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  • proliferation  (5)
  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; INVASION ; proliferation ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; human ; INHIBITION ; LUNG ; COMMON ; lung cancer ; LUNG-CANCER ; HEPATOCELLULAR-CARCINOMA ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; LINES ; FAMILY ; TISSUES ; DYNAMICS ; CELL-LINES ; DOWN-REGULATION ; MEMBERS ; SEQUENCE ; TARGET ; LOCALIZATION ; MIGRATION ; MICROTUBULES ; MORPHOLOGY ; adenocarcinoma ; squamous cell carcinoma ; OVEREXPRESSION ; cell lines ; non-small cell lung cancer ; HUMAN BREAST-CANCER ; MATRIX ; CELL CARCINOMA ; FAMILIES ; cell proliferation ; USA ; MICROTUBULE DYNAMICS ; MOTILITY ; SQUAMOUS-CELL ; MALIGNANT PHENOTYPE ; therapeutic ; WELL ; CELL-LUNG-CANCER ; additive ; HUMAN HEPATOCARCINOGENESIS ; MYC EXPRESSION
    Abstract: Dynamic instability of the microtubule network modulates processes such as cell division and motility, as well as cellular morphology. Overexpression of the microtubule-destabilizing phosphoprotein stathmin is frequent in human malignancies and represents a promising therapeutic target. Although stathmin inhibition gives rise to antineoplastic effects, additional and functionally redundant microtubule-interacting proteins may attenuate the efficiency of this therapeutic approach. We have systematically analyzed the expression and potential protumorigenic effects of stathmin family members in human non-small cell lung cancer (NSCLC). Both stathmin and stathmin-like 3 (SCLIP) were overexpressed in adenocarcinoma as well as squamous cell carcinoma (SCC) tissues and induced tumor cell proliferation, migration, and matrix invasion in respective cell lines. Accordingly, reduced stathmin and SCLIP levels affected cell morphology and were associated with a less malignant phenotype. Combine inhibition of both factors caused additive effects on tumor cell motility, indicating partial functional redundancy. Because stathmin and SCLIP expression significantly correlated in NSCLC tissues, we searched for common upstream regulators and identified the far upstream sequence element-binding protein-1 (FBP-1) as a pivotal inducer of several stathmin family members. Our results indicate that the coordinated overexpression of microtubule-destabilizing factors by FBP-1 is a critical step to facilitate microtubule dynamics and subsequently increases proliferation and motility of tumor cells. [Cancer Res 2009;69(6):2234-43]
    Type of Publication: Journal article published
    PubMed ID: 19258502
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  • 2
    Keywords: brain ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; INVASION ; proliferation ; tumor ; CELL ; CELL-PROLIFERATION ; Germany ; human ; IN-VIVO ; MODEL ; VITRO ; VIVO ; GENE-EXPRESSION ; PROTEIN ; transcription ; cell line ; TISSUE ; TUMORS ; LINES ; MICE ; PATIENT ; TISSUES ; KERATINOCYTES ; SKIN ; T cell ; T-CELL ; CELL-LINES ; SIGNAL ; MOUSE ; STAGE ; UP-REGULATION ; MEMBRANE ; skin carcinogenesis ; CELL-LINE ; LINE ; ADHESION ; MIGRATION ; MORPHOLOGY ; INVOLVEMENT ; MOUSE MODEL ; TRANSLOCATION ; beta-catenin ; ECTODOMAIN ; cell lines ; SUBSTRATE-SPECIFICITY ; MATRIX ; E-cadherin ; ONCOLOGY ; RE ; CAPACITY ; keratinocyte ; cell proliferation ; LEVEL ; NUCLEAR ; USA ; TISSUE INHIBITOR ; cancer research ; in vivo ; PLASMID ; DEFECT ; PROMOTES ; matrix metalloproteinase ; METALLOPROTEINASE ; ectodomain shedding ; MATRIX-METALLOPROTEINASE ; OVARIAN-CARCINOMA ; GROWTH-CONTROL ; EXTRACELLULAR CLEAVAGE ; HUMAN TISSUE KALLIKREINS ; PROTEINASE-ACTIVATED RECEPTORS ; SERINE PROTEINASE ; SERUM BIOMARKER
