Characterization of candidate factors associated with the metastasis and progression of high-grade serous ovarian cancer / 中华医学杂志(英文版)

BACKGROUND@#High-grade serous ovarian cancer (HGSOC) is the biggest cause of gynecological cancer-related mortality because of its extremely metastatic nature. This study aimed to explore and evaluate the characteristics of candidate factors associated with the metastasis and progression of HGSOC.@*METHODS@#Transcriptomic data of HGSOC patients' samples collected from primary tumors and matched omental metastatic tumors were obtained from three independent studies in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were selected to evaluate the effects on the prognosis and progression of ovarian cancer using data from The Cancer Genome Atlas (TCGA) database. Hub genes' immune landscapes were estimated by the Tumor Immune Estimation Resource (TIMER) database. Finally, using 25 HGSOC patients' cancer tissues and 10 normal fallopian tube tissues, immunohistochemistry (IHC) was performed to quantify the expression levels of hub genes associated with International Federation of Gynecology and Obstetrics (FIGO) stages.@*RESULTS@#Fourteen DEGs, ADIPOQ , ALPK2 , BARX1 , CD37 , CNR2 , COL5A3 , FABP4 , FAP , GPR68 , ITGBL1 , MOXD1 , PODNL1 , SFRP2 , and TRAF3IP3 , were upregulated in metastatic tumors in every database while CADPS , GATA4 , STAR , and TSPAN8 were downregulated. ALPK2 , FAP , SFRP2 , GATA4 , STAR , and TSPAN8 were selected as hub genes significantly associated with survival and recurrence. All hub genes were correlated with tumor microenvironment infiltration, especially cancer-associated fibroblasts and natural killer (NK) cells. Furthermore, the expression of FAP and SFRP2 was positively correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage, and their increased protein expression levels in metastatic samples compared with primary tumor samples and normal tissues were confirmed by IHC ( P = 0.0002 and P = 0.0001, respectively).@*CONCLUSIONS@#This study describes screening for DEGs in HGSOC primary tumors and matched metastasis tumors using integrated bioinformatics analyses. We identified six hub genes that were correlated with the progression of HGSOC, particularly FAP and SFRP2 , which might provide effective targets to predict prognosis and provide novel insights into individual therapeutic strategies for HGSOC.

Imunoexpressão das tetraspaninas (CD9 E UPIII) no carcinoma urotelial de bexiga / Immunoexpression of tetraspanin (CD9 e UPIII) in bladder urothelial carcinoma

Introdução: O carcinoma urotelial da bexiga é uma doença de alta incidência e letalidade. Recentemente, tem sido caracterizado em subtipos moleculares, com diferenças prognósticas e de resposta terapêutica. As tetraspaninas estão implicadas na adesão celular e sinalização intercelular, interferindo diretamente em fenômenos como a morfogênese dos tecidos e migração. Uma vez que os subtipos moleculares luminal e basal correspondem, respectivamente, a fenótipos celulares urotelial bem diferenciado e de reserva basal, é possível que a expressão das tetraspaninas acompanhe esse racional, o que traria possibilidade de integração no cenário clínico. Metodologia: Amostras de 88 pacientes operados (cistectomia radical) por carcinoma urotelial, preservadas em parafina, foram organizadas em TMA ou cortes inteiros, submetidos a imuno-histoquímica. As reações foram analisadas por microscopia ótica convencional e acessadas quanto à intensidade de expressão - negativo, fraco e forte (escore subjetivo) e extensão de expressão ­ negativo, focal e difuso (baseado na porcentagem das células positivas, em cortes de 1-50%; >50%). Os tumores foram classificados em Luminal, Basal e Sem tipo definido, a partir da expressão imuno-histoquímica de GATA3, CK5/6 e CK14. A expressão citoplasmática das tetraspaninas (CD9 e UPIII) foi avaliada em tecidos tumoral e urotelial não neoplásico pareado, e correlacionadas com parâmetros patológicos e clínicos. Resultados: A idade média foi de 66.9 anos, com relação H:M de 2:1 e 72% de tabagistas ou ex-tabagistas. A maior parte (62%) das cirúrgicas foram indicadas por doença músculo-invasiva já ao diagnóstico e o restante por doença não músculo-invasiva extensa/recorrente ou progredida para carcinoma músculo invasor, sendo o estadiamento final na cistectomia 14%

