682

BSG

basigin (Ok blood group);BSG;basigin (Ok blood group)

CD147 antigen|OK blood group antigen|basigin|collagenase stimulatory factor|extracellular matrix metalloproteinase inducer|leukocyte activation antigen M6|tumor cell-derived collagenase stimulatory factor

19p13.3

protein-coding

OBJECTIVE: To investigate effects of P-glycoprotein (gp) substrate drugs on the expression of CD147 and MMP2 and 9 in multidrug resistant breast cancer cells. METHODS: MDR human breast cancer cell line, MCF7/AdrR, and its sensitive parental line, MCF7, were treated with various concentrations of P-gp substrate drugs, including paclitoxel and vincristine, and P-gp nonsubstrate drugs, bleomycin, in serum-free media. At the end of the treatment, expressions of CD147 and MMP2 and 9 were determined by real-time PCR and western blot. RESULTS: Increased expressions of CD147 and MMP2 and 9 were observed in multidrug resistant cancer cells compared with their parental MCF7 cells. After treatment with bleomycin, the expression of CD147 and MMP2 and 9 in both MCF7 and MCF7/AdrR cells remained unchanged (P > 0.05). However, treatment with paclitoxel and vincristine resulted in a remarkable over-expression of CD147 and MMP2 and 9 at both transcription and protein levels in MCF7/AdrR cell line (P < 0.05), while MCF7 cells failed to show similar response. CONCLUSIONS: P-gp substrate drugs can greatly upregulate the expression of CD147 and MMP2 and 9 in multidrug resistant breast cancer cells, therefore enhancing the tumor metastatic capability.

OBJECTIVE: To investigate the expression of CD147, matrix metalloproteinase (MMP)-2, MMP-9, Transforming growth factor (TGFbeta1) and TGFbetaRI proteins and their relationships to breast cancer. METHODS: The expression of CD147, MMP-2, MMP-9, TGFbeta1 and TGFbetaRI proteins was examined on tissue chips containing 160 cases of breast carcinomas by S-P immunohistochemical method. RESULTS: The positive rates of CD147, MMP-2, MMP-9, TGFbeta1 and TGFbetaRI proteins were 87.5% (140/160), 96.9% (155/160), 95.0% (152/160), 73.7% (118/160) and 60.6% (97/160), respectively. The expression of CD147 was positively correlated with axillary lymph node metastasis, TNM staging and HER2 over expression (P < 0.01, P < 0.05 and P < 0.01, respectively), and inversely correlated with PR expression (P < 0.05). The patients' relapse-free survival was shorter in TGFbeta1-positive group than in TGFbeta1 negative group (P < 0.05). Both the expression of MMP-2 and MMP-9 were positively correlated with CD147 expression; and both the expression of TGFbeta1 and TGFbetaRI were positively correlated with CD147 expression (P < 0.01 and P < 0.05, respectively). CONCLUSION: The expression of CD147 is considered closely correlated with tumor invasion, metastasis and prognosis in breast cancer, and has also a close correlation with MMP-2, MMP-9, TGFbeta1 and TGFbetaRI expression.

The aim of this study was to investigate expression of CD147 and MMP-9 in triple-negative breast cancer (TNBC) so as to determine whether these two proteins may be correlated with poor prognosis of TNBC patients. We examined the expression levels of the CD147 and MMP-9 in 127 patients with TNBC and 30 patients with mammary gland fibroma using immunohistochemical staining before any treatments. Furthermore, we analyzed the correlation between the expression of these two proteins and various clinicopathologic factors including survival status of patients with TNBC. Positive stain of CD147 and MMP-9 was observed in all samples of TNBC. A statistically positive correlation was observed between the expression levels of CD147 and MMP-9 in TNBC tissues. The incidences of high expression were 48.0 % for CD147 and 53.5 % for MMP-9 in 127 TNBC tissues, respectively. High expression of either CD147 or MMP-9 was significantly correlated with clinical feature and shorter progression-free survival (PFS) (P(CD147) = 0.039; P(MMP-9) = 0.017) and overall survival (OS) (P(CD147) = 0.037; P(MMP-9) = 0.023). The expression levels of CD147 and MMP-9 are positively correlated with invasion, metastasis and shorter PFS/OS of TNBC. Patients with high expression of CD147 and MMP-9 had poor prognosis than TNBC patients with low expression.

Breast cancer is the most common cancer in women for which the metastatic process is still poorly understood. CD147 is upregulated in breast cancer and has been associated with tumor progression, but little is known about its regulatory mechanisms. In this study, we demonstrated that CD147 was overexpressed in breast cancer tissues and cell lines, and the high expression correlated with tumor invasion and metastasis. We also found that the transcription factors Sp1 and c-Myc could bind to the CD147 promoter and enhance its expression. The CD147 mRNA has a 748-bp 3'-untranslated region (UTR) with many miRNA target sites, suggesting possible regulation by miRNAs. We discovered that miR-22 repressed CD147 expression by directly targeting the CD147 3'UTR. We also determined that miR-22 could indirectly participate in CD147 modulation by downregulating Sp1 expression. miR-22 could form an autoregulatory loop with Sp1, which repressed miR-22 transcription by binding to the miR-22 promoter. Together with the c-Myc-mediated inhibition of miR-22 expression, our investigation identified a miR-22/Sp1/c-Myc network that regulates CD147 gene transcription. In addition, miR-22 overexpression suppressed breast cancer cell invasion, metastasis, and proliferation by targeting CD147 in vitro and in vivo. Furthermore, we found that miR-22 was significantly downregulated in breast cancer tissues and that its expression was inversely correlated with the tumor-node-metastasis stage and lymphatic metastasis in patients. Our study provides the first evidence that an miR-22/Sp1/c-Myc network regulates CD147 upregulation in breast cancer and that miR-22 represses breast cancer invasive and metastatic capacities.

