EMMPRIN Expression Research Articles

Expression and significance of EMMPRIN, MMP-9 and TIMP-1 in non-small cell lung carcinoma tissues of Guangxi Province, China

Background: Although radical operation to treat lung cancer is thought to be an important treatment measure, prognosis of advanced lung cancer is still poor. A reasonable treatment procedure for advanced lung cancer is an issue worthy of investigating nowadays. The further research on the role and the co-relationship of EMMPRIN, MMP-9, TIMP-1 will not only help to approach the mechanisms of the non-small cell lung carcinoma (NSCLC) incidence and development in depth, but also offer help for the gene targeted therapy of NSCLC. This study was to examine the expression and significance of tumor metastasis genes EMMPRIN , MMP-9 , TIMP-1 in Guangxi NSCLC)tissues, cancer adjacent tissues and benign lung tissues. Methods: Reverse transcription polymerase chain reaction (RT-PCR) was used to measure the expression level of EMMPRIN, MMP-9, TIMP-1 in 80 cases of NSCIC, 40 cases of tumor adjacent tissues and 10 cases of benign lesion lung tissues, then we analysed the sequence of PCR products of these gene. Results: The positive expression rate of EMMPRIN, MMP-9 and TIMP-1 in lung cancer cells was higher than in the cancer adjacent tissues (P 0.05). Patients with EMMPRIN or MMP-9 negative expression had a significantly longer OS (P=0.016 and P=0.026) than those with positive expression. Conclusions: In NSCLC, the detected level of EMMPRIN, MMP-9 and TIMP-1 was higher than in cancer adjacent tissue and benign lung tissue, suggesting that they were involved in NSCLC incidence and development; EMMPRIN, MMP-9, TIMP-1 expression can not only serve as the indicator to determine the pathological classification, metastasis and prognosis of NSCLC, but also offer help for targeted gene therapy of NSCLC.

Dihydrotestosterone induces pro-angiogenic factors and assists homing of MSC into the cardiac tissue.

The use of mesenchymal stem cells (MSC) as a therapeutic tool in cardiovascular diseases is promising. Since androgens exert some beneficial actions on the cardiovascular system, we tested our hypothesis that this hormone could promote MSC-mediated repair processes, also. Cultured MSCs isolated from Wharton's jelly were exposed to 30 nM dihydrotestosterone (DHT) for 1 or 4 days and the effects of the hormone on their growth/migration/adhesion and the underlying mechanisms were assessed. Results were obtained by real-time cell impedance measurements, and DNA quantification showed that DHT increased MSC proliferation by ~30%. As determined by xCELLigence system, DHT augmented (~2 folds) the migration of MSC toward cardiac tissue slices (at 12 h), and this effect was blocked by flutamide, an androgen receptor (AR) antagonist. Exposure of cells to DHT, upregulated the gene and protein expression of AR, EMMPRIN and MMP-9 and downregulated the expression of MMP-2 DHT significantly induced the release of nitric oxide by MSC (≥2-fold) and flutamide blocked this effect. When MSCs were co-cultured with cardiac slices, immunohistochemical analysis and qRT-PCR showed that the integration of DHT-stimulated MSC was significantly higher than that of in controls. In conclusion, our findings provide the first evidence that DHT promotes MSC growth, migration and integration into the cardiac slices. The modulating effects of DHT were associated with upregulation of ARs and of key molecules known to promote tissue remodeling and angiogenesis. Our findings suggest that priming of MSC with DHT may potentially increase their capability to regenerate cardiac tissue; in vivo studies are needed to confirm our in vitro findings.

Influence of intra-tumoral heterogeneity on the evaluation of BCL2, E-cadherin, EGFR, EMMPRIN, and Ki-67 expression in tissue microarrays from breast cancer