Introduction: Urothelial carcinoma of the bladder is a disease with high incidences and letality. It has recently been carachterized in molecular subtypes, with differences regarding prognosis and response to treatment. Tetraspanins are implicated in cell adhesion and intercellular signaling, directly interfering in phenomena such as tissue morphogenesis and migration. Considering that luminal and basal molecular subtypes correspond, repectively, to well differentiated urotelial and basal reserve cell phenotypes, it is possible that tetraspanin expression may follow this rationale, which could bare potential to integration into the clinical scenario. Methodology: Paraffin-preserved samples from 88 patients submitted to radical cystectomy for urothelial carcinoma were organized into TMAs or whole sections, labeled with immunohistochemistry. Reactions were analyzed by conventional optical microscopy and accessed as to expression intensity ­ negative, weak or strong (subjective scoring) and extent ­ negative, focal or diffuse (based on percentage of positive cells in cut-offs of 1-50%; >50%). Tumors were classified into Luminal, Basal and Non-type based on immunoexpression of GATA3, CK14 and CK5/6. Cytoplasmic expression of tetraspanins was evaluated in neoplastic and non-neoplastic urotelial tissue and correlated with clinical and morphological parameters. Results: Mean age was 66.9 years, with M:F ratio of 2:1 and 72% smokers or ex-smokers. The majority (62%) of surgeries was indicated because of muscle-invasive disease at presentation and the rest for extensive/recurrent non muscle-invasive disease or progression to invasive carcinoma (final pathological stage at cystectomy: 14%

Urinary Nucleic Acid TSPAN13-to-S100A9 Ratio as a Diagnostic Marker in Prostate Cancer

The potential use of urinary nucleic acids as diagnostic markers in prostate cancer (PCa) was evaluated. Ninety-five urine samples and 234 prostate tissue samples from patients with PCa and benign prostatic hyperplasia (BPH) were analyzed. Micro-array analysis was used to identify candidate genes, which were verified by the two-gene expression ratio and validated in tissue mRNA and urinary nucleic acid cohorts. Real-time quantitative polymerase chain reaction (qPCR) was used to measure urinary nucleic acid levels and tissue mRNA expression. The TSPAN13-to-S100A9 ratio was selected to determine the diagnostic value of urinary nucleic acids in PCa (P = 0.037) and shown to be significantly higher in PCa than in BPH in the mRNA and nucleic acid cohort analyses (P < 0.001 and P = 0.013, respectively). Receiver operating characteristic (ROC) analysis showed that the area under the ROC curve was 0.898 and 0.676 in tissue mRNA cohort and urinary nucleic acid cohort, respectively. The TSPAN13-to-S100A9 ratio showed a strong potential as a diagnostic marker for PCa. The present results suggest that the analysis of urine supernatant can be used as a simple diagnostic method for PCa that can be adapted to the clinical setting in the future.

Expression and clinical significance of Tspan 1 and Integrin α6 in human pancreatic ductal adenocarcinoma / 中华外科杂志

<p><b>OBJECTIVE</b>To explore the clinicopathological significance and relationship of Tspan 1 and Integrin α6 expression in pancreatic ductal adenocarcinoma (PDAC) tissue and pancreatic cancer cell lines.</p><p><b>METHODS</b>Immunohistochemistry was used to detect the expression of Tspan 1 and Integrin α6 in 95 paraffin-embedded PDAC specimens and 55 adjacent non-cancerous pancreatic tissues which were collected from May 2004 to January 2013.Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detected the protein and mRNA expression in 16 paired fresh PDAC specimens of the pancreas and adjacent non-cancerous pancreatic tissues and 6 different pancreatic cancer cell lines.χ(2) test, Spearman-rank correlation analysis, Kaplan-Meier method and multivariate Cox regression analysis were used to analyze the data.</p><p><b>RESULTS</b>Tspan 1 and Integrin α6 were significantly over-expressed in PDAC than in adjacent non-cancerous pancreatic tissues (χ(2) = 7.429, P < 0.05; χ(2) = 15.1, P < 0.01). Lymph node metastasis, TNM stage and post-operation recurrence were positively correlated with the expression of Tspan 1 (χ(2) = 6.688, P < 0.01; χ(2) = 13.055, P < 0.01; χ(2) = 6.116, P < 0.05) . TNM stage was positively correlated with the expression of Integrin α6 (χ(2) = 8.896, P < 0.05) . Tspan 1 was correlated with Integrin α6 (r = 0.223, P < 0.05) . The expressions of Tspan 1 and Integrin α6 were negatively correlated with survival time (χ(2) = 5.263, P < 0.05;χ(2) = 10.124, P < 0.01) . Multivariate analysis revealed that Tspan 1 and Integrin α6 expressions were independent prognostic factors in PDAC patients (χ(2) = 6.152, P < 0.05; χ(2) = 9.479, P < 0.01). Western blot (t = 2.278, P < 0.05; t = 3.153, P < 0.05) and qRT-PCR (t = 2.439, P < 0.05; t = 3.258, P < 0.05) showed that Tspan 1 and Integrin α6 expressions were higher in PDAC tissues than in adjacent non-cancerous pancreatic. Tspan 1 and Integrin α6 were expressed in all six pancreatic cancer cell lines.In SW1990 which derived from metastasis PDAC, Tspan 1 and Integrin α6 expressions were higher than the cell lines from primary tumor.</p><p><b>CONCLUSION</b>Tspan 1 and Integrin α6 expression can up-regulate the invasion and metastasis of PDAC and may be used to predict the prognosis of PDAC.</p>

