Abstract 2534: miRNA expression as potential biomarker for synovial sarcoma
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Abstract Synovial sarcoma (SS) is a rare tumor, with dismal survival when metastatic. SS contains a characteristic translocation (X;18)(p11;q11), representing the fusion of SYT on chromosome 18 with either SSX1, SSX2, or rarely SSX4 on chromosome X The resulting fusion genes appear to be mutually exclusive and concordant in primary and metastatic tumours. New prognostic and predictive factors are needed. Chemokine receptor 4 (CXCR4) is a seven-transmembrane G protein-coupled chemokine receptor and it is the chemokine receptor most commonly expressed in tumour cells, involved in cell migration and invasion, as well as angiogenesis. microRNAs (miRNAs) are involved in post-transcriptional gene expression regulation and control important physiological processes like development, cell differentiation and cell signaling. Altered expression of miRNAs is strongly correlated with the malignant phenotype and there is data reporting a strong association between microRNA expression, patient age and STS prognosis. By three different databases (miRBase, TargetScan , miRanda) and by literature data we identified two miRNA regulators of CXCR4, miR-133b and miR-494. The expression of these miRNAs was evaluated by RT-PCR in 42 SS primary samples stored at Rizzoli biobank. 20 tissues from non oncologic patients were used as control. Our results showed a significant lower expression of miR-133b and miR-494 (respectively p=0.0005 and p=0.001) when compared to non tumor tissue. In vitro study on SW982 cell line with miR-133b precursor show a CXCR4 downregulation and a decrease of cell proliferation. Our preliminary data confirmed a miR-133b and miR-494 downregulation in SS. Correlation with clinical data, with CXCR4 expression and in vitro studies also with miR-494 in several SS cell lines are on-going to better investigate their role as potential prognostic and therapeutic markers. Citation Format: Laura Pazzaglia, Serena Pollino, Mattia Vitale, Amalia Conti, Piero Picci, Maria Serena Benassi. miRNA expression as potential biomarker for synovial sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2534. doi:10.1158/1538-7445.AM2017-2534Keywords:
Synovial Sarcoma
MiRBase
Chemokine receptor CCR5
Tissue tropism
CCR1
CCR5 receptor antagonist
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The CXCR4 chemokine receptor plays an essential role in the homing of cells to organs expressing its ligand, CXCL12. CXCR4 expressed on tumor cells might regulate their traffic during metastasis. Here, we investigated whether the activation of CXCR4 on B16 murine melanoma cells regulates biological functions associated with metastasis, in vitro and in vivo. Flow cytometry and PCR analysis showed that B16 constitutively expresses high levels of CXCR4 (CXCR4-B16). Biological assays showed that the activation of CXCR4, by its ligand CXCL12, increases the migration, invasion, and proliferation of CXCR4-B16. AMD3100 significantly inhibited the stimulatory migrating effect induced by CXCL12. Treatment of CXCR4-B16 with CXCL12 increases their adhesion to liver sinusoidal endothelial cell (LSEC) monolayers. LSEC, expressing CXCL12, increased the migration of CXCR4-B16. In a liver metastasis model, CXCR4-B16 metastasis was associated with an increased expression of CXCL12 in LSEC territories. CXCR4-B16 cells were located close to LSEC microenvironments expressing CXCL12. Increased liver metastasis was observed after injecting CXCR4-B16 cells previously treated with CXCL12. Our results provide evidence showing that CXCR4 plays an important role in regulating biological functions associated with B16 liver metastasis.
CXCR4 antagonist
Homing (biology)
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The CXCR4/CXCL12 pathway has recently been reported to be involved in stimulating the metastasis of many different neoplasms, in which CXCR4 activates various phenomena such as chemotaxis, invasion, angiogenesis and proliferation. The purpose of this study was to analyze a possible association between the expression of chemokine receptors CXCR4, CCR6 and CCR7 with the clinicopathological features of cutaneous malignant melanoma, and to assess the usefulness of these chemokine receptors for diagnosis and prognosis. In our study, a percentage of immunoexpression of both CXCR4 and its ligands CXCL12 was associated with high clinical risk. In contrast, the patients with a low immunoexpression of CXCR4 and CXCL12 had low clinical risk. CCR6 and CCR7 immunoexpressions were also correlated with some clinical parameters, but seemed no more useful than CXCR4. These data suggest that the assessment of CXCR4 immunoexpression is a novel tool for predicting tumor aggressiveness in malignant melanomas, and in particular, a high immunoexpression percentage of CXCR4 and CXCL12 might be a sign of a poor prognosis.
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[Objective]To explore distribution of chemokine receptor CXCR4 on clear cell renal carcinoma. CXCR4 were stained on clear cell renal carcinoma samples with monoclonal antibody by immunohistochemistry and the results were statistically analyzed With their surgical,pathological and clinical data. All the samples were positively stained with CXCR4.They were divided into focal and diffuse groups based on the staining pattern and the diffuse group was divided into the high-expression and low-expression ones.The significant difference was found between focal and diffuse groups,high-expression and low-expression groups as well. [Conclusion] Expression of CXCR4 may be close related with prognosis and metastasis.
