Expression Of Extracellular Matrix Metalloproteinase Inducer Research Articles

Pro-inflammatory activities induced by CyPA–EMMPRIN interaction in monocytes

Excessive reactive oxygen species (ROS) is a critical driver of vascular inflammation in atherosclerosis. Cyclophilin A (CyPA) is the main ROS-induced factor that enhances the inflammatory activity of monocytes/macrophages in atherosclerotic plaque. However, the means by which CyPA interacts with monocytes/macrophages is unclear. Through Chemotaxis assay and ELISA test, we found CyPA strongly induced migration of monocytes and the expression of mmp-9, IL-6 and TNF-alpha. By Western blot, it demonstrated that CyPA activated NF-kappaB by ERK1/2 pathway. When blocking extracellular matrix metalloproteinase inducer (EMMPRIN) in monocytes, most of the CyPA effects including chemoattractant migration, activation of MAPK/NF-kappaB and cytokines releasing were significantly inhibited. Finally, CyPA simulation had no effect on EMMPRIN expression in monocytes. The current study shows that CyPA–EMMPRIN interaction is one of the key pro-inflammatory signaling pathways in monocytes, perhaps especially in response to ROS stimulation. This could be a potential target for atherosclerosis therapy.

Anti-EMMPRIN antibody treatment of head and neck squamous cell carcinoma in an ex-vivo model

Targeting the molecular pathways associated with carcinogenesis remains the greatest opportunity to reduce treatment-related morbidity and mortality. Extracellular matrix metalloproteinase inducer (EMMPRIN), also known as CD147, is a cell surface molecule known to promote tumor growth and angiogenesis in preclinical studies of head and neck carcinoma making it an excellent therapeutic target. To evaluate the feasibility of anti-EMMPRIN therapy, an ex-vivo human head and neck cancer model was established using specimens obtained at the time of surgery (n=22). Tumor slices were exposed to varying concentrations of anti-EMMPRIN monoclonal antibody and cetuximab for comparison purposes. Cetuximab is the only monoclonal antibody currently approved for the treatment of head and neck carcinoma. After treatment, tumor slices were assessed by immunohistochemistry and western blot analysis for apoptosis (TUNEL) and EMMPRIN expression. Of the tumor specimens 33% showed a significant reduction in mean ATP levels after treatment with cetuximab compared with untreated controls, whereas 58% of the patients responded to anti-EMMPRIN therapy (P<0.05). Samples, which showed reactivity to anti-EMMPRIN, also had greater EMMPRIN expression based on immunohistochemistry staining (49%) when compared with nonresponders (25%, P=0.06). In addition, TUNEL analysis showed a larger number of cells undergoing apoptosis in antibody-treated tumor slices (77%) compared with controls (30%, P<0.001) with activation of apoptotic proteins, caspase 3 and caspase 8. This study shows the potential of anti-EMMPRIN to inhibit proliferation and promote apoptosis and suggests its future role in the targeted treatment of head and neck carcinoma.

Expression of EMMPRIN in adenoid cystic carcinoma of salivary glands: Correlation with tumor progression and patients’ prognosis

Extracellular matrix metalloproteinase inducer (EMMPRIN) plays a critical role in the progression of malignancies by stimulating expression of metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) in stromal cells. However, the expression of EMMPRIN in adenoid cystic carcinoma (ACC) of salivary glands, and its correlation with patients' prognosis have never been investigated thus far. In the present study, the expression of EMMPRIN was examined in 72 ACCs and 20 normal salivary gland tissues by immunohistochemistry. The expression of MMP-2, MMP-9, VEGF, Ki-67 index, and microvessel density (MVD) labeled by CD31 were also assessed by immunohistochemistry in ACCs. The positivity of EMMPRIN in ACCs was 62.5%, which was significantly higher than that in normal salivary gland tissues (P<0.01). EMMPRIN expression was positively correlated with tumor size, histotypes, clinical stage, perineural invasion, vascular invasion, metastasis, expression of MMP-2, MMP-9, VEGF, Ki-67 index, and MVD (P<0.05), but not with gender, age, tumor site or recurrence (P>0.05). Multivariate analysis showed that EMMPRIN expression, Ki-67 index, and solid histotype had an independent prognostic effect on overall survival (P<0.05). According to our findings, EMMPRIN might actively be involved in the growth, angiogenesis, invasion and metastasis of ACCs. Measurement of EMMPRIN may be helpful in predicting patients' prognosis and understanding the malignant behaviors of ACCs.

