Tocilizumab (TCZ) Decreases Angiogenesis in Rheumatoid Arthritis Through Its Regulatory Effect on miR-146a-5p and EMMPRIN/CD147.

Background: Angiogenesis is a major contributor to the development of inflammation during Rheumatoid arthritis (RA), as the vascularization of the pannus provides nutrients and oxygen for the infiltrating immune cells and proliferating synoviocytes. Tocilizumab (TCZ) is an anti-IL-6 receptor antibody that is used in the treatment of RA patients, and has been shown to exert anti-inflammatory effects. However, its effects on angiogenesis are not fully elucidated, and the molecular mechanisms regulating this effect are unknown. Methods: We evaluated the concentrations of several pro- and anti-angiogenic factors and the expression levels of several microRNA molecules that are associated with RA and angiogenesis in serum samples obtained from 40 RA patients, before and 4 months after the initiation of TCZ treatment. Additionally, we used an in vitro co-culture system of fibroblasts (the HT1080 cell line) and monocytes (the U937 cell line) to explore the mechanisms of TCZ action. Results: Serum samples from RA patients treated with TCZ exhibited reduced circulating levels of EMMPRIN/CD147, enhanced expression of circulating miR-146a-5p and miR-150-5p, and reduced the angiogenic potential as was manifested by the lower number of tube-like structures that were formed by EaHy926 endothelial cell line. In vitro, the accumulation in the supernatants of the pro-angiogenic factors EMMPRIN, VEGF and MMP-9 was increased by co-culturing the HT1080 fibroblasts and the U937 monocytes, while the accumulation of the anti-angiogenic factor thrombospondin-1 (Tsp-1) and the expression levels of miR-146a-5p were reduced. Transfection of HT1080 cells with the miR-146a-5p mimic, decreased the accumulation of EMMPRIN, VEGF and MMP-9. When we neutralized EMMPRIN with a blocking antibody, the supernatants derived from these co-cultures displayed reduced migration, proliferation and tube formation in the functional assays. Conclusions: Our findings implicate miR-146a-5p in the regulation of EMMPRIN and propose that TCZ affects angiogenesis through its effects on EMMPRIN and miR-146a-5p.

Clinical Significance of CD147 in Children with Inflammatory Bowel Disease.

BACKGROUND: CD147/basigin (Bsg), a transmembrane glycoprotein, activates matrix metalloproteinases and promotes inflammation. OBJECTIVE: The aim of this study is to explore the clinical significance of CD147 in the pathogenesis of inflammatory bowel disease (IBD). RESULTS: In addition to monocytes, the clinical analysis showed that there is no significance obtained in leucocyte, neutrophil, eosinophil, basophil, and erythrocyte between IBD and controls. Immunohistochemistry analysis showed that CD147 was increased in intestinal tissue of patients with active IBD compared to that in the control group. What is more, CD147 is involved in intestinal barrier function and intestinal inflammation, which was attributed to the fact that it has an influence on MCT4 expression, a regulator of intestinal barrier function and intestinal inflammation, in HT-29 and CaCO2 cells. Most importantly, serum level of CD147 content is higher in active IBD than that in inactive IBD or healthy control, which could be a biomarker of IBD. CONCLUSION: The data suggested that increased CD147 level could be a biomarker of IBD in children.

CD147 Aggravated Inflammatory Bowel Disease by Triggering NF-κB-Mediated Pyroptosis.

BACKGROUND: Pyroptosis, a novel form of inflammatory programmed cell death, was recently found to be a cause of mucosal barrier defect. In our pervious study, CD147 expression was documented to increase in intestinal tissue of inflammatory bowel disease (IBD). OBJECTIVE: The aim of this study was to determine the function of serum CD147 in pyroptosis. METHODS: The study group consisted of 96 cases. The centration of CD147, IL-1ß, and IL-18 levels in serum was assessed by ELISA. Real-time PCR and WB were performed to analyze the effect of CD147 on pyroptosis. RESULTS: In this study, our results showed that CD147 induced cell pyroptosis in intestinal epithelial cells (IECs) by enhancement of IL-1ß and IL-18 expression and secretion in IECs, which is attributed to activation of inflammasomes, including caspase-1 and GSDMD as well as GSDME, leading to aggregate inflammatory reaction. Mechanically, CD147 promoted phosphorylation of NF-κB p65 in IECs, while inhibition of NF-κB activity by the NF-κB inhibitor BAY11-7082 reversed the effect of CD147 on IL-1ß and IL-18 secretion. Most importantly, serum CD147 level is slightly clinically correlated with IL-1ß, but not IL-18 level. CONCLUSION: These findings revealed a critical role of CD147 in the patients with IBD, suggesting that blockade of CD147 may be a novel therapeutic strategy for the patients with IBD.