Introduction: The influence of intra-tumoral heterogeneity on the evaluation of immunohistochemical (IHC) biomarker expression may affect the analytical validity of new biomarkers substantially and hence compromise the clinical utility. The aim of this study was to examine the influence of intra-tumoral heterogeneity as well as inter-observer variability on the evaluation of various IHC markers with potential prognostic impact in breast cancer (BCL2, E-cadherin, EGFR, EMMPRIN and Ki-67).Material and methods: From each of 27 breast cancer patients, two tumor-containing paraffin blocks were chosen. Intra-tumoral heterogeneity was evaluated (1) within a single tumor-containing paraffin block (‘intra-block agreement’) by comparing information from a central, a peripheral tissue microarray (TMA) core and a whole slide section (WS), (2) between two different tumor-containing blocks from the same primary tumor (‘inter-block agreement’) by comparing information from TMA cores (central/peripheral) and WS. IHC markers on WS and TMA cores were evaluated by two observers independently, and agreements were estimated by Kappa statistics.Results: For BCL2, E-cadherin and EGFR, an almost perfect intra- and inter-block agreement was found. EMMPRIN and Ki-67 showed a more heterogeneous expression with moderate to substantial intra-block agreements. For both stainings, there was a moderate inter-block agreement that improved slightly for EMMPRIN, when using WS instead of TMA cores. Inter-observer agreements were found to be almost perfect for BCL2, E-cadherin and EGFR (WS: κ > 0.82, TMAs: κ > 0.90), substantial for EMMPRIN (κ > 0.63), but only fair to moderate for Ki-67 (WS: κ = 0.54, TMAs: κ = 0.33).Conclusions: BCL2, E-cadherin and EGFR were found to be homogeneously expressed, whereas EMMPRIN and Ki-67 showed a more pronounced degree of intra-tumoral heterogeneity. The results emphasize the importance of securing the analytical validity of new biomarkers by examining the intra-tumoral heterogeneity of immunohistochemical stainings applied to TMA cores individually in each type of cancer.

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

BackgroundPrevious 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.MethodsThe 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.ResultsNSCLC 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).ConclusionOverexpression of EMMPRIN was associated with lymphatic metastasis and advanced stage of NSCLC and test of serum EMMPRIN contributes to the NSCLC diagnosis.

Expression and significance of EMMPRIN, MMP-9 and TIMP-1 in non-small cell lung carcinoma tissues of Guangxi Province, China

Background: Although radical operation to treat lung cancer is thought to be an important treatment measure, prognosis of advanced lung cancer is still poor. A reasonable treatment procedure for advanced lung cancer is an issue worthy of investigating nowadays. The further research on the role and the co-relationship of EMMPRIN, MMP-9, TIMP-1 will not only help to approach the mechanisms of the non-small cell lung carcinoma (NSCLC) incidence and development in depth, but also offer help for the gene targeted therapy of NSCLC. This study was to examine the expression and significance of tumor metastasis genes EMMPRIN, MMP-9, TIMP-1 in Guangxi NSCLC)tissues, cancer adjacent tissues and benign lung tissues.

Characterisation of tumour-derived microvesicles in cancer patients’ blood and correlation with clinical outcome

ABSTRACTTo evaluate whether tumour-derived microvesicles (T-MV), originating from the plasma membrane, represent suitable cancer biomarkers, we isolated MV from peripheral blood samples of cancer patients with locally advanced and/or metastatic solid tumours (n = 330, including 79 head & neck cancers, 74 lung cancers, 41 breast cancers, 28 colorectal cancers and 108 with other cancer forms) and controls (n = 103). Whole MV preparations were characterised using flow cytometry. While MV carrying the tumour-associated proteins MUC1, EGFR and EpCAM were found to be enhanced in a tumour-subtype-specific way in patients’ blood, expression of the matrix metalloproteinase inducer EMMPRIN was increased independent of tumour type. Higher levels of EMMPRIN+-MV correlated significantly with poor overall survival, whereas the other markers were prognostic only in specific tumour subgroups. By combining all four tumour-associated antigens, cancer patients were separated from healthy controls with an AUC of up to 0.85. Ex vivo, whole MV preparations from cancer patients, in contrast to those of controls, induced a tumour-supporting phenotype in macrophages and increased tumour cell invasion, which was dependent on the highly glycosylated isoform of EMMPRIN. In conclusion, the detection of T-MV in whole blood, even in minor amounts, is feasible with standard techniques, proves functionally relevant and correlates with clinical outcome.

Immunohistochemical expression of EMMPRIN (CD147) in oral squamous cell carcinoma