Extracellular matrix metalloproteinase inducer expression in the baboon endometrium: menstrual cycle and endometriosis

Extracellular matrix metalloproteinase inducer (EMMPRIN; BSG) regulates tissue remodeling through matrix metalloproteinases (MMPs). In human and non-human primates, endometrial remodeling is important for menstruation and the pathogenesis of endometriosis. We hypothesized that as in humans, BSG and MMPs are expressed in the endometrium of cycling baboons, and their expression is hormonally regulated by ovarian hormones, but endometriosis disrupts this regulation. BSG expression was evaluated in the baboon endometrium by q-PCR and immunohistochemistry. In the endometrium of control cycling animals, BSG mRNA levels were highest in late secretory stage tissue. BSG protein localized to glandular epithelial cells during the proliferative phase; whereas, secretory stage tissues expressed BSG in glandular and luminal epithelia with weak stromal staining. Several MMPs were differentially expressed throughout the menstrual cycle with the highest levels found during menstruation. In ovariectomized animals, BSG endometrial mRNA levels were highest with treatment of both estrogen and progesterone than that with only estrogen. Estrogen alone resulted in BSG protein localization primarily in the endometrial glandular epithelia, while estrogen and progesterone treatment displayed BSG protein localization in both the glandular and stromal cells. Exogenous hormone treatment resulted in differential expression patterns of all MMPs compared with the control cycling animals. In the eutopic endometrium of endometriotic animals, BSG mRNA levels and protein were elevated early but decreased later in disease progression. Endometriosis elevated the expression of all MMPs except MMP7 compared with the control animals. In baboons, BSG and MMP endometrial expression is regulated by both ovarian hormones, and their expression patterns are dysregulated in endometriotic animals.

Receptor Activator of NF-κB Ligand Enhances Breast Cancer–Induced Osteolytic Lesions through Upregulation of Extracellular Matrix Metalloproteinase Inducer/CD147

Breast cancer shows a strong predilection to metastasize to bone. Cell surface glycoprotein extracellular matrix metalloproteinase inducer (EMMPRIN)/CD147 induces metalloproteinases (MMP) and vascular endothelial growth factor (VEGF), which may support osteoclastic activity and increased incidence of breast cancer bone metastases. In support of this hypothesis, we observed that MDA-MB-231 human breast tumor cells engineered to overexpress EMMPRIN strongly induced osteolytic lesions in immunodeficient mice, which was blunted by in vivo treatment with an EMMPRIN blocking antibody. Similarly, these cells exhibited increased expression of MMP-9 and VEGF relative to control cells. Treatment of MDA-MB-231 cells with the osteoclastogenic cytokine receptor activator of NF-kappaB ligand (RANKL) upregulated EMMPRIN expression with a parallel increase of MMP-9 and VEGF. Conditioned medium from osteoblasts similarly increased EMMPRIN, MMP-9, and VEGF expression in cells. Osteoblast treatment with the RANKL decoy receptor osteoprotegerin abolished this effect. EMMPRIN overexpression stimulated MDA-MB-231 cell invasion but not proliferation. Conversely, small interfering RNA-mediated knockdown of EMMPRIN downregulated MMP-9 and VEGF basal expression and RANKL-stimulated expression, and reduced cell invasion. Our results argue that EMMPRIN drives breast cancer-induced osteolytic lesions and that activation of the RANKL pathway increases EMMPRIN in osteotropic tumor cells, in turn enhancing tumor-induced bone resorption.