The Combination of CD147 and MMP-9 Serum Levels Is Identified as Novel Chemotherapy Response Markers of Advanced Non-Small-Cell Lung Cancer.

To evaluate the correlation between the changes in serum concentrations of cluster of differentiation-147 (scCD147) and chemotherapy outcome in patients with NSCLC and evaluate the combination of scCD147 with serum matrix metalloproteinase-9 (scMMP-9) levels in the prediction of chemotherapy response, eighty-two patients with advanced LC were enrolled. Newly diagnosed cases were treated with platinum-based chemotherapy. We measured scCD147 protein levels in LC cases by ELISA and used receiver operating characteristic (ROC) curves to analyze the results. Four time points were chosen to examine the association between the changes in scCD147 and chemotherapy outcome: before chemotherapy and 21 days after the start of the first, second, and fourth chemotherapy cycles. We assessed the combination of scCD147 and scMMP-9 serum levels in predicting the chemotherapy response. scCD147 was higher in LC cases than that in healthy volunteers (HVs). scCD147 was associated with distant metastases and TNM stage. scCD147 and scMMP-9 appeared to be independent predictive factors for chemotherapy outcomes after the first and second chemotherapy cycles for patients with NSCLC. Multivariable analysis also demonstrated that variations in scCD147 and scMMP-9 could be independent factors for monitoring chemotherapy outcome for patients with NSCLC. Furthermore, when scCD147 and scMMP-9 are combined into a new risk model, it has a markedly better prediction of chemotherapy outcomes than each protein alone. scCD147 and MMP-9 are potential predictive biomarkers for efficacy, and their combination significantly improves the predictive power for chemotherapy response in patients with NSCLC.

Peptidome profiles in melamine diet-induced bladder stones in C57BL/6 mice.

The aim of this research was to detect potential serum biomarkers of melamine diet-induced bladder stones in C57BL/6 mice. Magnetic bead-based weak cationexchange chromatography (MB-WCX) and matrix-assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS) were employed to detect serum biomarkers in 10 mice fed a melamine diet and 10 control mice. Seventeen peaks (fold change>1.5) with a mass to charge (m/z) value of 1000-10,000 Da were detected in the two groups. Among the significant peaks, five were upregulated and the other 12 were downregulated in the model group. Among the upregulated peaks, 2954.49 and 1710.49 were found to correspond to the peptide regions of NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8(Ndufα8) and basigin, respectively, by liquid chromatography with electrospray ionization and tandem triple quadrupole mass spectrometry(LC-ESI-MS/MS). Western blot analysis was used to detect the expression of Ndufα8 and basigin in another 10 model mice and 10 control mice. The western blot results confirmed the LC-ESI-MS/MS data. The expression of serum basigin and Ndufα8 was partly dependent the concentration of melamine, but no time dependence. In conclusion, Ndufα8 and basigin may be potential serum biomarkers for the detection of melamine diet-induced bladder stones in C57BL/6 mice.

Soluble EMMPRIN levels discriminate aortic ectasia in Marfan syndrome patients.