Aberrant glycosylation of cell surface glycoproteins is commonly associated with the invasion and metastasis of colorectal carcinomas, which can be attributed to the upregulated expression of glycosyltransferases. Therefore, elucidation of glycosyltransferases and their substrates may improve our understanding of their roles in tumor metastasis. beta-1,3-N-acetylglucosaminyltransferase-8 (beta3GnT8) is a key enzyme that catalyzes the formation of poly-N-acetyllactosamine (polylactosamine) chains on beta1,6-branched N-glycans in vitro, which is also involved in tumor invasion. In the present study, we analyzed the expression of beta3GnT8 and its product polylactosamine in four human colorectal carcinoma cell lines (LS-174T, SW620, SW480 and LoVo) with different metastatic potential. We found that the levels of beta3GnT8 and polylactosamine chains were gradually increased in the colorectal cancer cell lines in a trend from low to high metastatic potential. Notably, a significantly positive relationship between beta3GnT8 expression and HG-CD147 was noted in the colorectal cancer cell lines. To further investigate their relationships, exogenous beta3GnT8 was introduced into the LS-174T cells, while expression of beta3GnT8 was downregulated in the LoVo cells. The overexpression of beta3GnT8 in LS-174T cells increased the level of HG-CD147. Conversely, downregulation of beta3GnT8 expression in LoVo cells significantly decreased the expression of HG-CD147. HG-CD147 is a major carrier of beta1,6-branched polylactosamine sugars; therefore, the regulation of beta3GnT8 significantly altered the beta1,6-branched polylactosamine structures on CD147. Hence, we suggest that beta3GnT8 plays a key role in the metastasis of colorectal cancer cells by altering the beta1,6-branched polylactosamine sugars of CD147.

Matrix metalloproteinase 9 (MMP9) and CD147 play a role in invasion and metastasis of many types of human malignancies. The correlation of the expression of MMP9 and CD147 with invasion and metastasis of invasive squamous cell carcinoma (SCC) of the uterine cervix has not been examined. In the present study, RT-PCR assay was used to detect the expression level of MMP9 mRNA semiquantitatively, and immunohistochemical stain was adapted to evaluate the score of CD147 on the cell membrane or in the cytoplasm of tumor cells of 65 cases of invasive squamous cell carcinoma of the uterine cervix and 21 cases of chronic cervitis tissues. MMP9 and CD147 expression in correlation with invasion, metastasis, and differentiation of invasive SCC of the uterine cervix was analyzed statistically. We found that MMP9 and CD147 expression was elevated significantly in tumor tissue compared to the control (cervical epithelium of chronic cervitis) (P<0.01). In the comparison of MMP9 and CD147 expression in 47 cases with lymph node metastasis and 18 cases without lymph node metastasis, there was a significantly higher expression of MMP9 and CD147 in the group with lymph node metastasis (P<0.05 for MMP9, P<0.01 for CD147). MMP9 expression was significantly higher in 24 cases of poor differentiation than in 41 cases of moderate differentiation (P<0.05). No difference was found in CD147 expression between poor and moderate differentiation (P>0.05). No significant difference in MMP9 and CD147 expression levels was obtained between 26 cases of FIGO stage I tumors and 39 cases of stage II tumors (P>0.05 for MMP9, P>0.05 CD147). There was no correlation between MMP9 or CD147 expression levels and the resected tumor size (P>0.05). The positive correlation (r=0.568, P<0.001) of MMP9 expression and CD147 score was seen in the tumor tissues of 65 cases. The data in this study show that MMP9 and CD147 expression are correlated with invasion, metastasis of squamous cell carcinoma of the uterine cervix, and that MMP9 expression is correlated with poor differentiation of invasive squamous cell carcinoma of the uterine cervix.

AIM: To investigate whether the presence of CD147 and MMP-2 in cancerous gallbladder tissues might help us to predict the patients' prognosis. METHODS: Tissue samples from 168 patients with gallbladder carcinomas and 37 patients with chronic cholecystitis were stained with anti-CD147 and anti-MMP-2 antibodies for immunohistochemical analysis. Then, the association of their expression with clinicopathologic characteristics and 108 patients' prognosis was analyzed. RESULTS: CD147 and MMP-2 were detected mainly in cancerous tissues, but also expressed in some chronic cholecystitis patients. Out of 168 patients with gallbladder carcinoma 121 (72.02%) and 136 (80.95%) patients showed CD147 and MMP-2 positive expression, whereas the 37 patients with chronic cholecystitis only 5 (13.51%) and 3 (8.11%) patients expressed them, respectively. Pathologic findings demonstrated that the intensity of CD147 and MMP-2 staining in cancerous tissues was associated significantly with histological types (P = 0.03), distant metastasis (P < 0.01), and Nevin stages (P = 0.02) of gallbladder carcinomas. Using a proportional hazard model, the survival rate of the patients with CD147+/MMP-2+ expression was the lowest (P < 0.01), and including information on CD147 and MMP-2 staining patterns within cancerous tissues along with clinical cancer staging may improve the accuracy of predicting patients' prognosis. CONCLUSION: The results suggest that the expression of CD147 and MMP-2 may be an important feature of gallbladder carcinomas. The detection of these two markers combined with cancerous staging may increase the ability of investigators to predict the prognosis of patients with gallbladder carcinomas.

The signaling pathways facilitating metastasis of head and neck squamous cell carcinoma (HNSCC) cells are not fully understood. CD147 is a transmembrane glycoprotein known to induce cell migration and invasion. AGR2 is a secreted peptide also known to promote cell metastasis. Here we describe their importance in the migration and invasion of HNSCC cells (FADU and OSC-19) in vitro and in vivo. In vitro, knockdown of CD147 or AGR2 decreased cellular proliferation, migration and invasion. In vivo, knockdown of CD147 or AGR2 expression decreased primary tumor growth as well as regional and distant metastasis.