Significance of CD37 expression in malignant B cells / 中国实验血液学杂志

The aim of this study was to clarify the clinical significance of CD37 expression in B cells from B acute lymphoblastic leukemia (B-ALL) and B cell non-Hodgkin's lymphoma (B-NHL). The expression level of CD37 on B cells from bone marrow samples of normal controls (n = 19), B-ALL patients [including untreated cases (n = 5) and cases with minimal residual disease (MRD, n = 15)] and B-NHL patients (n = 25) whose bone marrow was involved by lymphoma cells, was detected by multiple parameter flow cytometry. The results indicated that the B cells from both untreated cases and cases with MRD lowly expressed CD37 (1.04 ± 0.24 and 1.50 ± 0.89), the normal precursor B cells (control cases) also lowly expressed CD37 (1.64 ± 0.52). There was no difference of CD37 expression level between 3 groups of cases(P > 0.05). Meanwhile the normal mature B cells and B-NHL cells highly expressed CD37 (14.23 ± 7.84 and 14.53 ± 10.93), but there was no difference of CD37 expression between them (P > 0.05). The comparison of CD37 expression level in normal B cells of development stages showed that the progenitor B cells lowly expressed CD37 (0.88 ± 0.17), the CD37 expression of precursor B cells was enhanced (2.44 ± 0.69), while the CD37 expression level of mature B cells was highest. It is concluded that the low expression of CD37 is not the characteristic of B- ALL cells. The expression level of CD37 increases gradually during the mature process of B cells, i.e, the expression level of CD37 does not associate with benignity or malignancy of B cells.

The preliminary study of structure variation related to keloid based on the whole-gene resequencing technique / 中华整形外科杂志

<p><b>OBJECTIVE</b>To investigate the genome structure variation (SV) related with keloid using the whole-gene resequencing technology.</p><p><b>METHODS</b>We studied a keloid pedigree containing 4 generation of 27 people. 5 people (4 cases of keloid patients, and 1 case of normal) were selected to extract the genomic DNA. Then the whole-gene resequencing technique was used to check the variations.</p><p><b>RESULTS</b>Through database comparison and variation annotation analysis, we obtained 2 SVs associated with keloid formation. We used DAVID software to do the gene ontology and pathway analysis. We found a 168 bp inversion in gene tetraspanin 8 (TSPAN8) in all keloid patients, which contained the forth exon of TSPAN8.</p><p><b>CONCLUSIONS</b>There was no report about SVs related to keloid. In this study, we found 2 SVs associated with keloid, especially TSPAN8. The tumor cells express the TSPAN8 can up-regulate the vascular endothelial growth factor and its receptors, promote the adjacent fibroblasts secrete matrix metalloproteinases and uridylyl phosphate adenosine. So we hypothesis that the inversion of the forth exon in TSPAN8 may lead to the signal transduction disorder in the keloid patients. This study was a preliminary research. It needs a further study containing large sample to confirm.</p>

Exosomes: mediators of communication in eukaryotes

In addition to the established mechanisms of intercellular signaling, a new way of communication has gained much attention in the last decade: communication mediated by exosomes. Exosomes are nanovesicles (with a diameter of 40-120 nm) secreted into the extracellular space by the multivesicular endosome after its outer membrane fuses with the plasma membrane. Once released, exosomes modulate the response of the recipient cells that recognize them. This indicates that exosomes operate in a specific manner and participate in the regulation of the target cell. Remarkably, exosomes occur from unicellular organisms to mammals, suggesting an evolutionarily conserved mechanism of communication. In this review we describe the cascade of exosome formation, intracellular traffic, secretion, and internalization by recipient cells, and review their most relevant effects. We also highlight important steps that are still poorly understood.