Marfan syndrome (MFS) is a rare genetic disease characterized by a matrix metalloproteases (MMPs) dysregulation that leads to extracellular matrix degradation. Consequently, MFS patients are prone to develop progressive thoracic aortic enlargement and detrimental aneurysm. Since MMPs are activated by the extracellular MMP inducer (EMMPRIN) protein, we determined whether its plasmatic soluble form (sEMMPRIN) may be considered a marker of thoracic aortic ectasia (AE). Methods: We compared plasma sEMMPRIN levels of 42 adult Caucasian MFS patients not previously subjected to aortic surgery with those of matched healthy controls (HC) by ELISA. In the MFS cohort we prospectively evaluated the relationship between plasma sEMMPRIN levels and the main MFS-related manifestations. Results: MFS patients had lower plasma sEMMPRIN levels (mean±SD: 2071±637 pg/ml) than HC (2441±642 pg/ml, p=0.009). Amongst all considered MFS-related clinical features, we found that only aortic root dilatation associated with circulating sEMMPRIN levels. Specifically, plasma sEMMPRIN levels negatively correlated with aortic Z-score (r=-0.431, p=0.004), and were significantly lower in patients with AE (Z-score≥2, 1788±510 pg/ml) compared to those without AE (Z-score<2, 2355±634 pg/ml; p=0.003). ROC curve analysis revealed that plasma sEMMPRIN levels discriminated patients with AE (AUC [95%CI]: 0.763 [0.610-0.916], p=0.003) with 85.7% sensitivity, 76.2% specificity, and 81% accuracy. We defined plasma sEMMPRIN levels ≤2246 pg/ml as the best threshold discriminating the presence of AE in MFS patients with an odds ratio [95%CI] of 19.2 [3.947-93.389] (p<0.001). Conclusions: MFS patients are characterized by lower sEMMPRIN levels than HC. Notably, plasma sEMMPRIN levels are strongly associated with thoracic AE.

High Plasma sRAGE (Soluble Receptor for Advanced Glycation End Products) Is Associated With Slower Carotid Intima-Media Thickness Progression and Lower Risk for First-Time Coronary Events and Mortality.

Objective- RAGE (receptor for advanced glycation end products) and EMMPRIN (extracellular matrix metalloproteinase inducer) are immune receptors for proinflammatory mediators. These receptors can also be found in a soluble form in the circulation. Soluble RAGE (sRAGE) has shown atheroprotective properties in animal studies, possibly by acting as a decoy receptor for its ligands. Whether sEMMPRIN (soluble EMMPRIN) has similar roles is unknown. We hypothesized that sRAGE and sEMMPRIN might be associated with vascular disease progression, incident coronary events, and mortality. Approach and Results- We measured baseline sRAGE and sEMMPRIN in 4612 cardiovascular disease-free individuals from the population-based Malmö Diet and Cancer cohort. Measurements of intima-media thickness in the common carotid artery were performed at inclusion and after a median of 16.5 years. sRAGE was negatively correlated with carotid intima-media thickness progression, independently of traditional cardiovascular risk factors, kidney function, and hsCRP (high sensitive C-reactive protein). Additionally, sRAGE was associated with decreased risk for major adverse coronary events (hazard ratio=0.90 [0.82-0.97]; P=0.009) and mortality (hazard ratio=0.93 [0.88-0.99]; P=0.011) during a follow-up period of 21 years. The relationship with mortality was independent of all considered potential confounders. We found no correlations between EMMPRIN, intima-media thickness progression, or prognosis. Conclusions- Individuals with high levels of circulating sRAGE have a slower rate of carotid artery disease progression and a better prognosis. Although its predictive value was too weak to promote sRAGE as a useful clinical biomarker in the population, the findings support further research into the potential anti-inflammatory and atheroprotective properties of this soluble receptor.

Plasma soluble cluster of differentiation 147 levels are increased in breast cancer patients and associated with lymph node metastasis and chemoresistance.

INTRODUCTION: Cluster of differentiation 147 (CD147) contributes to breast cancer invasion, metastasis, and multidrug resistance. Recent studies have shown that peripheral soluble CD147 (sCD147) is increased in hepatocellular tumour and multiple myeloma patients and correlated with disease severity. The primary aim of our study was to assess the level, as well as the biological and clinical significance of sCD147 in breast cancer. METHODS: We tested plasma sCD147 levels in 308 breast cancer patients by enzyme-linked immunosorbent assay between February 2014 and February 2017. A subset of 165 cases of benign breast diseases was included as a control group at the same period. We analysed the clinical significance of plasma sCD147 with relevance to clinicopathological factors of breast cancer patients. RESULTS: Plasma sCD147 levels were significantly higher in patients with primary breast cancer than those with benign breast diseases (P=0.001), in patients with locally advanced breast cancer (T3-T4 tumour) than those in early breast cancer (T1-T2 tumour; P=0.001), in patients with lymph node metastasis than in those without (P<0.001), and in patients with high recurrence risk than those with medium recurrence risk (P<0.001). Plasma sCD147 levels were also significantly higher in the chemotherapy-resistant group than in the chemotherapy-sensitive group (P=0.040). Plasma sCD147 was an independent predictor for lymph node metastasis in breast cancer patients (P=0.001). CONCLUSION: This is the first study to demonstrate that plasma sCD147 levels are elevated in breast cancer patients. Soluble CD147 is also associated with tumour size, lymph node metastasis, high recurrent risk, and chemoresistance. Our findings support that plasma sCD147 is an independent predictive factor for lymph node metastasis.