To assess the expression of COX-2,CD44v6 and CD147 in hypopharyngeal squamous cell carcinomas and the three biomarkers correlation with tumor invasion and lymph node metastasis of Chinese people. 101 cases of surgically excised primary tumor were included in this study, and 40 tissues of epithelium adjacent to carcinoma were used as controls. We characterized the immunohistochemical expression of COX-2, CD44v6, and CD147 in 141 formalin-fixed, paraffin-embedded tissues, and measured the mean optical density (OD) of the positive area to identify the expression of the three bio-markers and relationship with tumor invasion and lymph node metastasis. Our study demonstrates that the expression of the COX-2 and CD147 were significantly increased in carcinoma tissues compared to the epithelium adjacent to carcinoma. We also observed that the expression of COX-2, CD44v6, and CD147 were significantly associated with T classification, lymph node metastasis and clinical stage. There was strong significant correlation among the three biomarkers as well. Additionally, we indicated that recurrence and >/= P50 level of COX-2 expression had an independent prognostic effect on prognosis. In conclusion, the three biomarkers play important roles in tumor invasion and lymph node metastases and might be valuable indicators of tumor metastasis in hypopharyngeal squamous cell carcinoma.

Matrix metalloproteinases-2 (MMP-2, gelatinase A) has been regarded as a crucial enzyme for tumor progression, invasion, and metastasis by its capability to degrade the basement membrane components, and its activation process is critical for tumor development. Recently, EMMPRIN/CD147, which is a member of immunoglobulin superfamily, has been reported to be highly expressed in tumor cells and induce production of MMPs from fibroblasts adjacent to the tumor cells. In this study, we demonstrated that production of pro- and active forms of MMP-2 by human dermal fibroblasts was enhanced by the direct cell-cell contact with co-cultured HEp-2 cells derived from a human laryngeal epidermoid carcinoma. The results from immunoblotting and reverse transcription-polymerase chain reaction (RT-PCR) analysis indicated that HEp-2 cells express a higher level of EMMPRIN but only a low level of MMP-2 and membrane type 1-matrix metalloproteinase (MT1-MMP), whereas fibroblasts express a higher level of MMP-2 and MT1-MMP and a low level of EMMPRIN. In a mixed co-culture with direct cell-cell contacts, co-cultured HEp-2 cells stimulated the pro- and active MMP-2 production from fibroblasts, but not in a separated co-culture through polycarbonate membrane. Production of pro/active MMP-2 and MT1-MMP (activator of pro-MMP-2) in fibroblasts was induced by the addition of membrane fractions prepared from HEp-2 cells to the fibroblast culture, and the induction was suppressed by the EMMPRIN depletion after immunoprecipitation, signifying the participation of EMMPRIN for the induction and activation of MMP-2. Our results suggest an importance of the direct cell-cell interaction involving EMMPRIN rather than humoral factors such as cytokines for pro-MMP-2 production and activation followed by tumor progression, invasion, and metastasis in laryngeal cancer.

OBJECTIVE: To investigate the expressions of extracellular matrix metalloproteinase inducer (CD147), matrix metalloproteinases-2 (MMP-2) and matrix metalloproteinases-9 (MMP-9) in human laryngeal carcinoma and study their relationship with invasion, metastasis and prognosis. METHODS: The EnVision immunohistochemical method was used to detect the expressions of CD147, MMP-2 and MMP-9 in 48 cases of laryngeal carcinoma and 15 cases of laryngitis. The results were compared with their clinical pathological features and prognosis. RESULTS: The positive expression rates of CD147, MMP-2 and MMP-9 were significantly higher in laryngeal carcinoma than those in laryngitis (87.5%, 75.0%, 79.2% vs 26.7%, 6.7%, 33.3%); there was a positive correlation between a high-level expression of CD147, MMP-2, MMP-9 and clinical stage and the status of lymph node metastasis (P < 0.01); univariate analysis indicated that the overall survival rate was higher in patients with a negative expression of CD147, MMP-2, MMP-9 than those with a positive expression (83.3%, 83.3%, 90.0% vs 25.0%, 7.7%, 18.2%); multivariate analysis showed that MMP-9 was a risk predictor. A higher expression of MMP-9 was associated with a shorter survival time. CONCLUSION: CD147 and MMP-2 play a role in invasion and metastasis of laryngeal carcinoma; increased levels of MMP-2 and MMP-9 are induced by CD147 in laryngeal tumor cells; MMP-9 may be an independent prognostic factor.

AIM: To evaluate the relationship of expression of paxillin, syndecan-1 and EMMPRIN proteins with clinicopathological features in hepatocellular carcinoma (HCC). METHODS: Fifty-one patients who underwent HCC resection were recruited in the study. Paxillin, syndecan-1 and EMMPRIN proteins in HCC tissues were detected with immunohistochemical staining. RESULTS: Of 51 cases of HCC, 23 (45%) exhibited paxillin protein positive expression. Of 42 cases of adjacent non-tumor liver tissues, 24 (57%) exhibited positive expression. Positive paxillin protein expression was associated with low differentiation (r = 0.406, P = 0.004), with the presence of portal vein thrombosis (r = 0.325, P = 0.021), with extra-hepatic metastasis (r = 0.346, P = 0.014). Of 51 cases of HCC, 28 (55%) exhibited syndecan-1 protein positive expression. Of 42 cases of adjacent non-tumor liver tissues, 23 (55%) exhibited positive expression. Positive snydecan-1 protein expression was associated with well differentiation (r = 0.491, P = 0.001), with no extra-hepatic metastasis (r = 0.346, P = 0.014). Of 51 cases of HCC, 28 (55%) exhibited EMMPRIN protein positive expression. Of 42 cases of adjacent non-tumor liver tissues, 21 (50%) exhibited positive expression. expression of EMMPRIN protein was not associated with serum AFP level, HBsAg status, presence of microsatellite nodule, tumor size, presence of cirrhosis and necrosis, differentiation, presence of portal vein thrombosis, extra-hepatic metastasis, disease-free survival and overall survival (P>0.05). expression of paxillin protein was correlated conversely with the expression of syndecan-1 protein in HCC (r = -0.366, P = 0.010). CONCLUSION: expression of paxillin and syndecan-1 proteins in HCC may affect its invasive and metastatic ability of the tumor. There may be a converse correlation between the expression of paxillin and syndecan-1 protein in HCC. expression of EMMPRIN protein may be detected in HCC, but it may play little role in the invasion and metastasis of HCC.

