effects of a C4b-derived peptide (VPAGSARPVAFSVVPTAAA), named HP2 (highly homologous peptide 2), on the IFN-β-induced production of CXCL10 in human blood and the in vivo effects of the administration of HP2 on Th1/2 cytokine production in the spleen in mice. We also tested whether the administration of HP2 influences symptoms of experimentally induced ulcerative colitis in mice. HP2 inhibited CXCL10 production in human blood, and the administration of HP2 significantly suppressed the production of Th1 cytokines, such as IL-2, IFN-γ, and TNF-α, in spleen cells isolated from mice. The administration of HP2 in the mice significantly improved the symptoms of colitis, with down-regulation of colitogenic CD4+CD45RBhigh T cells and up-regulation of CD4+LAP/TGF-β1+ T cells. The amino acid sequence described above is suggested to be the active site in C4b for the inhibition of Th1 cytokine production. These results should contribute to the development of new drugs suppressing autoimmune responses.

Suppression of Th1 cytokine production by a peptide derived from C4b

Basigin is a member of the immunoglobulin (Ig) superfamily which has strong homology with both Ig Vκ domain and the β-chain of the major histocompatibility complex (MHC) class II antigen. Human basigin is also known as M6 antigen, neurothelin and EMMPRIN (extracellular matrix metalloproteinase inducer). In this study, we developed a novel anti-human basigin monoclonal antibody, J-BIT-1 and used it to map out the distribution of basigin in human tissues. The specificity of J-BIT-1 was confirmed by western blot analysis and immunocytochemical techniques utilizing basigin cDNA transfected L cells. J-BIT-1 appropriated to immunohistochemical staining for formalin-fixed, paraffin-embedded tissues and methanol-fixed cells. Excellent immunostaining results were obtained with formalin-fixed tissues after the antigen retrieval procedure. Our immunohistochemical observations revealed that basigin is widely expressed in various organs, but on specific cell types, such as blood capillaries of the brain, proximal convoluted tubules of the kidney, cardiac muscle of the heart, trophoblasts of the placenta and basal cells of the stratified squamous epithelium. The location of basigin is the cell surface, especially the site of cell adhesion. These observations suggest that basigin might be involved in basic cell functions which are promoted with cell-cell and cell-extracellular matrix interaction.

Fumie Jimma

Papers

Studies on the mechanisms of leukocyte adhesion to cellulose acetate beads : an in vitro model to assess the efficacy of cellulose acetate carrier-based granulocyte and monocyte adsorptive apheresis

Structure of the Mouse Basigin Gene, a Unique Member of the Immunoglobulin Superfamily

MK615, A Compound Extract from the Japanese Apricot "Prunus mume" Inhibits In vitro Cell Growth and Interleukin-8 Expression in Non-small Cell Lung Cancer Cells

Suppression of Th1 cytokine production by a peptide derived from C4b

Immunohistochemical Distribution of Human Basigin by Using a Novel Monoclonal Antibody