The clinical relevance of plasma CD147/basigin in biopsy-proven kidney diseases.

BACKGROUND: Precise understanding of kidney disease activity is needed to design therapeutic strategies. CD147/basigin is involved in the pathogenesis of acute kidney injury and renal fibrosis through inflammatory cell infiltration. The present study examined the clinical relevance of CD147 in biopsy-proven kidney diseases that lead to the progression of chronic kidney disease. METHODS: Kidney biopsy specimens and plasma and urine samples were obtained from patients with kidney diseases, including IgA nephropathy (IgAN), Henoch-Schönlein purpura nephritis (HSPN), diabetic kidney disease (DKD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN), who underwent renal biopsy between 2011 and 2014. Plasma and urinary CD147 levels were measured and evaluated for their ability to reflect histological features. Disease activity of IgAN tissues was evaluated according to the Oxford classification and the Japanese histological grading system. RESULTS: In biopsy tissues, CD147 induction was detected in injured lesions representing renal inflammation. Plasma CD147 values correlated with eGFR in patients with inflammation-related kidney diseases such as IgAN, HSPN, and DKD. Particularly in IgAN patients, plasma CD147 levels were correlated with injured regions comprising more than 50% of glomeruli or with tubular atrophy/interstitial injury in biopsy tissues. Proteinuria showed a closer correlation with urinary values of CD147 and L-FABP. Of note, plasma and urinary CD147 levels showed a strong correlation with eGFR or proteinuria, respectively, only in DKD patients. CONCLUSION: Evaluation of plasma and urinary CD147 levels might provide key insights for the understanding of the activity of various kidney diseases.

Active Vaccination With EMMPRIN-Derived Multiple Antigenic Peptide (161-MAP) Reduces Angiogenesis in a Dextran Sodium Sulfate (DSS)-Induced Colitis Model.

Ulcerative colitis (UC) is an autoimmune disease that affects the colon and shares many clinical and histological features with the dextran sulfate sodium (DSS)-induced colitis model in mice. Angiogenesis is a critical component in many autoimmune diseases, as well as in the DSS-induced colitis model, and is it partially mediated by EMMPRIN, a multifunctional protein that can induce the expression of both the potent pro-angiogenic vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). We asked whether targeting EMMPRIN by active vaccination, using a novel, specific epitope in the protein, synthesized as a multiple antigenic peptide (MAP), could trigger beneficial effects in the DSS-induced colitic C57BL/6J mice. Mice were vaccinated with four boost injections (50 µg each) of either 161-MAP coding for the EMMPRIN epitope or the scrambled control peptide (Scr-MAP) emulsified in Freund's adjuvant. We show that male mice that were vaccinated with 161-MAP lost less weight, demonstrated improved disease activity indices (DAI), had reduced colitis histological score, and their colons were longer in comparison to mice vaccinated with the Scr-MAP. The 161-MAP vaccination also reduced serum and colon levels of EMMPRIN, colon concentrations of VEGF, MMP-9, and TGFß, and vessel density assessed by CD31 staining. A similar effect was observed in female mice vaccinated with 161-MAP, including weight loss, colitis histological score, colon length, colon levels of EMMPRIN and colon concentrations of VEGF. However, for female mice, the changes in DAI values, EMMPRIN serum levels, and MMP-9 and TGFß colon concentrations did not reach significance. We conclude that our strategy of alleviating autoimmunity in this model through targeting angiogenesis by actively vaccinating against EMMPRIN was successful and efficient in reducing angiogenesis.

Overexpression of EMMPRIN is associated with lymph node metastasis and advanced stage of non-small cell lung cancer: a retrospective study.