EMMPRIN (CD147)

In 50% of all cases, bladder cancer patients develop tumor progression despite modern surgical methods such as radical cystectomy. A solution to the problem might be the identification and understanding of molecular biomarkers which could result in the development of advanced methods with better preventive, diagnostic, and therapeutic potential. One suitable approach is the identification of a bladder cancer-specific molecular marker in order to enhance patients' outcome. We and others have identified EMMPRIN as a prognostic biomarker in a variety of tumor diseases. EMMPRIN (CD147, extracellular matrix metalloproteinase inducer) is a cell surface protein that is expressed among other cell types, in particular in tumor cells. Since its first description in 1982 it is established that overexpression of EMMPRIN correlates with tumor progression and patient outcome. EMMPRIN expression levels can be used as an independent prognostic factor for survival. Recently, EMMPRIN has been defined as a potential target for tumor therapy in preclinical studies.

The effect of the expression of angiotensin II on extracellular matrix metalloproteinase inducer (EMMPRIN) in macrophages is mediated via the AT1/COX-2/PGE2 pathway

To explore the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) in THP-1 macrophages induced by angiotensin II (Ang II) and the mechanism of EMMPRIN expression. THP-1 cells were cultured and induced into macrophages, then stimulated with 10(-6) mol/L Ang II. Levels of EMMPRIN gene and its protein were measured by real-time polymerase chain reaction and western blotting. Prostaglandin E(2) (PGE(2)) expression was assayed by enzyme-linked immunosorbent assay. Antagonists of the angiotensin type-1 receptor (AT(1)R) and angiotensin type-2 receptor (AT(2)R) were used to inhibit the effect of Ang II, and PGE(2) added to detail the mechanism of Ang II-induced EMMPRIN expression. Ang II clearly induced the expression of EMMPRIN mRNA and protein in macrophages; this expression peaked at 12 h and declined after 24 h. The tendency of enhancement of the levels of cyclooxygenase-2 (COX-2) and PGE(2) was coincident with EMMPRIN expression. AT(1)-receptor antagonists and COX-2 inhibitors inhibited the effect of Ang II, but AT(2)-receptor antagonists did not. Ang II can up-regulate EMMPRIN expression in THP-1 macrophages via the AT(1)/COX-2/PGE(2) signal transduction pathway, and the effect can be inhibited by losartan and NS-398.

EMMPRIN activates multiple transcription factors in cardiomyocytes, and induces interleukin-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-κB andMKK7/JNK/AP-1 signaling

The transmembrane glycoprotein extracellular matrix metalloproteinase inducer (EMMPRIN), and the pleiotropic proinflammatory cytokine interleukin (IL)-18, play critical roles in myocardial remodeling, by inducing matrix degrading metalloproteinases (MMPs). Previously we showed that IL-18 induces EMMPRIN expression in cardiomyocytes via MyD88/IRAK4/TRAF6/JNK-dependent Sp1 activation. Here in reciprocal studies we demonstrate that EMMPRIN is a potent inducer of IL-18 transcription, protein expression and protein secretion in primary mouse cardiomyocytes. We show for the first time that EMMPRIN stimulates the activation of NF-κB, AP-1, CREB, and ATF-2 in cardiomyocytes, and induces IL-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-κB and MKK7/JNK/AP-1 signaling. Moreover, EMMPRIN induces robust time-dependent induction of various MMP mRNAs. EMMPRIN also induces the mRNA of TIMPs 1 and 3, but in a delayed fashion. These results suggest that IL-18-induced EMMPRIN expression may favor net MMP expression and ECM destruction, and thus identify both as potential therapeutic targets in countering adverse myocardial remodeling.