ObjectiveEMMPRIN (CD147) is known largely for its ability to stimulate matrix metalloproteinase production in stromal cells. Since it modulates tumor microenvironment and orchestrate epithelial to mesenchymal transition, it is likely to play an important role in oral squamous cell carcinoma (OSCC) progression. The aim of the present study was to determine the immuohistochemical expression of EMMPRIN (CD147) and its association with clinicopathological parameters in OSCC patients presenting in our part of the world. MethodsTissue biopsies from 100 OSCC patients, with detailed account of their clinical data were included. After histological examination, samples were subjected to immunohistochemistry using monoclonal CD147 antibody. Cases were microscopically scored on the basis of staining intensity and proportion of positive tumor cells and were then assigned a total score from 0 to +3. Statistical analysis was carried out using SPSS 21.0. ResultsImmunohistochemical staining of the histological tissue sections of all n=100 cases of conventional (n=92), papillary 0SCC (n=6) and verrucous carcinoma (n=2) demonstrated extensive but varying immunopositivity for CD147 antibody. More than half of the OSCC cases (60%) expressed strong positive score. A significant association was found between EMMPRIN (CD147) total score and histological grades of the tumor (P=0.003). ConclusionsEMMPRIN protein is extensively expressed in OSCC patients with a significant association with degree of differentiation of the tumor. In this regard EMMPRIN might be an attractive target for antibody-based immunotherapy in OSCC patients in Pakistan.

Expression of PTEN and EMMPRIN in Lung Adenocarcinoma Tissues and Their Correlation with EGFR Mutation

Expression of PTEN and EMMPRIN in Lung Adenocarcinoma Tissues and Their Correlation with EGFR Mutation

The prostate metastasis suppressor gene NDRG1 differentially regulates cell motility and invasion.

Experimental and clinical evidence suggests that N‐myc downregulated gene 1 (NDRG1) functions as a suppressor of prostate cancer metastasis. Elucidating pathways that drive survival and invasiveness of NDRG1‐deficient prostate cancer cells can help in designing therapeutics to target metastatic prostate cancer cells. However, the molecular mechanisms that lead NDRG1‐deficient prostate cancer cells to increased invasiveness remain largely unknown. In this study, we demonstrate that NDRG1‐deficient prostate tumors have decreased integrin expression and reduced cell adhesion and motility. Our data indicate that loss of NDRG1 differentially affects Rho GTPases. Specifically, there is a downregulation of active RhoA and Rac1 GTPases with a concomitant upregulation of active Cdc42 in NDRG1‐deficient cells. Live cell imaging using a fluorescent sensor that binds to polymerized actin revealed that NDRG1‐deficient cells have restricted actin dynamics, thereby affecting cell migration. These cellular and molecular characteristics are in sharp contrast to what is expected after loss of a metastasis suppressor. We further demonstrate that NDRG1‐deficient cells have increased resistance to anoikis and increased invasiveness which is independent of its elevated Cdc42 activity. Furthermore, NDRG1 regulates expression and glycosylation of EMMPRIN, a master regulator of matrix metalloproteases. NDRG1 deficiency leads to an increase in EMMPRIN expression with a concomitant increase in matrix metalloproteases and thus invadopodial activity. Using a three‐dimensional invasion assay and an in vivo metastasis assay for human prostate xenografts, we demonstrate that NDRG1‐deficient prostate cancer cells exhibit a collective invasion phenotype and are highly invasive. Thus, our findings provide novel insights suggesting that loss of NDRG1 leads to a decrease in actin‐mediated cellular motility but an increase in cellular invasion, resulting in increased tumor dissemination which positively impacts metastatic outcome.

Cerium Oxide Nanoparticles as Novel Tool in Glioma Treatment: An In vitro Study

The interaction between cancer cells and the stromal microenvironment is an important aspect in tumor progression and reflects a big challenge especially in context of an efficient treatment of brain tumors such as gliomas. An intensive crosstalk between glioma cells and stromal cells such as endothelial cells inter alia being part of the blood-brain barrier (BBB) often results in the occurrence of a relapse and poor prognosis. A complete resection of gliomas which are characterized by a high proliferation rate and invasiveness as well as extensive vascularization is not possible until yet and a post-operative care with existing therapies is crucial and often not as successful as expected. In that context, redox-active nanoparticles such as cerium oxide nanoparticles (CNP) are a promising tool and may solve some treatment problems closely associated with brain tumors. In this study, CNP have a cytotoxic effect on anaplastic astrocytoma (grade III glioma) cells while the same concentration shows no cytotoxicity on microvascular endothelial cells used as stromal cell model. However, the migration capacity of endothelial cells, their invasiveness and the formation of new blood capillaries is lowered as well as the expression and/or secretion of the angiogenesis marker EMMPRIN, being a positive aspect in anticancer therapies. These data are a first indication that CNP may have potential for an application in a therapy against malignant gliomas (grade III and IV glioma).