BACKGROUND: Previous studies show that overexpression of EMMPRIN involved in the malignant biological behavior of tumors. This investigation was to disclose the expression status of EMMPRIN in non-small cell lung cancer (NSCLC) and its clinical value for the diagnosis of NSCLC. METHODS: The expression of EMMPRIN was examined using immunohistochemistry and enzyme-linked immunosorbent assay. The clinical value of EMMPRIN was evaluated by drawing a receiver operating characteristic (ROC) curve. RESULTS: NSCLC tissues and serum exhibited higher expression levels of EMMPRIN than the normal control (p < 0.05), and the expression of the EMMPRIN was significantly associated with lymphatic invasion and advanced stage of NSCLC (p < 0.05). ROC curve suggested that the threshold level of serum EMMPRIN for distinguishing NSCLC from control group was 80.3 pg/mL, and displayed a sensitivity of 97.22% and a specificity of 95%. And higher EMMPRIN expression in serum and tissues appeared to be risk factors for NSCLC development (risk ratio =1.56 and 1.1). CONCLUSION: Overexpression of EMMPRIN was associated with lymphatic metastasis and advanced stage of NSCLC and test of serum EMMPRIN contributes to the NSCLC diagnosis.

The prognostic and clinicopathologic characteristics of CD147 and esophagus cancer: A meta-analysis.

OBJECTIVE: The prognostic significance of CD147 expression in esophageal cancer patients remains controversial. Using a meta-analysis, we investigated the prognostic and clinicopathologic characteristics of CD147 in esophageal cancer. METHODS: A comprehensive literature search of the PubMed (1966-2016), EMBASE (1980-2016), Cochrane Library (1996-2016), Web of Science (1945-2016), China National Knowledge Infrastructure (1982-2016), and Wanfang databases (1988-2016) was performed to identify studies of all esophageal cancer subtypes. Correlations between CD147 expression and survival outcomes and clinicopathological features were analyzed using meta-analysis methods. RESULTS: Seventeen studies were included. High CD147 expression reduced the 3-year survival rate (OR = 3.26, 95% CI = (1.53, 6.93), p = 0.02) and 5-year survival rate(OR = 4.35, 95% CI = (2.13, 8.90), p < 0.0001). High CD147 expression reduced overall survival in esophageal cancer (HR = 1.60, 95% CI = (1.19, 2.15), p = 0.02). Additionally, higher CD147 expression was detected in esophageal cancer tissues than noncancerous tissues (OR = 9.45, 95% CI = (5.39, 16.59), p < 0.00001), normal tissues (OR = 12.73, 95% CI = (3.49, 46.46), p = 0.0001), para-carcinoma tissues (OR = 12.80, 95% CI = (6.57, 24.92), p < 0.00001), and hyperplastic tissues (OR = 3.27, 95% CI = (1.47, 7.29), p = 0.004). CD147 expression was associated with TNM stage (OR = 3.66, 95% CI = (2.20, 6.09), p < 0.00001), tumor depth (OR = 7.97, 95% CI = (4.13, 15.38), p < 0.00001), and lymph node status (OR = 5.14, 95% CI = (2.03,13.01), p = 0.0005), but not with tumor differentiation, age, or sex. CONCLUSION: Our meta-analysis suggests that CD147 is an efficient prognostic factor in esophageal cancer. High CD147 expression in patients with esophageal cancer was associated with worse survival outcomes and common clinicopathological indicators of poor prognosis.

Dosimetry study on radioactive particle brachytherapy in oral carcinoma.

PURPOSE: To investigate the therapeutic effects of different doses of 125I radioactive particle brachytherapy on oral cancer. METHODS: Between September 2012 and September 2015, 78 patients with oral cancer who received 125I radioactive particle brachytherapy for the first time in our hospital were enrolled in this study. Patients were divided into high dose (≥3) and low dose (<3) groups. The treatment outcome, serum tumor marker levels and the expression levels of autophagy and apoptotic genes in tumor cells were compared between groups. RESULTS: Complete remission (CR)+partial remission (PR) ratio in the high dose group was significantly higher than that of the low dose group. Stable disease (SD)+ progressive disease (PD) ratio was significantly lower in the high dose group. The serum levels of TSGF, SCCA, CEA, CA125, CA15.3, CA19.9 and PSA oral cancer markers were significantly lower than those of the low dose group. In the high dose group, the expression levels of Beclin-1 and MAP1LC3 (autophagic genes) mRNAs were significantly higher than those of the low dose group, while the expression levels of EMMPRIN and MMP-14 (invasive genes) mRNAs were significantly lower in the high dose group. Also survival rates in the responsive patients were significantly better in comparison to non-responsive patients. CONCLUSION: High dose particle brachytherapy with radioactive 125I is a safe and effective treatment and its clinical results were more beneficial than the low dose therapy.