Up-regulated EMMPRIN/CD147 protein expression might play a role in colorectal carcinogenesis and its subsequent progression without an alteration of its glycosylation and mRNA level

Extracellular matrix metalloproteinase inducer (EMMPRIN) was reported to involve in the invasion and metastasis of malignancies by regulating the expression of vascular endothelial growth factor (VEGF) in stromal and cancer cells. The study aimed to clarify the role of EMMPRIN expression in tumorigenesis and progression of colorectal carcinomas (CRC). EMMPRIN expression was examined on tissue microarray containing colorectal carcinomas, adenoma and non-neoplastic mucosa (NNM) by immunohistochemistry and in situ hybridization (ISH). Colorectal carcinoma cell lines (DLD-1, HCT-15, SW480 and WiDr) and tissues were studied for EMMPRIN expression by Western blot or RT-PCR, followed by sequencing. All carcinoma cell lines showed EMMPRIN expression at both mRNA and protein levels. Two synonymous mutations were found in carcinoma cell lines at codon109 (GCT → GCC: Ala) or 179 (GAT → GAC: Asp). Frozen CRC tissues displayed higher EMMPRIN expression than paired NNM (P < 0.05). EMMPRIN expression was immunohistochemically stronger in colorectal high-grade adenoma, adenocarcinoma and metastatic carcinoma than non-neoplastic superficial epithelium and low-grade adenoma (P < 0.05). In contrast, its mRNA level was similar from colorectal NNM, adenoma to adenocarcinoma by ISH, in line with the findings of RT-PCR (P > 0.05). Immunohistochemically, EMMPRIN expression was positively correlated with tumor size, depth of invasion, vascular or lymphatic invasion, grade of infiltration (INF), ki-67 and VEGF expression of CRCs (P < 0.05). Among them, depth of invasion was an independent associated factor for EMMPRIN expression in CRCs (P < 0.05). Up-regulated EMMPRIN protein expression might contribute to colorectal carcinogenesis without the alteration of its glycosylation and mRNA level. Aberrant EMMPRIN protein expression might promote growth or invasion of CRCs possibly through increased ki-67 expression and inducible angiogenesis via up-regulating VEGF expression.

Extracellular matrix metalloproteinase inducer expression has an impact on survival in human bladder cancer

Aim: Extracellular matrix metalloproteinase inducer (EMMPRIN) has been shown to promote tumor invasion and metastasis via stimulating matrix metalloproteinase synthesis in neighboring fibroblasts, to enhance angiogenesis via vascular endothelial growth factor, to induce chemoresistant tumor cells via the production of hyaluronan, and to confer resistance of cancer cells to anoikis through inhibition of Bim. The purpose of this study was to investigate the expression of EMMPRIN in human primary bladder cancer and to evaluate its prognostic value. Methods: EMMPRIN expression patterns were detected by immunohistochemistry. In order to determine its prognostic value, overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan–Meier method, and multivariate analysis was performed using the Cox proportional hazard analysis. Results: Of the 101 cases with bladder cancers, 68 (67.3%) cases were positive for EMMPRIN expression. When categorized into negative vs. positive expression, EMMPRIN was associated with the stage ( p = 0.006), the grade ( p = 0.002), carcinoma in situ ( p = 0.01), the recurrence ( p = 0.009), the progression ( p = 0.009), and the death ( p = 0.01) of patients with bladder cancer. Moreover, positive EMMPRIN expression clearly predicted poorer PFS ( p = 0.008) and OS ( p = 0.006). In the multivariate analysis, positive EMMPRIN expression was an independent prognostic factor for PFS ( p = 0.03) and OS ( p = 0.03). Conclusion: EMMPRIN expression was greater in bladder cancers than in the adjacent normal tissues and may be a useful prognostic marker for patients with bladder cancer.

Abstract 1434: EMMPRIN expression is associated with metastatic progression in osteosarcoma