    Abstract: Recently, we described phorbol ester-induced expression of the brain and skin serine proteinase Bssp/kallikrein 6 (Klk6), the mouse orthologue of human KLK6, in mouse back skin and in advanced tumor stages of a well-established multistage tumor model. Here, we show KLK6 up-regulation in squamous skin tumors of human patients and in tumors of other epithelial tissues. Ectopic Klk6 expression in mouse keratinocyte cell lines induces a spindle-like morphology associated with accelerated proliferation, migration, and invasion capacity. We found reduced E-cadherin protein levels in the cell membrane and nuclear translocation of beta-catenin in Klk6-expressing mouse keratinocytes and human HEK293 cells transfected with a KLK6 expression plasmid. Additionally, HEK293 cells exhibited induced T-cell factor-dependent transcription and impaired cell-cell adhesion in the presence of KLK6, which was accompanied by induced E-cadherin ectodomain shedding. Interestingly, tissue inhibitor of metalloproteinase (TIMP)-l and TIMP-3 interfere with KLK6-induced F-cadherin ectodomain shedding and rescue the cell-cell adhesion defect in vitro, suggesting the involvement of matrix metalloproteinase and/or a disintegrin and metalloproteinase (ADAM) proteolytic activity. In line with this assumption, we found increased levels of the mature 62-kDa ADAM10 proteinase in cells expressing ectopic KLK6 compared with mock controls. Finally, enhanced epidermal keratinocyte proliferation and migration in concert with decreased E-cadherin protein levels are confirmed in an in vivo Klk6 transgenic mouse model
    Type of Publication: Journal article published
    PubMed ID: 17804733
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  • 3
  • 4
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; proliferation ; SURVIVAL ; tumor ; carcinoma ; CELL ; CELL-PROLIFERATION ; Germany ; human ; INHIBITION ; VITRO ; HEPATOCELLULAR-CARCINOMA ; liver ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; RNA ; TISSUE ; LINES ; PATIENT ; ACTIVATION ; MECHANISM ; FAMILY ; REDUCTION ; TISSUES ; CONTRAST ; mechanisms ; DYNAMICS ; BINDING ; CELL-LINES ; DOWN-REGULATION ; MEMBERS ; treatment ; TARGET ; ELEMENT ; polymer ; hepatocarcinogenesis ; hepatocellular carcinoma ; MOBILITY ; CELL-LINE ; CANCER-CELLS ; MIGRATION ; MORPHOLOGY ; PHENOTYPE ; BINDING-PROTEINS ; C-MYC ; OVEREXPRESSION ; cell lines ; MITOSIS ; BINDING PROTEIN ; HUMAN BREAST-CANCER ; FAMILIES ; TUMOR-GROWTH ; PATIENT SURVIVAL ; cell proliferation ; structure ; MOLECULAR-MECHANISMS ; LEVEL ; bioavailability ; STATHMIN ; USA ; MICROTUBULE DYNAMICS ; MOTILITY ; HUMAN HEPATOCELLULAR-CARCINOMA ; DIVISION ; MALIGNANT PHENOTYPE ; MODIFIERS ; HUMAN HEPATOCARCINOGENESIS
    Abstract: Microtubule-dependent effects are partly regulated by factors that coordinate polymer dynamics such as the microtubule-destabilizing protein stathmin (oncoprotein 18). In cancer cells, increased microtubule turnover affects cell morphology and cellular processes that rely on microtubule dynamics such as mitosis and migration. However, the molecular mechanisms deregulating modifiers of microtubule activity in human hepatocarcinogenesis are poorly understood. Based on profiling data of human hepatocellular carcinoma (HCC), we identified far upstream element binding proteins (FBPs) as significantly coregulated with stathmin. Coordinated overexpression of two FBP family members (FBP-1 and FBP-2) in 〉70% of all analyzed human HCCs significantly correlated with poor patient survival. In vitro, FBP-1 predominantly induced tumor cell proliferation, while FBP-2 primarily supported migration in different HCC cell lines. Surprisingly, reduction of FBP-2 levels was associated with elevated FBP-1 expression, suggesting a regulatory interplay of FBP family members that functionally discriminate between cell division and mobility. Expression of FBP-1 correlated with stathmin expression in HCC tissues and inhibition of FBP-1 but not of FBP-2 drastically reduced stathmin at the transcript and protein levels. In contrast, further overexpression of FBP-1 did not affect stathmin bioavailability. Accordingly, analyzing nuclear and cytoplasmic areas of HCC cells revealed that reduced FBP-1 levels affected cell morphology and were associated with a less malignant phenotype. Conclusion: The coordinated activation of FBP-1 and FBP-2 represents a novel and frequent pro-tumorigenic mechanism promoting proliferation (tumor growth) and motility (dissemination) of human liver cancer cells. FBPs promote tumor-relevant functions by at least partly employing the microtubule-destabilizing factor stathmin and represent a new potential target structure for HCC treatment. (HEPATOLOGY 2009;50:1130-1139.)