CD147 molecule is reported to be correlated with the malignancy of some cancers; however, it remains unclear whether it is involved in the progression of hepatocellular carcinoma (HCC). Here, we investigated the function of HAb18G/CD147, a member of CD147 family, and its antibodies, HAb18 and LICARTIN, in HCC invasion and metastasis. We observed that HAb18G/CD147 gene silence in HCC cells significantly decreased the secretion of matrix metalloproteinase (MMP) and the invasive potential of HCC cells (P < 0.001). MMP silence in HCC cells also significantly suppressed the invasion of the cells when cocultured with fibroblasts; however, its inhibitory effect was significantly weaker than that of both HAb18G/CD147 silence in HCC cells and that of MMP silence in fibroblasts (P < 0.001). Blocking theHAb18G/CD147 molecule on HCC cells with HAb18 monoclonal antibody resulted in a similar suppressive effect on MMP secretion and cell invasion, but with no significant effects on the cell growth. (131)I-labeled HAb18 F(ab')(2) (LICARTIN), however, significantly inhibited the in vitro growth of HCC cells (P < 0.001). In an orthotopic model of HCC in nude mice, HAb18 and LICARTIN treatment effectively reduced the tumor growth and metastasis as well as the expression of three major factors in the HCC microenviroment (MMPs, vascular endothelial growth factor, and fibroblast surface protein) in the paracancer tissues. Overall, these results suggest that HAb18G/CD147 plays an important role in HCC invasion and metastasis mainly via modulating fibroblasts, as well as HCC cells themselves to disrupt the HCC microenviroment. LICARTIN can be used as a drug targeting to HAb18G/CD147 in antimetastasis and recurrence therapy of HCC.

Mechanism of HAb18G/CD147 underlying the metastasis process of human hepatoma cells has not been determined. In the present study, we found that integrin alpha3beta1 colocalizes with HAb18G/CD147 in human 7721 hepatoma cells. The enhancing effect of HAb18G/CD147 on adhesion, invasion capacities and matrix metalloproteinases (MMPs) secretion was decreased by integrin alpha3beta1 antibodies (p<0.01). The expressions of integrin downstream molecules including focal adhesion kinase (FAK), phospho-FAK (p-FAK), paxillin, and phospho-paxillin (p-paxillin) were increased in human hepatoma cells overexpressing HAb18G/CD147. Deletion of HAb18G/CD147 reduces the quantity of focal adhesions and rearranges cytoskeleton. Wortmannin and LY294002, specific phosphatidylinositol kinase (PI3K) inhibitors, reversed the effect of HAb18G/CD147 on the regulation of intracellular Ca(2+) mobilization, significantly reducing cell adhesion, invasion and MMPs secretion potential (p<0.01). Together, these results suggest that HAb18G/CD147 enhances the invasion and metastatic potentials of human hepatoma cells via integrin alpha3beta1-mediated FAK-paxillin and FAKPI3K-Ca(2+) signal pathways.

BACKGROUND: HAb18G/CD147 plays pivotal roles in invasion by hepatoma cells, but the underlying mechanism remains unclear. Our previous study demonstrated that overexpression of HAb18G/CD147 promotes invasion by interacting with integrin alpha3beta1. However, it has never been investigated whether alpha3beta1 is solely responsible for this process or if other integrin family members also interact with HAb18G/CD147 in human hepatoma cells. METHODS: Human SMMC-7721 and FHCC98 cells were cultured and transfected with siRNA fragments against HAb18G/CD147. The expression levels of HAb18G/CD147 and integrin alpha6beta1 were determined by immunofluorescent double-staining and confocal imaging analysis. Co-immunoprecipitation and Western blot analyses were performed to examine the native conformations of HAb18G/CD147 and integrin alpha6beta1. Invasion potential was evaluated with an invasion assay and gelatin zymography. RESULTS: We found that integrin alpha6beta1 co-localizes and interacts with HAb18G/CD147 in human hepatoma cells. The enhancing effects of HAb18G/CD147 on invasion capacity and secretion of matrix metalloproteinases (MMPs) were partially blocked by integrin alpha6beta1 antibodies (P < 0.01). Wortmannin, a specific phosphatidylinositol kinase (PI3K) inhibitor that reverses the effect of HAb18G/CD147 on the regulation of intracellular Ca2+ mobilization, significantly reduced cell invasion potential and secretion of MMPs in human hepatoma cells (P < 0.05). Importantly, no additive effect between Wortmannin and alpha6beta1 antibodies was observed, indicating that alpha6beta1 and PI3K transmit the signal in an upstream-downstream relationship. CONCLUSION: These results suggest that alpha6beta1 interacts with HAb18G/CD147 to mediate tumor invasion and metastatic processes through the PI3K pathway.