Cancer-associated circulating large extracellular vesicles in cholangiocarcinoma and hepatocellular carcinoma.

BACKGROUND & AIMS: Large extracellular vesicles, specifically AnnexinV+ EpCAM+ CD147+ tumour-associated microparticles (taMPs), facilitate the detection of colorectal carcinoma (CRC), non-small cell lung carcinoma (NSCLC) as well as pancreas carcinoma (PaCa). Here we assess the diagnostic value of taMPs for detection and monitoring of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Specifically, the aim of this study was to differentiate liver taMPs from other cancer taMPs, such as CRC and NSCLC. METHODS: Fluorescence-activated cell scanning (FACS) was applied to detect various taMP populations in patients' sera that were associated with the presence of a tumour (AnnexinV+ EpCAM+ CD147+ taMPs) or could discriminate between cirrhosis (due to HCV or HBV) and liver cancers (AnnexinV+ EpCAM+ ASGPR1+ taMPs). In total 172 patients with liver cancer (HCC or CCA), 54 with cirrhosis and no liver neoplasia, and 202 control subjects were enrolled. RESULTS: The results indicate that AnnexinV+ EpCAM+ CD147+ taMPs were elevated in HCC and CCA. Furthermore, AnnexinV+ EpCAM+ ASGPR1+ CD133+ taMPs allowed the distinction of liver malignancies (HCC or CCA) and cirrhosis from tumour-free individuals and, more importantly, from patients carrying other non-liver cancers. In addition, AnnexinV+ EpCAM+ ASGPR1+ taMPs were increased in liver cancer-bearing patients compared to patients with cirrhosis that lacked any detectable liver malignancy. The smallest sizes of successfully detected cancers were ranging between 11-15mm. AnnexinV+ EpCAM+ ASGPR1+ taMPs decreased at 7days after curative R0 tumour resection suggesting close correlations with tumour presence. ROC values, sensitivity/specificity scores and positive/negative predictive values (>78%) indicated a potent diagnostic accuracy of AnnexinV+ EpCAM+ ASGPR1+ taMPs. CONCLUSION: These data provide strong evidence that AnnexinV+ EpCAM+ ASGPR1+ taMPs are a novel biomarker of HCC and CCA liquid biopsy that permit a non-invasive assessment of the presence and possible extent of these cancers in patients with advanced liver diseases. LAY SUMMARY: Microparticles (MPs) are small vesicles that bleb from the membrane of every cell, including cancer cells, and are released to circulate in the bloodstream. Since their surface composition is similar to the surface of their underlying parental cell, MPs from the bloodstream can be isolated and by screening their surface components, the presence of their parental cells can be identified. This way, it was possible to detect and discriminate between patients bearing liver cancer and chronic liver cirrhosis.

Circulating CD147 predicts mortality in advanced hepatocellular carcinoma.

BACKGROUND AND AIM: The glycoprotein CD147 has a role in tumor progression, is readily detectable in the circulation, and is abundantly expressed in hepatocellular carcinoma (HCC). Advanced HCC patients are a heterogeneous group with some individuals having dismal survival. The aim of this study was to examine circulating soluble CD147 levels as a prognostic marker in HCC patients. METHODS: CD147 was measured in 277 patients (110 HCC, 115 chronic liver disease, and 52 non-liver disease). Clinical data included etiology, tumor progression, Barcelona Clinic Liver Cancer (BCLC) stage, and treatment response. Patients with HCC were stratified into two groups based upon the 75th percentile of CD147 levels (24 ng/mL). RESULTS: CD147 in HCC correlated inversely with poor survival (P = 0.031). Increased CD147 predicted poor survival in BCLC stages C and D (P = 0.045), and CD147 levels >24 ng/mL predicted a significantly diminished 90-day and 180-day survival time (hazard ratio [HR] = 6.1; 95% confidence interval [CI]: 2.1-63.2; P = 0.0045 and HR = 2.8; 95% CI: 1.2-12.6; P = 0.028, respectively). In BCLC stage C, CD147 predicted prognosis; levels >24 ng/mL were associated with a median survival of 1.5 months compared with 6.5 months with CD147 levels ≤24 ng/mL (P = 0.03). CD147 also identified patients with a poor prognosis independent from treatment frequency, modality, and tumor size. CONCLUSIONS: Circulating CD147 is an independent marker of survival in advanced HCC. CD147 requires further evaluation as a potential new prognostic measure in HCC to identify patients with advanced disease who have a poor prognosis.