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis

Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a transmembrane glycoprotein that is upregulated on leukocytes in active lesions in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Administration of anti-EMMPRIN Abs reduces the severity of EAE. Minocycline is a tetracycline antibiotic with immune-modulatory properties that decreases the severity of EAE; it was recently found to attenuate the conversion from a first demyelinating event to clinically definite MS in a phase III trial. We investigated whether and how minocycline affects the expression of EMMPRIN on T cells in culture and in mice afflicted with EAE. EMMPRIN expression in cultures of mouse splenocytes or human PBMCs was elevated upon polyclonal T cell activation, and this was reduced by minocycline correspondent with decreased P-Akt levels. An established MS medication, IFN-β, also diminished EMMPRIN levels on human cells whereas this was not readily observed for fingolimod or monomethylfumarate. In EAE-afflicted mice, minocycline treatment significantly reduced EMMPRIN levels on splenic lymphocytes at the presymptomatic (day 7) phase, and prevented the development of disease. Day 7 spleen transcripts from minocycline-treated EAE mice had a significantly lower MMP-9/TIMP-1 ratio, and significantly lower MCT-1 and CD98 levels, factors associated with EMMPRIN function. Day 16 (peak clinical severity) CNS samples from EAE mice had prominent representation of inflammatory perivascular cuffs, inflammatory molecules and EMMPRIN, and these were abrogated by minocycline. Overall, minocycline attenuated the activation-induced elevation of EMMPRIN on T cells in culture and in EAE mice, correspondent with reduced immune function and EAE CNS pathology.

EMMPRIN Down-regulating miR-106a/b Modifies Breast Cancer Stem-like Cell Properties via Interaction with Fibroblasts Through STAT3 and HIF-1α.

Extracellular matrix metalloproteinase inducer (EMMPRIN) is a heavily glycosylated protein and expresses in cancer cells widely, which plays important roles in tumor progression. However, the role of EMMPRIN in breast cancer stem-like cell properties by interaction with fibroblasts is not known. In the present study, we investigated the effects of fibroblasts on breast cancer stem-like cells. We found that fibroblasts activated by co-cultured breast cancer cells produced higher levels of EMMPRIN, which stimulated the stem-like cell specific, self-renewal and sphere-forming phenotype in breast cancer cells. Increased EMMPRIN expression in activated fibroblasts increased the expression of STAT3 and HIF-1α and showed cancer stem-like cell features in breast cancer cells. We also found that EMMPRIN could down-regulate miR-106a and miR-106b expression in breast cancer cells, which led to activating STAT3 and enhancing HIF-1α expression. Our results illustrated that EMMPRIN has an important role in breast cancer stem-like cells by activation STAT3/HIF-1α through interaction with cancer cells and fibroblasts. The study for the first time indicated that cancer cells and fibroblasts interaction promotes breast cancer cells showing stem-like cells through up-regulation EMMPRIN, and led to inhibiting miR-106a/b expression which targets both STAT3 and HIF-1α expression.

Effect of ADAM17 on EMMPRIN Expression after Vesicant Injury to the Cornea

In a cancer cell line expressing EMMPRIN and ADAM17, it has been shown that inhibiting EMMPRIN expression has no effect on ADAM17 levels, but inhibiting ADAM17 expression significantly inhibits EMMPRIN expression (Xu et al. Tumour Biol. 35:7575‐75‐86, 2014). To verify that this sequence of events was not a phenomenon peculiar to cancer cells, but instead represented a cell's normal response to injury, we examined whether ADAM17 was activated quickly in corneas injured by nitrogen mustard (NM), and whether inhibiting ADAM17 activation had any effect on EMMPRIN expression. Rabbit corneal organ cultures were exposed to topical NM for 0 min (i.e., immediately washed off), or 5 min, or 10 min. NM was washed off at the appointed times and the corneal proteins extracted for ADAM17 activity assays using the Innozyme TACE activity assay kit. This revealed that ADAM17 activity was turned on immediately by NM exposure. We then looked at EMMPRIN in exposed corneas, as well as in exposed corneas where ADAM17 activity was inhibited by hydroxamate NDH4417 (N‐octyl‐N‐hydroxy‐2‐[4‐hydroxy‐3‐methoxyphenyl acetamide). Western analyses showed that inhibiting ADAM17 in exposed corneas reduced EMMPRIN levels by 10 fold, as compared to NM‐exposed corneas not treated with the hydroxamate. Furthermore, reducing EMMPRIN resulted in reduced MMP‐9 activity. These data support the idea that, upon injury, ADAM17 activation impacts EMMPRIN expression, and thereby plays a key role in the downstream activation of matrix metalloproteinase, such as MMP9.Support or Funding InformationNIAMD U54AR055073 Counter ACT award and NIEHS P30ES005022 Center for Environmental Exposures and Disease

EMMPRIN (CD147) Expression in Smooth Muscle Tumors of the Uterus.