The chronic infection of hepatitis C virus (HCV) becomes a main factor evoking hepatocellular carcinoma, where the HCV core protein plays a central role in hepatocarcinogenesis. Whether the core protein directly contributes to metastasis of hepatocytes still remains to be reported in literature. Transwell chamber migration assay, Boyden chamber invasion assays and scanning electron microscopy observations were performed to determine the prometastatic ability of HCV core protein when expressed in human hepatocyte L02 cells. In addition, western blots, dual-luciferase assays, and chromatin immunoprecipitation assays were used to elucidate HCV core protein dependent pathways that promote metastasis in hepatocytes. Our investigation suggests that HCV core protein markedly enhances the capability of migration and invasion in L02 clones expressing HCV core proteins. The metastasis-promoting effect of the core protein is, in part, highly dependent on its effect on promoting the binding of transcription factor Sp1 to the extracellular matrix metalloproteinase inducer promoter. The effect of Sp1 binding resulted in an increase in extracellular matrix metalloproteinase inducer expression and progression of metastasis. Thus, we report that the expression of HCV core protein contributes to the metastasis of hepatocyte cells through activating transcription of extracellular metalloproteinase inducer.

BACKGROUND AND OBJECTIVE: It has been proven that CD147 was an extracellular matrix metalloproteinase inducer reportedly involved in the invasion and metastasis of malignancies. The aim of this study is to investigate CD147 and MMP-2 expression in squamous cell carcinoma and adenocarcinoma of the lungs and to analyze their clinical significance. METHODS: Tissue samples from 55 patients with squamous cell carcinoma and adenocarcinoma of the lungs and their corresponding non-cancerous tissues were examined for CD147 and MMP-2 expression using immunohistochemistry. RESULTS: The positive expression rates of CD147 and MMP-2 in the squamous cell carcinoma and adenocarcinoma among the lung tissues were significantly higher than those in the corresponding normal lung tissues. Moreover, the CD147 and MMP-2 expression in squamous cell carcinoma and adenocarcinoma of the lungs were related to lymph node metastasis and TNM stages (P<0.05), but not to age, gender and histologic type (P>0.05). MMP-2 expression was highly correlated with CD147 expression. CONCLUSIONS: CD147 and MMP-2 expression is correlated with the invasion and metastasis of squamous cell carcinoma and adenocarcinoma of the lungs and may be used as objective markers for predicting the behavior of squamous cell carcinoma and adenocarcinoma of the lungs.

CD147/basigin, a transmembrane protein belonging to the immunoglobulin super family, was originally cloned as a carrier of Lewis X carbohydrate antigen. CD147 is strongly related to cancer progression; it is highly expressed by various cancer cells including malignant melanoma (MM) cells and it plays important roles in tumor invasiveness, metastasis, cellular proliferation, and in vascular endothelial growth factor (VEGF) production, tumor cell glycolysis, and multi-drug resistance (MDR). CD147 on cancer cells induces matrix metalloproteinase expression by neighboring fibroblasts, leading to tumor cell invasion. In a nude mouse model of pulmonary metastasis from MM, the metastatic potential of CD147-expressing MM cells injected into the tail vein is abolished by CD147 silencing. CD147 enhances cellular proliferation and VEGF production by MM cells; it promotes tumor cell glycolysis by facilitating lactate transport in combination with monocarboxylate transporters, resulting in tumor progression. CD147 is responsible for the MDR phenotype via P-glycoprotein expression. These findings strongly suggest CD147 as a possible therapeutic target for overcoming metastasis and MDR, major obstacles to the effective treatment of malignant cancers.

tumor invasion and metastasis are multistep processes which require extracellular matrix remodeling by proteolytic enzymes such as matrix metalloproteinases (MMPs). The production of these enzymes is stimulated by many soluble or cell-bound factors. Among these factors, extracellular matrix metalloproteinase inducer (EMMPRIN) is known to increase in vitro stromal cell production of MMP-1, MMP-2 and MMP-3. In this study, we demonstrated that EMMPRIN-transfected MDA-MB-436 tumor cells displayed a more invasive capacity than vector-transfected cells in a modified Boyden chamber invasion assay. Using gelatin zymography and protein analyses, we showed that EMMPRIN-transfected cancer cells produced significantly more latent and active MMP-2 and MMP-3 than vector-transfected cancer cells. We found that EMMPRIN did not regulate MMP-1, MMP-9, membrane type-1 MMP (MT1-MMP) expression and had also no effect on the production of the specific tissue inhibitors of MMPs (TIMPs), TIMP-1 and TIMP-2. We also demonstrated that tumor-derived EMMPRIN stimulated MMP-1, -2, and -3 without modification of MMP-9, MT1-MMP, TIMP-1 and TIMP-2 production in human umbilical vein endothelial cells (HUVEC). These data provide support for the role of EMMPRIN in tumor invasion, metastasis, and neoangiogenesis by stimulating extracellular matrix remodeling around tumor cell clusters, stroma, and blood vessels.

BACKGROUND AND OBJECTIVE: It has been proven that CD147 was an extracellular matrix metalloproteinase inducer reportedly involved in the invasion and metastasis of malignancies. The aim of this study is to investigate CD147 and MMP-2 expression in squamous cell carcinoma and adenocarcinoma of the lungs and to analyze their clinical significance. METHODS: Tissue samples from 55 patients with squamous cell carcinoma and adenocarcinoma of the lungs and their corresponding non-cancerous tissues were examined for CD147 and MMP-2 expression using immunohistochemistry. RESULTS: The positive expression rates of CD147 and MMP-2 in the squamous cell carcinoma and adenocarcinoma among the lung tissues were significantly higher than those in the corresponding normal lung tissues. Moreover, the CD147 and MMP-2 expression in squamous cell carcinoma and adenocarcinoma of the lungs were related to lymph node metastasis and TNM stages (P<0.05), but not to age, gender and histologic type (P>0.05). MMP-2 expression was highly correlated with CD147 expression. CONCLUSIONS: CD147 and MMP-2 expression is correlated with the invasion and metastasis of squamous cell carcinoma and adenocarcinoma of the lungs and may be used as objective markers for predicting the behavior of squamous cell carcinoma and adenocarcinoma of the lungs.

