α2-Macroglobulin Inhibits the Malignant Properties of Astrocytoma Cells by Impeding β-Catenin Signaling

Lindner, Inge; Hemdan, Nasr Y. A.; Buchold, Martin; Huse, Klaus; Bigl, Marina; Oerlecke, Ilka; Ricken, Albert; Gaunitz, Frank; Sack, Ulrich; Naumann, Andreas; Hollborn, Margrit; Thal, Dietmar Rudolf; Gebhardt, Rolf; Birkenmeier, Gerd

doi:10.1158/0008-5472.can-09-1462

Cited by 56 publications

(47 citation statements)

References 46 publications

(40 reference statements)

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“…Amongst these, adherens junctions connect intercellular adhesion to the actin cytoskeleton and thus are crucial not only during morphogenesis of epithelial tissues but also in tissue homeostasis. The adhesive backbone of adherens junctions is formed by cadherins [12], calcium-dependent transmembrane glycoproteins, which via binding to catenins like b-catenin, a-catenin and/or p120-catenin are linked to and interact with the cytoskeleton and also play important roles in cell polarity and signaling [13,14]. In healthy liver, it was shown that E-cadherin is expressed in periportal but not in perivenous hepatocytes [15].…”

Section: Introductionmentioning

confidence: 99%

Pathological implications of cadherin zonation in mouse liver

Hempel

Schmitz

Winkler

et al. 2015

Cell. Mol. Life Sci.

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Both acute and chronic liver diseases are associated with ample re-modeling of the liver parenchyma leading to functional impairment, which is thus obviously the cause or the consequence of the disruption of the epithelial integrity. It was, therefore, the aim of this study to investigate the distribution of the adherens junction components E- and N-cadherin, which are important determinants of tissue cohesion. E-cadherin was expressed in periportal but not in perivenous hepatocytes. In contrast, N-cadherin was more enriched towards the perivenous hepatocytes. In agreement, β-catenin, which links both cadherins via α-catenin to the actin cytoskeleton, was expressed ubiquitously. This zonal expression of cadherins was preserved in acute liver injury after treatment with acetaminophen or partial hepatectomy, but disrupted in chronic liver damage like in non-alcoholic steatohepatitis (NASH) or α1-antitrypsin deficiency. Hepatocyte proliferation during acetaminophen-induced liver damage was predominant at the boundary between the damaged perivenous and the intact periportal parenchyma indicating a minor contribution of periportal hepatocytes to liver regeneration. In NASH livers, an oval cell reaction was observed pointing to massive tissue damage coinciding with the gross impairment of hepatocyte proliferation. In the liver parenchyma, metabolic functions are distributed heterogeneously. For example, the expression of phosphoenolpyruvate carboxykinase and E-cadherin overlapped in periportal hepatocytes. Thus, during liver regeneration after acute damage, the intact periportal parenchyma might sustain essential metabolic support like glucose supply or ammonia detoxification. However, disruption of epithelial integrity during chronic challenges may increase susceptibility to metabolic liver diseases such as NASH or vice versa. This might suggest the regulatory integration of tissue cohesion and metabolic functions in the liver.

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Section: Introductionmentioning

confidence: 99%

Pathological implications of cadherin zonation in mouse liver

Hempel

Schmitz

Winkler

et al. 2015

Cell. Mol. Life Sci.

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“…[17]’[23] As a protease inhibitor, it is reported to inhibit tumor cell proliferation when binding to low-density lipoprotein receptor-related protein 1 (LRP 1). [24] The N-glycosylation of A2MG has been chosen as an initial system to demonstrate our method for the study of fucosylation ratios since it is a relatively high abundance protein with eight potential fucosylation sites and is efficiently purified with an available commercial antibody. In this study, we utilized a label-free LC-MS/MS method to monitor changes of human A2MG core-fucosylation at specific glycosylation sites based on precursor ion intensities of Endo F3 treated glycopeptides.…”

Section: Introductionmentioning

confidence: 99%

Label‐free relative quantification of alpha‐2‐macroglobulin site‐specific core‐fucosylation in pancreatic cancer by LC‐MS/MS

Lin

Yin

et al. 2013

Electrophoresis

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We describe a label-free relative quantification LC-MS/MS method for core-fucosylationin alpha-2-macroglobulin (A2MG) immunoprecipitated from human sera. The method utilizes endoglycosidase F partial deglycosylation to reduce glycosylation microheterogeneity, while retaining the innermost N-acetylglucosamine (GlcNAc) and core fucose. Precursor ion peak areas of partially deglycosylated peptides were obtained and site-specific core-fucosylation ratios based on the peak areas of core-fucosylated and non-fucosylated counterparts were calculated and evaluated for assay development. This assay was applied in a preliminary study of sera samples from normal controls and patients with pancreatic diseases, including pancreatic cancer and chronic pancreatitis. A2MG fucosylation levels at site N396 and N1424 were found to decrease in both chronic pancreatitis and pancreatic cancer compared to normal controls. The two sites were identified by two peptides and their core-fucosylation ratios were found to be internally consistent. This method provides a platform to quantify fucosylation levels and can be used to study site-specific core-fucosylation aberrations in other glycoproteins for other diseases.

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“…Many cancer-related genes were found closest to LCN2. For example, interaction of A2M (alpha2-macroglobulin) with low-density lipoprotein receptor-related protein-1 (LRP1) is associated with an inhibition of tumor cell proliferation, migration, invasion, spheroid formation, and anchorage-independent growth through inhibition of beta-catenin signaling in astrocytoma cells37. DCN (also called decorin) is known to interfere with cellular events of tumorigenesis mainly by blocking various receptor tyrosine kinases (RTK) such as the EGFR, Met, IGF-IR, PDGFR and VEGFR2.…”

Section: Disscussionmentioning

confidence: 99%

Network based analyses of gene expression profile of LCN2 overexpression in esophageal squamous cell carcinoma

et al. 2014

Sci Rep

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LCN2 (lipocalin 2) is a member of the lipocalin family of proteins that transport small, hydrophobic ligands. LCN2 is elevated in various cancers including esophageal squamous cell carcinoma (ESCC). In this study, LCN2 was overexpressed in the EC109 ESCC cell line and we applied integrated analyses of the gene expression data to identify protein-protein interactions (PPI) network to enhance our understanding of the role of LCN2 in ESCC. Through further mining of PPI sub-networks, hundreds of differentially expressed genes (DEGs) were identified to interact with thousands of other proteins. Subcellular localization analyses found the DEGs and their directly or indirectly interacting proteins distributed in multiple layers, which was applied to analyze the possible paths between two DEGs. Gene Ontology annotation generated a functional annotation map and found hundreds of significant terms, especially those associated with the known and potential roles of LCN2 protein. The algorithm of Random Walk with Restart was applied to prioritize the DEGs and identified several cancer-related DEGs ranked closest to LCN2 protein. These analyses based on PPI network have greatly expanded our understanding of the mRNA expression profile of LCN2 overexpresssion for future examination of the roles and mechanisms of LCN2.

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α2-Macroglobulin Inhibits the Malignant Properties of Astrocytoma Cells by Impeding β-Catenin Signaling

Cited by 56 publications

References 46 publications

Pathological implications of cadherin zonation in mouse liver

Pathological implications of cadherin zonation in mouse liver

Label‐free relative quantification of alpha‐2‐macroglobulin site‐specific core‐fucosylation in pancreatic cancer by LC‐MS/MS

Network based analyses of gene expression profile of LCN2 overexpression in esophageal squamous cell carcinoma

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