6403

SELP

selectin P (granule membrane protein 140kDa, antigen CD62);SELP;selectin P (granule membrane protein 140kDa, antigen CD62)

CD62 antigen-like family member P|GMP-140|P-selectin|granule membrane protein 140|granulocyte membrane protein|leukocyte-endothelial cell adhesion molecule 3|platelet activation dependent granule-external membrane protein|platelet alpha-granule membrane p

1q24.2

protein-coding

INTRODUCTION: We have previously demonstrated that chondroitin sulfate glycosaminoglycans (CS-GAGs) on breast cancer cells function as P-selectin ligands. This study was performed to identify the carrier proteoglycan (PG) and the sulfotransferase gene involved in synthesis of the surface P-selectin-reactive CS-GAGs in human breast cancer cells with high metastatic capacity, as well as to determine a direct role for CS-GAGs in metastatic spread. METHODS: Quantitative real-time PCR (qRT-PCR) and flow cytometry assays were used to detect the expression of genes involved in the sulfation and presentation of chondroitin in several human breast cancer cell lines. Transient transfection of the human breast cancer cell line MDA-MB-231 with the siRNAs for carbohydrate (chondroitin 4) sulfotransferase-11 (CHST11) and chondroitin sulfate proteoglycan 4 (CSPG4 ) was used to investigate the involvement of these genes in expression of surface P-selectin ligands. The expression of CSPG4 and CHST11 in 15 primary invasive breast cancer clinical specimens was assessed by qRT-PCR. The role of CS-GAGs in metastasis was tested using the 4T1 murine mammary cell line (10 mice per group). RESULTS: The CHST11 gene was highly expressed in aggressive breast cancer cells but significantly less so in less aggressive breast cancer cell lines. A positive correlation was observed between the expression levels of CHST11 and P-selectin binding to cells (P < 0.0001). Blocking the expression of CHST11 with siRNA inhibited CS-A expression and P-selectin binding to MDA-MB-231 cells. The carrier proteoglycan CSPG4 was highly expressed on the aggressive breast cancer cell lines and contributed to the P-selectin binding and CS-A expression. In addition, CSPG4 and CHST11 were over-expressed in tumor-containing clinical tissue specimens compared with normal tissues. Enzymatic removal of tumor-cell surface CS-GAGs significantly inhibited lung colonization of the 4T1 murine mammary cell line (P = 0.0002). CONCLUSIONS: Cell surface P-selectin binding depends on CHST11 gene expression. CSPG4 serves as a P-selectin ligand through its CS chain and participates in P-selectin binding to the highly metastatic breast cancer cells. Removal of CS-GAGs greatly reduces metastatic lung colonization by 4T1 cells. The data strongly indicate that CS-GAGs and their biosynthetic pathways are promising targets for the development of anti-metastatic therapies.

Histone deacetylase 1 (HDAC1) and metastasis-associated protein 1 (MTA1) form the nucleosome remodeling and histone deacetylation (NuRD) complex and may possibly play a central role in cancer development. However, limited data has been reported regarding the expression of both HDAC1 and MTA1. The aim of the present study was to clarify the clinical role of HDAC1 and MTA1 expression in colon cancer. Seventy-four patients with colon cancer, who underwent colectomy at our institution, were enrolled in this study. expression of HDAC1 and MTA1 was examined immunohistochemically. The patients were divided into four groups: HDAC1-positive group (n=58), HDAC1-negative group (n=16), MTA1-positive group (n=38) and MTA1-negative group (n=36). Clinicopathological factors and survival rates were compared between the groups. Regarding the clinicopathological factors, the depth of tumor invasion and stage correlated significantly with HDAC1 expression (p<0.05). Age, depth of tumor invasion and vascular invasion tended to correlate with MTA1 expression. The 5-year survival rate in the HDAC1-positive group (55.1%) was significantly worse compared to the HDAC1-negative group (86.5%) (p<0.05), and the 5-year survival rate of the MTA1-positive group (50.5%) was significantly worse than that of the MTA1-negative group (73.1%) (p=0.05). In patients with stages II-IV and curability A, B, the survival rate in those with HDAC1-positive expression was significantly worse than those with HDAC1-negative expression (p<0.05), and the survival rate of the MTA1-positive group tended to be worse than that of the MTA1-negative group (p=0.07). Overall survival in both the HDAC1 and MTA1-positive groups was significantly worse than overall survival of the other groups (p<0.05). Disease-free survival in both the HDAC1- and MTA1-positive groups, among patients with stages II-IV and curability A, B, was also significantly worse than that of the other groups (p<0.05). HDAC1 and MTA1 expression levels were significantly related to poorer prognosis. Therefore, HDAC1 and MTA1 expression levels are potential prognostic indicators for colon cancer.