Abstract Introduction: Despite the improvement of survival in localized osteosarcoma patients, patients with metastasis still carry a poor prognosis. Thus, identification of factors contributing to metastasis is needed. Extracellular matrix metalloproteinase inducer (EMMPRIN) is a cell-surface glycoprotein which plays multiple roles in physiologic and pathologic conditions. EMMPRIN is highly expressed in several cancers and stimulates adjacent stromal cells or tumor cells to produce matrix metalloproteinase (MMP). EMMPRIN also stimulates expression of vascular endothelial growth factor (VEGF) which leads to angiogenesis. These findings have made EMMPRIN an attractive therapeutic target in many cancer types. The goals of this study were; to investigate the expression of EMMPRIN in osteosarcoma; to examine if EMMPRIN, via tumor-stroma interaction, is associated with metastatic potential in osteosarcoma. Methods: Level of EMMPRIN mRNA expression was evaluated by RT-PCR in 6 tumor-derived osteosarcoma cell lines and by immunohistochemistry prechemotherapy biopsies from 52 patients. Clinical data of these patients were reviewed to examine the association of EMMPRIN expression and clinical outcome. Transfection of EMMPRIN-targeting siRNA in SaOS-2 was performed to test the role of EMMPRIN in osteosarcoma progression. To study the role of EMMPRIN in tumor-stromal interaction, co-culture of SaOS-2 with osteoblast (hFOB) was experimented. Functional in vitro assays that reflect metastatic potential of osteosarcoma cells were performed. MMP production, VEGF production, cell invasion and proliferation were studied by gelatin zymography, VEGF ELISA, Matrigel invasion assay and WST-1 assay, respectively. Results: EMMPRIN was expressed in 90% by immunohistochemistry with strong accentuation along the cell membrane. Level of EMMRIN mRNA expression was significantly higher in 5 of 6 tumor-derived cell lines compared to MG63. Patients with high EMMPRIN expression had significantly worse metastasis-free survival. EMMPRIN mRNA levels was significantly down-regulated by siRNA transfection compared to control-siRNA transfected cell. Co-culture of osteoblast and SaOS-2 enhanced stimulation of pro-MMP2. This stimulation was reversed by transfection of SaOS-2 with EMMPRIN-targeting siRNA. Number of cells crossing the chamber was statistically lower in EMMPRIN-siRNA transfected cells. When osteoblast and SaOS-2 were co-cultured, VEGF expression was increased compared to SaOS-2 only culture. EMMPRIN-targeting siRNA transfection resulted in decrease of VEGF expression. SaOS-2 cells transfected with EMMPRIN-siRNA showed decreased proliferation potential compared to control-siRNA transfected cells. Conclusion: Our data suggest that highly expressed EMMPRIN plays an important role in metastatic potential of osteosarcoma. EMMPRIN could serve as a potential therapeutic target in osteosarcoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1434.

The temporal expression and localization of extracellular matrix metalloproteinase inducer (EMMPRIN) during the development of perio-dontitis in an animal model

We previously demonstrated extracellular matrix metalloproteinase inducer (EMMPRIN) was associated with the matrix metalloproteinases production of human periodontitis. The aim of this study was to investigate the temporal expression and localization of EMMPRIN during ligature-induced periodontitis in rats. Periodontitis was induced in rats by placing a thread around the cervix of the first mandibular molar. Animals were killed 3, 7, 11, 15 or 21 d after ligation. Mandibles were processed for paraffin sections and stained with hematoxylin and eosin or picrosirius red. The distance from the amelocemental junction to the alveolar crest (ACJ-AC) and the area fraction (Area%) of collagen fibers were measured. EMMPRIN was examined by immunohistochemistry and quantified by positive cell counting. Correlation analyses were then performed. Histologically, alveolar bone was gradually destroyed from day 3 to 11 and then stabilized. Collagen fibers were slightly dissociated on day 3 and extensively broken on day 7. They were reconstructed from day 11 to 21. EMMPRIN was localized predominantly in infiltrating cells and adjacent fibroblasts in interdental gingiva. The number of EMMPRIN-positive cells increased on day 3, peaked on day 7 and then gradually subsided from day 11 to 21. Statistically, there was a moderate positive correlation regarding the ACJ-AC distance (r = 0.552, p < 0.01) and a strong negative correlation with the Area% of collagen fibers (r = -0.808, p < 0.01). In gingival epithelium, the immunoreactivity was extremely strong in basal layer cells and sulcular epithelial cells in health. It was greatly enhanced in the inflamed conditions on days 3 and 7. In the interradicular bone, EMMPRIN was localized in the osteoclasts on days 3 and 7, as well as in the osteoblasts from day 11 onwards. The expression and localization of EMMPRIN are temporally varied during the development of periodontitis. In addition, the inflammation-dependent expression of EMMPRIN might be involved in alveolar bone resorption and collagen breakdown.