OBJECTIVES: We evaluated the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase-2 (MMP-2) in nasopharyngeal carcinoma (NPC) and studied their relationship with cervical lymph node metastasis. METHODS: Immunohistochemical staining was used to detect the expression of EMMPRIN and MMP-2 in specimens from patients with chronic nasopharyngitis (CN), nonmetastastic NPC (NM-NPC), and lymph node-metastatic NPC (LNM-NPC). RESULTS: The rates of positive EMMPRIN expression in CN, NM-NPC, and LNM-NPC were 13.3%, 30.0%, and 66.7%, respectively. Significant differences were found between the rates in CN and LNM-NPC (p <0.01) and between the rates in NM-NPC and LNM-NPC (p = 0.01). In the LNM-NPC group, NPC cells had a higher rate of expression of EMMPRIN in tumor metastases than in the primary tumor (81.8% versus 66.7%; p = 0.01). The rates of positive MMP-2 expression in CN, NM-NPC, and LNM-NPC were 13.3%, 35.0%, and 60.6%, respectively. A significant difference was found between the rates in CN and LNM-NPC (p < 0.01). In the LNM-NPC group, NPC cells had a higher rate of MMP-2 expression in tumor metastases than in the primary tumor (72.7% versus 60.6%; p <0.01). The expressions of MMP-2 and EMMPRIN were highly correlated (rs = 0.466; p <0.01). CONCLUSIONS: Nasopharyngeal carcinoma cells may attain enhanced metastastic capability through the expression of MMP-2 induced by EMMPRIN.

OBJECTIVE: To investigate the expression of macrophage migration inhibitory factor (MIF) and extracellular matrix metalloproteinase inducer (CD147) in non-small cell lung cancer (NSCLC) and its metastatic lymph node with tissue microarray technique, and to reveal clinical significance of these two molecules expression in NSCLC. METHODS: MIF and CD147 proteins were detected in 40 cases of benign pulmonary tissues, 327 cases of primary NSCLC and 112 cases of lymph node metastatic tissues by SP method of immunohistochemical staining. RESULTS: The expression of both MIF and CD147 in benign pulmonary tissues, NSCLC primary foci and metastatic lymph node appeared upward tendency (P < 0.05). Furthermore, expression level of MIF and CD147 proteins in NSCLC were related to the metastasis (P < 0.05) and TNM staging (P < 0.05). The Spearman correlation analysis showed that the expression of MIF and CD147 was positively correlated (r = 0.400, P = 0.000). Kaplan-Meier survival analysis indicated that the survival rate was markedly lower in patients with high expression level of MIF or CD147 than those with low expression level (P < 0.05). Multivariate analysis using Cox regression model identified that pathologic grading, metastasis, TNM staging and CD147 expression were independent prognostic factors of NSCLC patients (P < 0.05). CONCLUSION: MIF and CD147 may play important roles in invasion and metastasis in NSCLC, so might be employed to evaluate the prognosis of NSCLC patients.

cancer metastasis and anti-cancer drug resistance are the major reason for the failure of clinical cancer treatment. We evaluated CD147, monocarboxylate transporters (MCT1 and MCT4), and multidrug resistance (MDR) markers (MDR1 and MRP2) in 4 epithelial ovarian cancer (EOC) cell lines and primary tumors (n = 120) along with the matched metastatic lesions (n = 40) with immunofluorescence labeling. We correlated CD147 with MCT1, MCT4, MDR1 and MRP2 markers in primary and metastatic cells in cell lines and tissues using confocal microscopy. We also investigated the relationship of expression of CD147, MCT1 and MCT4 with various progression parameters. Our results indicate that the co-expression of CD147 with MCTs or MDR markers was found in primary and metastatic EOC cells and stromal cells; the over-expression of CD147, MCT1 and MCT4 was found in most primary and the matched metastatic lesions of EOC, and was significantly associated with tumor stage, grade, residual disease status and presence of ascites (P < 0.05) but not with histology type (P > 0.05). These results suggest that over-expression of CD147, MCT1 and MCT4 is correlated with EOC progression, and co-expression of CD147 and MCT1/MCT4 is related to drug resistance during EOC metastasis and could be useful therapeutic targets to prevent the development of incurable, recurrent and drug resistance EOC.

Ovarian cancer, a gynecological malignancy, is the most common cause of death in older women worldwide. The overall 5-year survival of ovarian cancer patients is only 20% because of late diagnosis, as well as distant metastasis and multidrug resistance. Therefore, predictive and prognostic markers are urgently required for the early diagnosis of ovarian cancer. CD147, an extracellular matrix metalloproteinase inducer, is overexpressed in ovarian cancers. Current knowledge suggests that CD147 is associated with the survival and progression of ovarian cancer, and is considered as a biomarker of poor outcome. Here, we specifically review the roles of CD147 in ovarian cancer progression and discuss the diagnostic and prognostic value of CD147 in patients with ovarian cancer. CD147 promotes ovarian cancer progression by its involvement in every facet of malignancy, including invasion, metastasis, survival, angiogenesis, and drug resistance. Although it is not fully confirmed, the combination of CD147 with other biomarkers might be of diagnostic value.