OBJECTIVE: To investigate the expression and significance of vascular cell adhesion molecule-1 (VCAM-1) and P-selectin in hypopharyngeal carcinoma, and explore the relationship of VCAM-1, P-selectin and microvessel density (MVD). METHOD: expression of VCAM-1 and P-selectin were detected by immunohistochemistry staining in 40 specimens of hypopharyngeal carcinoma and 10 specimens of normal mucosa of oral pharynx. MVD was assessed based on the expression of CD34. RESULT: VCAM-1 and P-selectin were detected in 26 out of 40 (65%) and 29 out of 40 (72.5%) respectively in hypopharyngeal carcinoma, but none that in normal mucosa (P<0.01). MVD in hypopharyngeal carcinoma was higher than that in normal mucosa and it was related to lymph node metastasis. MVD level was significantly higher in VCAM-1 and P-selectin-positive specimens than in negative ones (P<0.01), which also positively correlated with the expression of VCAM-1 and P-selectin (P<0.01). The expression of P-selectin positively correlated with VCAM-1 in hypopharyngeal carcinoma specimens with lymph node metastasis. CONCLUSION: The higher expression of VCAM-1 and P-selectin play key roles in the invasion and metastasis of hypopharyngeal carcinoma and were correlated with vascularization.

Stimulated endothelial cells and activated platelets express P-selectin (CD62P), a member of the selectin family of cell adhesion molecules, which interacts with P-selectin glycoprotein ligand-1 (PSGL-1, CD162) for leukocyte rolling on stimulated endothelial cells and heterotypic aggregation of activated platelets onto leukocytes. Cross-linking of PSGL-1 by P-selectin also primes leukocytes intracellularly for cytokine and chemoattractant-induced beta2-integrin activation for firm adhesion of leukocytes. Furthermore, P-selectin mediates heterotypic aggregation of activated platelets to cancer cells and adhesion of cancer cells to stimulated endothelial cells. Here we provide a comprehensive summary of the functional roles and the biological importance of P-selectin-mediated cell adhesive interactions in the pathogeneses of inflammation, thrombosis, and the growth and metastasis of cancers.

metastasis formation is the major reason for the extremely poor prognosis in small cell lung cancer (SCLC) patients. The molecular interaction partners regulating metastasis formation in SCLC are largely unidentified, however, from other tumor entities it is known that tumor cells use the adhesion molecules of the leukocyte adhesion cascade to attach to the endothelium at the site of the future metastasis. Using the human OH-1 SCLC line as a model, we found that these cells expressed E- and P-selectin binding sites, which could be in part attributed to the selectin binding carbohydrate motif sialyl Lewis A. In addition, protein backbones known to carry these glycotopes in other cell lines including PSGL-1, CD44 and CEA could be detected in in vitro and in vivo grown OH1 SCLC cells. By intravital microscopy of murine mesenterial vasculature we could capture SCLC cells while rolling along vessel walls demonstrating that SCLC cells mimic leukocyte rolling behavior in terms of selectin and selectin ligand interaction in vivo indicating that this mechanism might indeed be important for SCLC cells to seed distant metastases. Accordingly, formation of spontaneous distant metastases was reduced by 50% when OH-1 cells were xenografted into E-/P-selectin-deficient mice compared with wild type mice (p = 0.0181). However, as metastasis formation was not completely abrogated in selectin deficient mice, we concluded that this adhesion cascade is redundant and that other molecules of this cascade mediate metastasis formation as well. Using several of these adhesion molecules as interaction partners presumably make SCLC cells so highly metastatic.