EMMPRIN (CD147) expression and differentiation of papillary thyroid carcinoma: implications for immunocytochemistry in FNA cytology

Extracellular matrix metalloproteinase inducer (EMMPRIN) and its induced matrix metalloproteinases (MMPs) play a crucial role in tumour progression, invasion and metastasis. EMMPRIN expression has been demonstrated in several tumours, but its expression profile in thyroid cancer remains unclear. We evaluated the expression profile of EMMPRIN at various stages of differentiation of thyroid carcinoma, including 20 cases of well-differentiated papillary carcinoma (WDPC), 15 cases of papillary carcinoma with a poorly differentiated carcinoma component (PC/PDC) and four cases with an undifferentiated carcinoma (UDC) component, using paraffin-embedded sections for immunohistochemical stains. Also, we used 32 fine needle aspiration cytology and imprint smears from the same cases for immunocytochemical stains. The staining results were evaluated with a scoring system. Immunohistochemical staining showed that EMMPRIN expression was absent or weak in almost all WDPC specimens, whereas it was moderate or strong in PDC and UDC components. In tumours that showed a gradual morphological transformation from WDPC to PDC components, the expression of EMMPRIN was progressively stronger from the areas of WDPC to those of PDC. WDPC, PC/PDC and UDC had expression scores of 4.9, 45.0 and 245.7, respectively. Results of immunocytochemical staining showed almost the same staining profile as those of immunohistochemical staining. The cytological atypia of EMMPRIN-positive cells was greater than that of negative cells. These results indicated that EMMPRIN expression correlates significantly with the degree of dedifferentiation of thyroid carcinoma. This study demonstrates the feasibility of expression of EMMPRIN using fine needle aspiration samples. Therefore, immunocytochemical analysis of EMMPRIN may be a novel aid to evaluate the differentiation of thyroid carcinoma.

Evaluation of EMMPRIN and MMP-2 in the prognosis of primary cutaneous malignant melanoma

The aim of the study was to investigate whether the presence of matrix metalloproteinase-2 (MMP-2) and its inducer, extracellular matrix metalloproteinase inducer (EMMPRIN), in primary cutaneous malignant melanoma (PCMM) might help to predict patient prognosis. Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded sections of PCMM from 150 patients. Association of clinical variables (gender, age, tumor location, thickness, Clark level and AJCC stage) with EMMPRIN and MMP-2 expression were analyzed by Fisher's exact test. Survival rates were subsequently estimated using the Kaplan-Meier method and compared using the log-rank test. The expression of EMMPRIN and MMP-2 was detected in 117/150 (78.0%) and 115/150 (76.7%) of patients with PCMM, respectively. Higher positive rates of both EMMPRIN and MMP-2 expression were significantly correlated with increased tumor thickness (both P=0.004), higher Clark level (P=0.02 and 0.03) and higher AJCC stage (both P=0.006). A significant correlation was found between the expression of EMMPRIN and MMP-2 in PCMM (r=0.89, P=0.01). Kaplan-Meier analysis demonstrated that patients who had EMMPRIN+/MMP-2+ expression had a significantly decreased 3-year disease-free survival (P=0.005) and 5-year overall survival (P=0.006). In multivariate analyses, tumor thickness and EMMPRIN+/MMP-2+ co-expression were the significant predictors of clinical outcome. EMMPRIN and MMP-2 may be independent biomarkers for disease recurrence and overall survival in patients with PCMM. A combined detection of EMMPRIN/MMP-2 co-expression may benefit us in prediction of a poor survival of PCMM.

Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) Is Increased in Human Left Ventricle after Acute Myocardial Infarction

Elevated activities of matrix metalloproteinases (MMPs) following acute myocardial infarction (AMI) have been shown to mediate ventricular remodeling. The extracellular MMP inducer (EMMPRIN) plays a key regulatory role for MMP activities. The aim of this study was to evaluate changes of EMMPRIN, MMP-2 and MMP-9 and determine the correlation between EMMPRIN expression and MMPs in human left ventricle after AMI. Immunohistochemistry for MMP-2, MMP-9 and EMMPRIN were performed postmortem in 15 human left ventricles including 10 patients with AMI and five normal subjects who were accident victims. Western blot was used to determine protein levels of MMP-2, MMP-9 and EMMPRIN. The correlation between EMMPRIN expression and MMPs was determined by linear regression. Our results showed that there was slight EMMPRIN expression on the membranes of normal cardiac myocytes, whereas its expression strongly increased around the zone of necrosis in the AMI group. Compared with the control group, EMMPRIN (1.10+/-0.17 vs. 0.25+/-0.04, p<0.001), MMP-2 (0.25+/-0.03 vs. 0.64+/-0.11, p<0.001) and MMP-9 (0.16+/-0.03 vs. 0.39+/-0.07, p<0.001) protein levels were significantly increased in the AMI group. The expression of MMP-2 (r(2)=0.82, p<0.001), and MMP-9 (r(2)=0.424, p=0.041) were correlated with EMMPRIN expression in AMI patients. Our findings demonstrate for the first time that EMMPRIN expression increases in the human left ventricle after AMI. As one of the upregulators of local MMP expression, augmented expression of EMMPRIN may play a critical role in ventricular remodeling in AMI subjects.

High glucose and tea polyphenols on expression of matrix metalloproteinase-2 and extracellular matrix metalloproteinase inducer in human umbilical vein endothelial cells

To investigate the effects of high glucose on expression of matrix metalloproteinase-2 (MMP-2) and extracellular matrix metalloproteinase inducer (EMMPRIN) in human umbilical vein endothelial cells (HUVECs). HUVECs were cultured in DMEM media containing high glucose with or without polyphenols for 24 hours respectively. The activity of MMP-2 in the supernatant was detected by zymography. The expression of MMP-2 mRNA and protein in HUVECs were detected by RT-PCR and Western blot respectively. The expression of EMMPRIN mRNA and protein in the cells were determined by RT-PCR as well as immunocytochemistry and Western blot respectively. The expression of MMP-2 and EMMPRIN mRNA were suppressed by a high concentration of glucose. Both the MMP-2 activity and protein level of EMMPRIN expression were also significantly decreased. Polyphenols abolished all the above changes of HUVECs induced by a high glucose level (P < 0.05). An acute high glucose stimulation down-regulates the activity of MMP-2, the expressions of MMP-2 and EMMPRIN at RNA and protein levels in the endothelial cells, which may play an important roles in diabetic vascular complications in the early phase. Polyphenols treatment can diminish the detrimental effects of high glucose on HUVECs.

Expression of Matrix Metalloproteinase 2 and Extracellular Matrix Metalloproteinase Inducer are Unfavorable Postoperative Prognostic Factors in Intrahepatic Cholangiocarcinoma

Many investigators have indicated that overexpression and amplification of matrix metalloproteinase 2 (MMP-2) and extracellular matrix metalloproteinase inducer (EMMPRIN) are independent prognostic factors for primary tumors. We studied expression of them in tissues from intrahepatic cholangiocarcinoma (IHCCA) and normal bile ducts, and discussed the occurrence and development of IHCCA. Another goal was to explore possible association of MMP-2 and EMMPRIN with clinicopathologic parameters and prognosis of IHCCA. MMP-2 and EMMPRIN expression in 106 cases of IHCCA tissues and 15 cases of normal bile ducts were examined by immunohistochemical staining. Then, the association of MMP-2 and EMMPRIN expression with clinicopathologic parameters and patients' prognosis was analyzed. The positive expression levels of MMP-2 and EMMPRIN associated significantly with various clinicopathologic risk factors, such as poor histologic differentiation (p = 0.03, 0.02), higher TNM stages (p = 0.02, 0.01) and decreased tumor-specific survival. In particular, the tumor-specific survival rate of the patients with MMP-2+/ EMMPRIN+expression was the lowest (p < 0.01). Using Cox regression analysis of the 89 patients, the conjoined expressions of MMP-2-/ EMMPRIN-, MMP-2+/ EMMPRIN +, histologic differentiation, and the clinical TNM stages of tumorous tissues were independent prognostic indicators of IHCCA (p < 0.01, p < 0.01, p = 0.02, p = 0.01 and p = 0.01, respectively). MMP-2 and EMMPRIN expression in primary tumor predicts an unfavorable prognosis in IHCCA, suggesting a crucial role of the two markers in progression of human IHCCA.