Platelet receptors: an instrumental of platelet physiology

Platelets play an important role in hemostasis, inflammation, host defense, tumor growth and metastasis. Platelets receptors are instrumental in platelet-platelet aggregation and interaction of platelets with leukocytes, endothelial cells and coagulation factors. These receptors are also the targets for antiplatelet drugs. This review focuses on the role of platelet receptors in human physiology. Data were extracted from peer-reviewed journals using MEDLINE and EMBASE databases, and the following terms [platelets, platelet receptors, CD markers, integrins, tetraspanins, transmembrane receptors, prostaglandin receptors, immunoglobulin superfamily receptors] were used

Identification, structure and function of a novel tetraspaninhomologue from Spirometra erinaceieuropaei

OBJECTIVE@#To identify a full length c DNA sequence of a novel tetraspanin (TSP) homologue from Spirometra erinaceieuropaei and to predict the structure and function of its encoding protein using bioinformatics methods.@*METHODS@#Using the NCBI, EMBI, Expasy and other online sites, the open reading frame (ORF), conserved domain, physical and chemical parameters, signal peptide, transmembrane domain, epitope, topological structures of the protein sequences were predicted. And Vector NTI software was used for multiple sequence alignment and phylogenetic tree construction.@*RESULTS@#The target sequence was 1132 bp length with a 681 bpbiggest ORF encoding 226 amino acids protein with typical TSP conserved domain. It was confirmed as full length c DNA of TSP16 from Spirometra erinaceieuropaei and named as SeTSP16 (GenBank accession number: JF728872). The predicted molecular weight and isoelectric point of the deduced protein were 24 750.5 Da and 7.88 Da, respectively. Compared with TSP16s from Schistosoma japonicum and Schistosoma mansoni, it showed similarity of 59% and 59%, respectively. SeTSP16 contained four transmembrane domains (TM1-4), intracellular N and C-termini, one short small extracellular loop and one large extracellular loop. Four major epitopes that were significant different from the corresponding epitope regions of TSP16 from Schistosoma mansoni and Schistosoma japonicum were predicted.@*CONCLUSIONS@#The full length c DNA sequences of SeTSP16 are identified. It encodes a transmembrane protein which might be an ideal diagnosis antigen and target molecule for antiparasitic drugs.

Function of TM4SF-integrins complexes in regulating cancer metastasis / 浙江大学学报·医学版

Distant metastasis is the main cause of cancer death. Tetraspanins (transmembrane 4 superfamily, TM4SF) is capable of forming transmembrane complexes with integrin family participating in cell adhesion, migration and tumor metastasis. This review elucidates the structure of tetraspanins and its function in regulating metastasis as form of multimolecular transmembrane complexes with integrin.

Expression of TM4SF9 in human trophoblasts / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the expression of TM4SF9 in the villi of early pregnancy, hydatidiform mole, invasive hydatidiform mole and chorionic carcinoma tissue.</p><p><b>METHODS</b>Immunohistochemistry was used to detect the expression of TM4SF9 in normal villi of early pregnancy, hydatidiform mole, invasive hydatidiform mole and chorionic carcinoma tissues.</p><p><b>RESULTS</b>TM4SF9 was expressed in the cytotroblasts but not in the syncytiotrophoblast of normal villi. The intensity of TM4SF9 expression increased in the order of normal villi, hydatidiform mole, invasive hydatidiform mole and chorionic carcinoma, with strong positivity rates of 0, 10%, 36.4% and 100%, respectively, showing significant differences between the samples (P<0.001).</p><p><b>CONCLUSION</b>TM4SF9 expression in the trophoblasts may relate to their invasiveness and play an important role in the metastasis of trophoblastic tumor.</p>