BACKGROUND: Basigin, which has four isoforms, has been demonstrated to be involved in progression of various human cancers. The aim of this study was to examine the prognostic value of basigin-2 protein expression in epithelial ovarian cancer. Furthermore, the function of basigin-2 in ovarian cancer was further investigated in cell culture models. METHODS: Immunohistochemistry staining was performed to investigate basigin-2 expression in a total of 146 ovarian tissue specimens. Kaplan Meier analysis and Cox proportional hazards model were applied to assess the relationship between basigin-2 and progression-free survival (PFS) and overall survival (OS). Real-time PCR, RT-PCR and western blot were used to explore basigin-2, basigin-3 and basigin-4 expression in ovarian cancer cell lines and tissues. To evaluate possible contributions of basigin-2 to MMP secretion and cell migration and invasion, the overexpression vectors pcDNA3.1-basigin-2 and basigin-2 siRNA were transfected into HO-8910 and HO-8910 PM cells respectively. RESULTS: High basigin-2 expression was associated with lymph-vascular space involvement, lymph node metastasis and poor prognosis of epithelial ovarian cancer. Multivariate analyses indicated that basigin-2 positivity was an independent prognostic factor for PFS (P = 0.006) and OS (P = 0.019), respectively. Overexpression of basigin-2 increased the secretion of MMP-2/9 and cancer cell migration and invasion of HO-8910 cells, whereas knockdown of basigin-2 reduced active MMP-2/9 production, migration and invasion of HO-8910 PM cells. CONCLUSIONS: The expression of basigin-2 might be an independent prognostic marker and basigin-2 inhibition would be a potential strategy for epithelial ovarian cancer patients, especially in inhibiting and preventing cancer cell invasion and metastasis.

CD147, which belongs to the immunoglobulin superfamily, is a multifunctional glycoprotein that has been shown to increase tumor invasion, metastasis and multidrug resistance. To define the role of CD147 in invasion and metastasis more precisely, we utilized gene silencing to inhibit the expression of CD147 in pancreatic cancer cells. We observed that CD147 expression was significantly impeded at both the mRNA and protein levels and resulted in a decrease of MMP-2 and MMP-9 activities. There was also a decrease of MCT1 expression in the invasion and metastasis potential of pancreatic cancer cells, as well as increased chemosensitivity to gemcitabine in Panc-1 cells. Overall, these results suggest that CD147 plays an important role in the invasion, metastasis and chemosensitivity of the human pancreatic cancer cell line Panc-1, indicating that CD147 may be a promising therapeutic target for pancreatic cancer.

Novel molecular markers that are associated with prostate cancer (PCa) progression will provide valuable information in the diagnosis and treatment of the disease. Extracellular matrix metalloproteinase inducer (CD147) has been demonstrated to be involved in tumor invasion, metastasis, growth and survival. In our study, we examined whether the expression of CD147 can be used as a prognostic marker for predicting PCa progression. Tissue samples from 240 patients who received radical prostatectomy for PCa were obtained. CD147 expression in these samples was evaluated using immunohistochemical staining with a monoclonal antibody specifically against CD147. Increased expression of CD147 was correlated with higher Gleason scores (GS), positive surgical margin, prostate-specific antigen (PSA) failure, metastasis and reduced overall survival. Both univariate Cox regression analysis and multivariate analysis including competing biological variables demonstrated that increased CD147 expression was associated with increased risk for reduced PSA failure-free, metastasis-free and overall survival. Kaplan-Meier survival curves showed that the CD147 overexpression was a significant predictor for the PSA failure-free, metastasis-free and the overall survival in both pT2 and pT3 PCa patients. More significantly, higher expression of CD147 can serve as an independent prognostic predictor for PSA failure-free survival in PCa patients when they are stratified by GS. Our study results demonstrate the involvement of CD147 in PCa progression and suggest its potential role as an independent predictor of biochemical recurrence, development of metastasis and reduced overall survival in PCa.

CD44 and CD147 are associated with cancer metastasis and progression. Our purpose in the study was to investigate the effects of down-regulation of CD44 or CD147 on the metastatic ability of prostate cancer (CaP) cells, their docetaxel (DTX) responsiveness and potential mechanisms involved in vitro and in vivo. CD44 and CD147 were knocked down (KD) in PC-3M-luc CaP cells using short hairpin RNA (shRNA). expression of CD44, CD147, MRP2 (multi-drug resistance protein-2) and MCT4 (monocarboxylate tranporter-4) was evaluated using immunofluorescence and Western blotting. The DTX dose-response and proliferation was measured by MTT and colony assays, respectively. The invasive potential was assessed using a matrigel chamber assay. Signal transduction proteins in PI3K/Akt and MAPK/Erk pathways were assessed by Western blotting. An in vivo subcutaneous (s.c.) xenograft model was established to assess CaP tumorigenecity, lymph node metastases and DTX response. Our results indicated that KD of CD44 or CD147 decreased MCT4 and MRP2 expression, reduced CaP proliferation and invasive potential and enhanced DTX sensitivity; and KD of CD44 or CD147 down-regulated p-Akt and p-Erk, the main signal modulators associated with cell growth and survival. In vivo, CD44 or CD147-KD PC-3M-luc xenografts displayed suppressed tumor growth with increased DTX responsiveness compared to control xenografts. Both CD44 and CD147 enhance metastatic capacity and chemoresistance of CaP cells, potentially mediated by activation of the PI3K and MAPK pathways. Selective targeting of CD44/CD147 alone or combined with DTX may limit CaP metastasis and increase chemosensitivity, with promise for future CaP treatment.