Effect of Cnidium Lactone on Serum Mutant P53 and BCL-2/BAX Expression in Human Prostate Cancer Cells PC-3 Tumor-Bearing BALB/C Nude Mouse Model.

BACKGROUND: Cnidium lactone is a natural coumarin compound that can inhibit a variety of cancer cell proliferation and induce cancer cell apoptosis. This experiment investigated the effect of cnidium lactone on molecular marker expression in prostate cancer nude mice to study its effect in inducing apoptosis. MATERIAL AND METHODS: We randomly and equally divided 30 male BALB/C nude mice inoculated with human prostate cancer cells PC-3 into a negative control group, a cyclophosphamide group (500 mg/Kg), and cnidium lactone groups at 3 doses (280 mg/Kg, 140 mg/Kg, and 70 mg/Kg). The mice were weighed at 2 weeks after administration. Tunnel assay was applied to test the nude mice tumor cell apoptosis. ELISA was performed to detect serum AMACR, CD147, mutant P53, BCL-2, AND BAX expression levels. Tumor tissue was separated and weighed. RESULTS: Mice weight did not change significantly in the groups receiving 3 different doses of cnidium lactone(p>0.05), while it decreased obviously in the cyclophosphamide group (p<0.05). Tumor weight, CD147, mutant P53, and BCL-2 levels were significantly lower in the groups receiving 3 different doses of cnidium lactone than in the negative control group (p<0.05). Among them, the abovementioned indexes decreased markedly in the 280 mg/Kg and 140 mg/Kg dose groups than in the cyclophosphamide group (p<0.05). AMACR and BAX levels showed no significant difference in the cnidium lactone group or the cyclophosphamide group (p>0.05). CONCLUSIONS: Cnidium lactone may induce prostate cancer cell apoptosis and inhibit its proliferation through regulating CD147, mutant P53, and BCL-2 expression in nude mice.

Extracellular cyclophilin A activates platelets via EMMPRIN (CD147) and PI3K/Akt signaling, which promotes platelet adhesion and thrombus formation in vitro and in vivo.

OBJECTIVE: Cyclophilin A (CyPA) is secreted under inflammatory conditions by various cell types. Whereas the important role of intracellular CyPA for platelet function has been reported, the effect of extracellular CyPA on platelet function has not been investigated yet. APPROACH AND RESULTS: Inhibition of extracellular CyPA through a novel specific inhibitor MM284 reduced thrombus after ferric chloride-induced injury in vivo. In vitro extracellular CyPA enhanced thrombus formation even in CyPA(-/-) platelets. Treatment of isolated platelets with recombinant CyPA resulted in platelet degranulation in a time- and dose-dependent manner. Inhibition of the platelet surface receptor extracellular matrix metalloproteinase inducer (cluster of differentiation 147) by an anticluster of differentiation 147 monoclonal antibody significantly reduced CyPA-dependent platelet degranulation. Pretreatment of platelets with CyPA enhanced their recruitment to mouse carotid arteries after arterial injury, which could be inhibited by an anticluster of differentiation 147 monoclonal antibody (intravital microscopy). The role of extracellular CyPA in adhesion could be confirmed by infusing CyPA(-/-) platelets in CyPA(+/+) mice and by infusing CyPA(+/+) platelets in CyPA(-/-) mice. Stimulation of platelets with CyPA induced phosphorylation of Akt, which could in turn be inhibited in the presence of phosphoinositid-3-kinase inhibitors. Akt-1(-/-) platelets revealed a markedly decreased degranulation on CyPA stimulation. Finally, ADP-induced platelet aggregation was attenuated by MM284, as well as by inhibiting paracrine-secreted CyPA without directly affecting Ca(2+)-signaling. CONCLUSIONS: Extracellular CyPA activates platelets via cluster of differentiation 147-mediated phosphoinositid-3-kinase/Akt-signaling, leading to enhanced adhesion and thrombus formation independently of intracellular CyPA. Targeting extracellular CyPA via a specific inhibitor may be a promising strategy for platelet inhibition without affecting critical functions of intracellular CyPA.

Full-length soluble CD147 promotes MMP-2 expression and is a potential serological marker in detection of hepatocellular carcinoma.