Smooth muscle tumors of the uterus are the most common mesenchymal tumors of the gynecologic tract. The vast majority of these are benign leiomyomas that present no diagnostic difficulty. Because some benign smooth muscle tumors may degenerate and uncommon variants exist, the diagnosis can be challenging in some cases. The goal of this research was to investigate EMMPRIN expression in leiomyomas, leiomyoma variants, and leiomyosarcomas (LMS) to determine whether it has a potential role in differential diagnosis. EMMPRIN expression was investigated with immunohistochemistry in 103 uterine smooth muscle tumors, which included 19 usual leiomyomas, 52 leiomyoma variants, and 32 LMS. They were evaluated on the basis of staining extent, intensity, and also their combined score, and the groups were compared. EMMPRIN expression was present in 3 of 19 (15.7%) usual leiomyomas, 23 of 52 (44.3%) leiomyoma variants, and 28 of 32 (87.5%) LMS. There were statistically significant differences in staining extent and intensity, and also for their combined scores, between the LMS and benign groups. Although uterine smooth muscle tumors are usually diagnosed easily with conventional diagnostic criteria, the differentiation of LMS from some variants of leiomyoma can be challenging based soley on morphology. EMMPRIN may be a valuable immunohistochemical marker for differentiating LMS from benign smooth muscle tumors in problematic cases.

EMMPRIN regulates tumor growth and metastasis by recruiting bone marrow-derived cells through paracrine signaling of SDF-1 and VEGF.

EMMPRIN, a cell adhesion molecule highly expressed in a variety of tumors, is associated with poor prognosis in cancer patients. Mechanistically, EMMPRIN has been characterized to contribute to tumor development and progression by controlling the expression of MMPs and VEGF. In the present study, by using fluorescently labeled bone marrow-derived cells (BMDCs), we found that the down-regulation of EMMPRIN expression in cancer cells reduces tumor growth and metastasis, and is associated with the reduced recruitment of BMDCs. Further protein profiling studies suggest that EMMPRIN controls BMDC recruitment through regulating the secretion of soluble factors, notably, VEGF and SDF-1. We demonstrate that the expression and secretion of SDF-1 in tumor cells are regulated by EMMPRIN. This study reveals a novel mechanism by which EMMPRIN promotes tumor growth and metastasis by recruitment of BMDCs through controlling secretion and paracrine signaling of SDF-1 and VEGF.

Slug silencing inhibited perineural invasion through regulation of EMMPRIN expression in human salivary adenoid cystic carcinoma.

Salivary adenoid cystic carcinoma (SACC) is the most frequent salivary gland malignancy with a unique characteristic that has been named perineural invasion (PNI). EMMPRIN is a transmembrane glycoprotein that has been demonstrated to promote PNI in SACC. Slug, one of the most effective promoters of the epithelial-to-mesenchymal transition (EMT), has been found to be associated with PNI in SACC. The aim of the present study was to investigate the roles and relationships of Slug, EMMPRIN, and E-cadherin in the PNI process of SACC. The expression levels of Slug, EMMPRIN, and E-cadherin in 115 primary SACC cases were statistically analyzed by immunohistochemistry. Simultaneously, the SACC cell line SACC-83 was transfected with recombinant plasmids of silencing Slug (si-Slug) and/or silencing EMMPRIN (si-EMMPRIN). The functions of Slug and EMMPRIN in the EMT and PNI process were assessed by reverse transcription PCR (RT-PCR), western blotting, morphological observation, scratch test, migration assay, and in vitro perineural invasion assay. The immunohistochemical statistics revealed that the high expression of Slug and EMMPRIN and the low expression of E-cadherin were significantly associated with the PNI of SACC (P < 0.05). Slug expression was significantly associated with EMMPRIN expression (P < 0.05), and Slug expression and EMMPRIN expression were both significantly negatively associated with E-cadherin expression (P < 0.05). Slug and EMMPRIN silencing both significantly inhibited EMMPRIN expression but promoted E-cadherin expression in SACC-83 cells (P < 0.01). The series of in vitro assays revealed that silencing of Slug, EMMPRIN, or both induced cell morphology changes and inhibited tumor cell motility and PNI ability in SACC-83 cells (P < 0.01). These results suggested that Slug silencing could inhibit the EMT process by downregulating EMMPRIN and then upregulating E-cadherin in the PNI process of SACC. The present study indicated that Slug and EMMPRIN are potential biomarkers and therapeutic targets for the diagnosis and treatment of PNI in human SACC.