Matrix metalloproteinase 9 (MMP9) and CD147 play a role in invasion and metastasis of many types of human malignancies. The correlation of the expression of MMP9 and CD147 with invasion and metastasis of invasive squamous cell carcinoma (SCC) of the uterine cervix has not been examined. In the present study, RT-PCR assay was used to detect the expression level of MMP9 mRNA semiquantitatively, and immunohistochemical stain was adapted to evaluate the score of CD147 on the cell membrane or in the cytoplasm of tumor cells of 65 cases of invasive squamous cell carcinoma of the uterine cervix and 21 cases of chronic cervitis tissues. MMP9 and CD147 expression in correlation with invasion, metastasis, and differentiation of invasive SCC of the uterine cervix was analyzed statistically. We found that MMP9 and CD147 expression was elevated significantly in tumor tissue compared to the control (cervical epithelium of chronic cervitis) (P<0.01). In the comparison of MMP9 and CD147 expression in 47 cases with lymph node metastasis and 18 cases without lymph node metastasis, there was a significantly higher expression of MMP9 and CD147 in the group with lymph node metastasis (P<0.05 for MMP9, P<0.01 for CD147). MMP9 expression was significantly higher in 24 cases of poor differentiation than in 41 cases of moderate differentiation (P<0.05). No difference was found in CD147 expression between poor and moderate differentiation (P>0.05). No significant difference in MMP9 and CD147 expression levels was obtained between 26 cases of FIGO stage I tumors and 39 cases of stage II tumors (P>0.05 for MMP9, P>0.05 CD147). There was no correlation between MMP9 or CD147 expression levels and the resected tumor size (P>0.05). The positive correlation (r=0.568, P<0.001) of MMP9 expression and CD147 score was seen in the tumor tissues of 65 cases. The data in this study show that MMP9 and CD147 expression are correlated with invasion, metastasis of squamous cell carcinoma of the uterine cervix, and that MMP9 expression is correlated with poor differentiation of invasive squamous cell carcinoma of the uterine cervix.

BACKGROUND AND OBJECTIVE: It has been proven that CD147 was an extracellular matrix metalloproteinase inducer reportedly involved in the invasion and metastasis of malignancies. The aim of this study is to investigate CD147 and MMP-2 expression in squamous cell carcinoma and adenocarcinoma of the lungs and to analyze their clinical significance. METHODS: Tissue samples from 55 patients with squamous cell carcinoma and adenocarcinoma of the lungs and their corresponding non-cancerous tissues were examined for CD147 and MMP-2 expression using immunohistochemistry. RESULTS: The positive expression rates of CD147 and MMP-2 in the squamous cell carcinoma and adenocarcinoma among the lung tissues were significantly higher than those in the corresponding normal lung tissues. Moreover, the CD147 and MMP-2 expression in squamous cell carcinoma and adenocarcinoma of the lungs were related to lymph node metastasis and TNM stages (P<0.05), but not to age, gender and histologic type (P>0.05). MMP-2 expression was highly correlated with CD147 expression. CONCLUSIONS: CD147 and MMP-2 expression is correlated with the invasion and metastasis of squamous cell carcinoma and adenocarcinoma of the lungs and may be used as objective markers for predicting the behavior of squamous cell carcinoma and adenocarcinoma of the lungs.

BACKGROUND: Extracellular matrix metalloproteinase inducer (EMMPRIN) is identified as a tumor-cell membrane protein that stimulates matrix metalloproteinases (MMPs) production. Several studies have shown that higher EMMPRIN expression is associated with shorter survival time and correlated significantly with more advanced clinico-parameters of cancer. The aim of this study was to investigate the relationship between clinico-pathologic characteristics and EMMPRIN, and prognostic significance of EMMPRIN expression in human tongue squamous cell carcinoma. METHODS: Extracellular MMP inducer expression was examined immunohistochemically on paraffin-embedded tissue specimens from 68 patients with tongue squamous cell carcinoma and who underwent radical surgeries from 1996 to 2006. The 68 patients were followed up from 1 to 119 months, with an average of 27.5 months. Nonparametric tests were performed for the comparison of EMMPRIN expression between two independent groups. Survival analysis was performed to find the prognostic significance of EMMPRIN expression. RESULTS: We found that EMMPRIN expression in tongue squamous cell carcinoma is significantly higher than that in non-cancerous epithelium adjacent to carcinoma of tongue. In addition, EMMPRIN expression is significantly associated with tumor diameter and clinical stage in the samples, but did not correlate with gender, age, tumor metastasis, and pathological grade. Finally, survival analysis indicates that EMMPRIN overexpression correlates significantly with poor overall survival in the patient cohort. CONCLUSION: These results suggest that EMMPRIN might represent an attractive target for immunotherapeutic approaches in a subgroup of patients with tongue squamous cell carcinoma.

AIMS: We evaluated the association of ligand cyclophilin A (CypA) and receptor CD147 with hypoxia, angiogenesis, lymph node metastasis and prognosis of patients with tongue squamous cell carcinoma (TSCC). METHODS AND RESULTS: We studied the expression of CypA, CD147, hypoxia-inducible factor 1alpha (HIF-1alpha), vascular endothelial growth factor A and C (VEGF-A and VEGF-C) protein by immunohistochemistry in 80 specimens of TSCC. CypA, CD147, HIF-1alpha, VEGF-A and VEGF-C were overexpressed in TSCCs, and were significantly higher than those in normal oral mucosa tissues (P<0.01). Increased ligand CypA and receptor CD147 correlated significantly with expression of HIF-1alpha, VEGF-A and VEGF-C. A significant relationship between VEGF-A and VEGF-C was also detected (P<0.01). Patients with overexpression of CypA, CD147, HIF-1alpha and VEGF-C had significantly worse overall survival (P<0.05) using Kaplan-Meier analysis. Multivariate Cox regression analysis showed that HIF-1alpha, recurrence and distant metastasis were independent prognostic factors on overall survival in TSCC patients. CONCLUSIONS: The association of expression of ligand CypA and receptor CD147 with carcinogenesis, hypoxia, angiogenesis, metastasis and prognosis of TSCC suggests that ligand CypA and receptor CD147 may have prognostic value and could be regarded as potential therapeutic targets in TSCC.