    Type of Publication: Journal article published
    PubMed ID: 19585652
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  • 5
    Keywords: CANCER ; CELLS ; EXPRESSION ; proliferation ; tumor ; carcinoma ; CELL ; Germany ; INHIBITION ; MICROSCOPY ; PATHWAY ; PATHWAYS ; HEPATOCELLULAR-CARCINOMA ; PROTEIN ; PROTEINS ; TISSUE ; TUMORS ; MICE ; ACTIVATION ; CARCINOGENESIS ; BIOLOGY ; TARGET ; hepatocellular carcinoma ; CARCINOMA CELLS ; CANCER-CELLS ; LOCALIZATION ; PHENOTYPE ; CARCINOMAS ; STRATEGIES ; TARGETS ; pathology ; DIFFERENTIAL EXPRESSION ; PATTERN ; LIGHT ; tissue microarray ; adipophilin ; FATTY-ACID SYNTHASE ; TIP47 ; STRATEGY ; PROPOSAL ; HEPATIC STEATOSIS ; lipid droplet ; PERILIPIN
    Abstract: In many human cancers, lipogenic pathways are activated; in some tumors, such as hepatocellular carcinoma, this is reflected by the presence of visible lipid droplets. Yet, the biology of steatogenesis in malignant tumors is largely unknown. We have recently shown that lipid droplet-associated proteins of the PAT-family, named after their constituents perilipin (perilipin 1), adipophilin (perilipin 2), and TIP47 (perilipin 3) are differentially expressed in hepatic steatogenesis. We have comprehensively investigated PAT-expression in neoplastic steatogenesis as well as in respective normal tissues with immunohistology and electron microscopy as well as protein biochemical and molecular biological methods. By staining for PAT-proteins, we found lipid droplet accumulation to be a frequent phenomenon of carcinoma cells. Although adipophilin and TIP47 stained almost ubiquitously the rim of lipid droplets in various tumor types, especially those with clear cell phenotype, perilipin was restricted to lipid droplets of hepatocellular adenoma and carcinoma, sebaceous adenoma and carcinoma, and lipomatous tumors. In hepatocellular carcinoma, perilipin, adipophilin, and TIP47 were coexpressed, and showed regional heterogeneity with a predominantly mutually exclusive localization pattern. In step-wise carcinogenesis, adipophilin expression correlated with the proliferation rate and was upregulated during early tumorigenesis, whereas perilipin was often lost during hepatocarcinogenesis. In conclusion, expression analysis of PAT-proteins showed that by far more carcinomas contain (PAT-positive) lipid droplets than expected by conventional light microscopy. PAT-proteins, such as perilipin, are differentially expressed in different tumor types and thus may support diagnostic considerations. Because inhibition of lipogenesis has been shown to exert antineoplastic effects, PAT-proteins may represent targets for interventive strategies. Modern Pathology (2010) 23, 480-492; doi: 10.1038/modpathol.2009.191; published online 15 January 2010
    Type of Publication: Journal article published
    PubMed ID: 20081801
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