BACKGROUND: As a surface glycoprotein, CD147 is capable of stimulating the production of matrix metalloproteinases (MMPs) from neighboring fibroblasts. The aim of the present study is to explore the role of soluble CD147 on MMPs secretion from hepatocellular carcinoma (HCC) cells, and to investigate the diagnostic value of serum soluble CD147 in the HCC detection. METHODS: We identified the form of soluble CD147 in cell culture supernate of HCC cells and serum of patients with HCC, and explored the role of soluble CD147 on MMPs secretion. Serum CD147 levels were detected by the enzyme-linked immunosorbent assay, and the value of soluble CD147 as a marker in HCC detection was analyzed. RESULTS: Full length soluble CD147 was presented in the culture medium of HCC cells and serum of patients with HCC. The extracellular domain of soluble CD147 promoted the expression of CD147 and MMP-2 from HCC cells. Knockdown of CD147 markedly diminished the up-regulation of CD147 and MMP-2 which induced by soluble CD147. Soluble CD147 activated ERK, FAK, and PI3K/Akt pathways, leading to the up-regulation of MMP-2. The level of soluble CD147 in serum of patients with HCC was significantly elevated compared with healthy individuals (P < 0.001). Soluble CD147 levels were found to be associated with HCC tumor size (P = 0.007) and Child-Pugh grade (P = 0.007). Moreover, soluble CD147 showed a better performance in distinguishing HCC compared with alpha-fetoprotein. CONCLUSIONS: The extracellular domain of soluble CD147 enhances the secretion of MMP-2 from HCC cells, requiring the cooperation of membrane CD147 and activation of ERK, FAK, and PI3K/Akt signaling. The measurement of soluble CD147 may offer a useful approach in diagnosis of HCC.

Plasma CD147 reflects histological features in patients with lupus nephritis.

OBJECTIVE: A glycosylated transmembrane protein, CD147, has been implicated in regulating lymphocyte responsiveness and leukocyte recruitment. As lupus nephritis (LN) often follows a relapsing-remitting disease course, accurate understanding of the disease activity would be extremely helpful in improving prognosis. Unfortunately, neither clinical nor serological data can accurately reflect the histological features of LN. The present study investigated whether CD147 can accurately predict pathological features of LN. METHODS: Plasma and spot urine samples were collected from 64 patients who underwent renal biopsy between 2008 and 2011. Disease activity for LN tissues was evaluated using the biopsy activity index, and compared to levels of biomarkers including CD147. RESULTS: In LN tissues, CD147 induction was striking in injured glomeruli and infiltrating inflammatory cells, but not in damaged tubules representing atrophy. Plasma CD147 levels accurately reflected the histological disease activity. However, prediction using a single molecule would be quite difficult because of the complex pathogenesis of LN. The diagnostic accuracy of multiplex parameters indicated that the combination including plasma CD147 might yield excellent diagnostic abilities for guiding ideal LN therapy. CONCLUSION: Plasma CD147 levels might offer useful insights into disease activity as a crucial biomarker in patients with LN.

Circulating levels of soluble EMMPRIN (CD147) correlate with levels of soluble glycoprotein VI in human plasma.

Extracellular matrix metalloproteinase inducer (EMMPRIN; CD147), which binds to the platelet-specific collagen receptor glycoprotein (GP) VI, is expressed in a range of cell types including platelets and leukocytes, and has been implicated in neoplastic disease and atherosclerotic coronary disease. Both CD147 and GPVI can be shed from cell membranes and detected in plasma. However, while the relationship between soluble CD147 (sCD147), soluble GPVI (sGPVI) and standard markers of platelet activation has received little attention, such analysis may help reveal pathways mediating release of sCD147. We investigated the relationship between sCD147 and platelet markers including sGPVI, soluble and platelet-bound CD62P (P-selectin), active αIIbß3 (assessed by PAC-1 binding) and platelet CD147 in 25 patients with stable angina pectoris (SAP), 13 patients with no coronary artery disease (CAD) and 10 healthy donors. Plasma levels of sCD147 significantly correlated with sGPVI (r = 0.46, p = .004), but did not correlate with any other platelet markers examined. Linear regression analysis identified that sCD147 levels could be predicted by sGPVI levels (ß = .445, p = 0.003) and age (ß = 0.304, p = 0.038), but were independent of potential clinical confounders such as CAD, diabetes and medication usage. As sCD147 strongly correlates with platelet-specific sGPVI, a common platelet source and/or mechanism of release may contribute to sCD147 levels in vivo.