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Radiotherapy plays an important role in the treatment of malignant head and neck tumors. Chemokines are chemotactic cytokines, which can induce tumor proliferation as well as metastasis, although the influence of chemokines and their signaling pathways via chemokine receptors is not fully understood. Moreover, the radiation-induced expression of chemokines and chemokine receptors is poorly studied. Therefore, the purpose of this work was to analyze the expression of the chemokines of the CC-and CXC-class and their receptors in untreated and in irradiated squamous cell carcinoma of the head and neck (SCCHN). The expression of chemokines and chemokine receptors in 15 head and neck carcinoma cell lines and two normal tissue cell lines was analyzed. The spontaneous expression and the expression 6 hours after irradiation with 2 Gy was determined. To validate the results, certain chemokines and chemokine receptors were re-analyzed in selected cell lines. In this second independent analysis the expression was detected for 48 hours after irradiation. Gene expression of chemokines and their receptors was detected by real-time PCR. In addition, the protein expression of two chemokines was analyzed by ELISA. The results of the first analysis showed, that the chemokine receptors were less widely expressed in the investigated cell lines than the chemokines. Irradiation with 2 Gy caused an altered expression of the chemokines and chemokine receptors in all investigated cell lines. Radiation caused up- and downregulation in the expression of the chemokines, whereas the expression of the investigated receptors was predominantly downregulated after irradiation. The results of the chemokine expression were validated in the second, independent analysis. Radiation caused again up- and downregulation in the expression of the chemokines, but also showed that the expression of the chemokines and its receptors varies over the entire period of 48 hours after irradiation. The protein expression of the chemokines CXCL1 and CXCL12 corresponded well with the mRNA expression. In summary, irradiation of squamous cell carcinoma of the head and neck (SCCHN) and normal tissue cells caused a radiation-induced change of gene expression of the chemokine and its receptors. The results of this analysis show the complexity of the topic, so further studies will be needed to fully understand the influence of chemokines and chemokine receptors and their effect under a treatment of squamous cell carcinoma of the head and neck.
CCR10
CCL7
CXC chemokine receptors
CCR3
CCL13
CCR1
CCL21
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Monocyte
CCR2
CCR1
CCL13
CC chemokine receptors
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In different tumour entities, expression of the chemokine receptor 4 (CXCR4) has been linked to tumour dissemination and poor prognosis. Therefore, we evaluated, if the expression of CXCR4 exerts similar effects in human hepatocellular carcinoma (HCC). Expression analysis and functional assays were performed in vitro to elucidate the impact of CXCL12 on human hepatoma cells lines. In addition, expression of CXCR4 was evaluated in 39 patients with HCC semiquantitatively and correlated with both, tumour and patients characteristics. Human HCC and hepatoma cell lines displayed variable intensities of CXCR4 expression. Loss of p53 function did not impact on CXCR4 expression. Exposure to CXCL12 mediated a perinuclear translocation of CXCR4 in Huh7/Hep3B cells and increased the invasive potential of Huh7 cells. In HCC patients, CXCR4 expression significantly correlated with progressed local tumours (T-status; P=0.006), lymphatic metastasis (N-status; P=0.005) and distant dissemination (M-status; P=0.009), as well as with a decreased 3-year-survival rate (P=0.01). In summary, strong expression of CXCR4 is significantly associated with progressed hepatocellular cancer.
CXC chemokine receptors
CXCR4 antagonist
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The chemokine receptors CCR5 and CXCR4 are the main coreceptors of the macrophage-tropic and T-cell- tropic HIV-1 strains, respectively. CCR5 antagonists (such as TAK-779 and SCH-C) and CXCR4 antagonists (such as AMD3100 and T22) can block HIV-1 entering their target cells by binding to CCR5 and CXCR4, respectively. The mechan- isms of HIV-1 binding to these two coreceptors and progress of research and development of the coreceptor antagonists are reviewed.
CCR5 receptor antagonist
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CCR5 and CXCR4 are the two main coreceptors essential for HIV entry. Therefore, these chemokine receptors have become important targets in the search for anti-HIV agents. Here, we describe the establishment of a novel CD4+ cell line, U87.CD4.CCR5.CXCR4, stably expressing both CCR5 and CXCR4 at the cell surface. In these cells, intracellular calcium signalling through both receptors can be measured in a single experiment upon the sequential addition of CXCR4- and CCR5-directed chemokines. The U87.CD4.CCR5.CXCR4 cell line reliably supported HIV-1 infection of diverse laboratory-adapted strains and primary isolates with varying coreceptor usage (R5, X4 and R5/X4) and allows to investigate the antiviral efficacy of combined CCR5 and CXCR4 blockade. The antiviral effects recorded in these cells with the CCR5 antagonist SCH-C and the CXCR4 antagonist AMD3100 were similar to those noted in the single CCR5- or CXCR4-transfected U87.CD4 cells. Furthermore, the combination of both inhibitors blocked the infection of all evaluated HIV-1 strains and isolates. Thus, the U87.CD4.CCR5.CXCR4 cell line should be useful in the evaluation of CCR5 and CXCR4 antagonists with therapeutic potential and combinations thereof.
CCR5 receptor antagonist
CXCR4 antagonist
Chemokine receptor CCR5
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