Increased expression of metalloproteinase-2 and -9 (MMP-2, MMP-9), tissue inhibitor of metalloproteinase-1 and -2 (TIMP-1, TIMP-2), and EMMPRIN (CD147) in multiple myeloma

Introduction: Activity of metalloproteinases (MMP) is controlled both by specific tissue inhibitors (TIMP) and activators (extracellular matrix metalloproteinase inducer, EMMPRIN). There are few data available concerning concentration the bone marrow of MMP-2, MMP-9, TIMP-1, and TIMP-2, or EMMPRIM expression by bone marrow mesenchymal stromal cells (BMSCs) in patients with multiple myeloma (MM).Patients and methods: We studied 40 newly diagnosed, untreated patients: 18 males and 22 females with de novo MM and 11 healthy controls. Bone marrow was collected prior to therapy. BMSCs were derived by culturing bone marrow cells on MesenCult. Protein concentrations were determined in bone marrow plasma and culture supernatants by ELISA. EMMPRIN expression by BMSCs was assessed by flow cytometry.Results: The median concentrations of MMP-9, TIMP-1, and TIMP-2 in both marrow plasma and culture supernatants were significantly higher in MM patients than controls.Conclusion: EMMPRIN expression and ratios MMP-9/TIMP-1 and MMP-2/TIMP-2 were higher in MM patients, our results demonstrate that in MM patients MMP-2 and MMP-9 are secreted in higher amounts and are not balanced by inhibitors.

Significance of the expression of EMMPRIN, CD24 and p16INK4a promoter methylation in gastric carcinoma

Significance of the expression of EMMPRIN, CD24 and p16INK4a promoter methylation in gastric carcinoma

Emmprin Expression Predicts Response and Survival following Cisplatin Containing Chemotherapy for Bladder Cancer: A Validation Study

Neoadjuvant chemotherapy before cystectomy is recommended. To our knowledge the subset of patients likely to benefit has not been identified. We validate emmprin and survivin as markers of chemotherapy response. Tumor specimens were obtained before therapy from a total of 250 patients with T1-T4 bladder cancer enrolled in 2 randomized trials comparing neoadjuvant chemotherapy before cystectomy with a surgery only arm. Protein expression was determined by immunohistochemistry. Expression was categorized according to predefined cutoffs reported in the literature. Data were analyzed with the Kaplan-Meier method and Cox models. Patients in the chemotherapy cohort with negative emmprin expression had significantly higher down staging overall survival than those with positive expression (71% vs 38%, p<0.001). The values for cancer specific survival were 76% and 56%, respectively (p<0.027). In the cystectomy only cohort emmprin expression was not associated with overall survival (46% vs 35%, p=0.23) or cancer specific survival (55% vs 51%, p=0.64). Emmprin negative patients had an absolute risk reduction of 25% in overall survival (95% CI 11-40) and a number needed to treat of 4 (95% CI 2.5-9.3). Survivin expression was not useful as a biomarker in this study. Limitations were the retrospective design and heterogeneity coupled with the time difference between the trials. Patients with emmprin negative tumors have a better response to neoadjuvant chemotherapy before cystectomy than those with positive expression.

Involvement of miR-485-5p in hepatocellular carcinoma progression targeting EMMPRIN

EMMPRIN plays important roles in cancer development, which includes EMMPRIN 1, 2, 3, and 4 isoforms. EMMPRIN2 is the main component in human cancers, but its regulation by miRNAs is still unclear. In this study, we will investigate the mechanism of EMMPRIN regulation in hepatocellular carcinoma (HCC) by miRNAs. Through RT-PCR, we found that EMMPRIN2 was the main isoform in HCC cells. EMMPRIN2 was down-regulated significantly by predicted miRNAs and miR-485-5p was one of the miRNA that regulated EMMPRIN in HCC cell lines. It was verified that EMMPRIN was a target gene of miR-485-5p by using luciferase analysis assay. We found that miR-485-5p was significantly downregulated in HCC tissues and that its expression was inversely correlated with the TNM stage and metastasis in HCC samples. Results of cellular functions in HCC showed that miR-485-5p could inhibit cell proliferation and metastasis. Additionally, miR-485-5p overexpression suppressed HCC growth in vivo by down-regulation of EMMPRIN. Our study for the first time demonstrated that miR-485-5p represses HCC invasive and metastatic capacities by targeting EMMPRIN expression.