Berberine reduces both MMP-9 and EMMPRIN expression through prevention of p38 pathway activation in PMA-induced macrophages

Overproduction of MMPs (matrix metalloproteinases) and EMMPRIN (extracellular matrix metalloproteinase inducer) by monocytes/macrophages leads to atherosclerotic plaque rupture by degrading the extracellular matrix. Serum MMP-9 levels may therefore represent a novel marker of inflammation in patients with known coronary artery disease. The purpose of our study was to determine if berberine, a natural extract from Rhizoma coptidis, had any effect on the expression of MMP-9 and EMMPRIN in PMA-induced macrophages. Human monocytic THP-1 cells were pretreated with berberine for 1 h, and then induced by PMA for 48 h. Total RNA and protein were collected for Real-time PCR and Western blot analysis, respectively. Culture supernatants were collected to determine MMP-9 activity. In the present study, we demonstrated that berberine inhibited the expression of MMP-9 and EMMPRIN at both the mRNA and protein levels in a dose-dependent manner in PMA-induced macrophages, and that it also reduced MMP-9 activity. Furthermore, berberine also suppressed p38 signaling pathway activation in PMA-induced macrophages. The data indicate that berberine reduces MMP-9 and EMMPRIN expression by suppressing the activation of p38 pathway in PMA-induced macrophages. This suggests a potential role for berberine as a therapeutic aid for stabilizing atherosclerotic plaque.

EMMPRIN expression in tongue squamous cell carcinoma

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. 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. 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. These results suggest that EMMPRIN might represent an attractive target for immunotherapeutic approaches in a subgroup of patients with tongue squamous cell carcinoma.

Resveratrol blocks interleukin-18-EMMPRIN cross-regulation and smooth muscle cell migration

Vascular smooth muscle cell (SMC) migration is an important mechanism in atherogenesis and postangioplasty arterial remodeling. Previously, we demonstrated that the proinflammatory cytokine interleukin (IL)-18 is a potent inducer of SMC migration. Since extracellular matrix metalloproteinase inducer (EMMPRIN) stimulates ECM degradation and facilitates cell migration, we investigated whether IL-18 and EMMPRIN regulate each other's expression, whether their cross talk induces SMC migration, and whether the phytoalexin resveratrol inhibits IL-18-EMMPRIN signaling and SMC migration. Our studies demonstrate that 1) IL-18 induces EMMPRIN mRNA and protein expressions and stimulates EMMPRIN secretion from human aortic SMCs; 2) IL-18 stimulates EMMPRIN expression via oxidative stress and phosphatidylinositol 3-kinase (PI3K)-Akt-ERK signaling; 3) IL-18-stimulated SMC migration is significantly blunted by EMMPRIN knockdown, EMMPRIN function-blocking antibodies, or adenoviral transduction of mutant EMMPRIN; 4) conversely, EMMPRIN stimulates IL-18 expression and secretion via PI3K, Akt, and ERK; and 5) resveratrol attenuates IL-18- and EMMPRIN-mediated PI3K, Akt, and ERK activations; blunts IL-18-mediated oxidative stress; blocks IL-18-EMMPRIN cross-regulation; and inhibits SMC migration. Collectively, our results demonstrate that the coexpression and regulation of IL-18 and EMMPRIN in the vessel wall may amplify the inflammatory cascade and promote atherosclerosis and remodeling. Resveratrol, via its antioxidant and anti-inflammatory properties, has the potential to inhibit the progression of atherosclerosis by blocking IL-18 and EMMPRIN cross-regulation and SMC migration.