Lipocalin 2 Diminishes Invasiveness and Metastasis of Ras-transformed Cells

Hanai, Jun‐ichi; Mammoto, Tadanori; Seth, Pankaj; Mori, Kiyoshi; Karumanchi, S. Ananth; Barasch, Jonathan; Sukhatme, Vikas P.

doi:10.1074/jbc.m413047200

Cited by 113 publications

(115 citation statements)

References 43 publications

(29 reference statements)

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“…Hanai et al (2005) recently showed that NGAL has the ability to reverse this epithelial-mesenchymal transition, thereby diminishing invasiveness of cancer cells. Our results show that in pancreatic cancer, NGAL is predominantly expressed in the early dysplastic lesions as well as in the well-differentiated carcinomas (preserve ductal architecture); with almost no expression in the poorly differentiated tumours (have a predominantly mesenchymal appearance).…”

Section: Discussionmentioning

confidence: 99%

Early diagnosis of pancreatic cancer: neutrophil gelatinase-associated lipocalin as a marker of pancreatic intraepithelial neoplasia

et al. 2008

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Pancreatic cancer is a highly lethal malignancy with a dismal 5-year survival of less than 5%. The scarcity of early biomarkers has considerably hindered our ability to launch preventive measures for this malignancy in a timely manner. Neutrophil gelatinaseassociated lipocalin (NGAL), a 24-kDa glycoprotein, was reported to be upregulated nearly 27-fold in pancreatic cancer cells compared to normal ductal cells in a microarray analysis. Given the need for biomarkers in the early diagnosis of pancreatic cancer, we investigated the expression of NGAL in tissues with the objective of examining if NGAL immunostaining could be used to identify foci of pancreatic intraepithelial neoplasia, premalignant lesions preceding invasive cancer. To examine a possible correlation between NGAL expression and the degree of differentiation, we also analysed NGAL levels in pancreatic cancer cell lines with varying grades of differentiation. Although NGAL expression was strongly upregulated in pancreatic cancer, and moderately in pancreatitis, only a weak expression could be detected in the healthy pancreas. The average composite score for adenocarcinoma (4.26 ± 2.44) was significantly higher than that for the normal pancreas (1.0) or pancreatitis (1.0) (Po0.0001). Further, although both well-and moderately differentiated pancreatic cancer were positive for NGAL, poorly differentiated adenocarcinoma was uniformly negative. Importantly, NGAL expression was detected as early as the PanIN-1 stage, suggesting that it could be a marker of the earliest premalignant changes in the pancreas. Further, we examined NGAL levels in serum samples. Serum NGAL levels were above the cutoff for healthy individuals in 94% of pancreatic cancer and 62.5% each of acute and chronic pancreatitis samples. However, the difference between NGAL levels in pancreatitis and pancreatic cancer was not significant. A ROC curve analysis revealed that ELISA for NGAL is fairly accurate in distinguishing pancreatic cancer from non-cancer cases (area under curve ¼ 0.75). In conclusion, NGAL is highly expressed in early dysplastic lesions in the pancreas, suggesting a possible role as an early diagnostic marker for pancreatic cancer. Further, serum NGAL measurement could be investigated as a possible biomarker in pancreatitis and pancreatic adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Early diagnosis of pancreatic cancer: neutrophil gelatinase-associated lipocalin as a marker of pancreatic intraepithelial neoplasia

et al. 2008

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“…The involvement of lcn2 in the phenotypic change of cell morphology has been previously reported. lcn2 was an endogenous epithelial inducer (Yang et al, 2002) and stimulated the epithelial phenotype of transformed cells (Hanai et al, 2005;. lcn2 also promoted tubulogenesis by regulating epithelial morphogenesis (Gwira et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Locally, even higher levels may be achieved in pathologic conditions. At 50 g/ml, LCN2 induced kidney epithelia differentiation (Yang et al, 2002), epithelial transition of cancer cells (Hanai et al, 2005), and apoptosis of pro-B-cells (Devireddy et al, 2005) in an iron-dependent manner (Mori and Nakao, 2007). Purified GST protein (Fig.…”

Section: Lcn2 Increased the Sensitivity Of Astrocytes To Cytotoxic Stmentioning

confidence: 99%

Lipocalin-2 Is an Autocrine Mediator of Reactive Astrocytosis

Lee¹,

Park²,

Lee³

et al. 2009

J. Neurosci.

237

238

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Astrocytes, the most abundant glial cell type in the brain, provide metabolic and trophic support to neurons and modulate synaptic activity. In response to a brain injury, astrocytes proliferate and become hypertrophic with an increased expression of intermediate filament proteins. This process is collectively referred to as reactive astrocytosis. Lipocalin 2 (lcn2) is a member of the lipocalin family that binds to small hydrophobic molecules. We propose that lcn2 is an autocrine mediator of reactive astrocytosis based on the multiple roles of lcn2 in the regulation of cell death, morphology, and migration of astrocytes. lcn2 expression and secretion increased after inflammatory stimulation in cultured astrocytes. Forced expression of lcn2 or treatment with LCN2 protein increased the sensitivity of astrocytes to cytotoxic stimuli. Iron and BIM (Bcl-2-interacting mediator of cell death) proteins were involved in the cytotoxic sensitization process. LCN2 protein induced upregulation of glial fibrillary acidic protein (GFAP), cell migration, and morphological changes similar to characteristic phenotypic changes termed reactive astrocytosis. The lcn2-induced phenotypic changes of astrocytes occurred through a Rho-ROCK (Rho kinase)-GFAP pathway, which was positively regulated by nitric oxide and cGMP. In zebrafishes, forced expression of rat lcn2 gene increased the number and thickness of cellular processes in GFAP-expressing radial glia cells, suggesting that lcn2 expression in glia cells plays an important role in vivo. Our results suggest that lcn2 acts in an autocrine manner to induce cell death sensitization and morphological changes in astrocytes under inflammatory conditions and that these phenotypic changes may be the basis of reactive astrocytosis in vivo.

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“…LCN2 was found to be highly expressed after malignant transformation of the breast, lung, colon, and pancreatic epithelia by immunohistochemistry (39). More recently, it has been described that LCN2 decreases the invasiveness and metastasis of Ras-transformed cells (40). BMP4 is a member of the bone morphogenetic protein family, which is part of the transforming growth factor-␤ superfamily.…”

Section: Discussionmentioning

confidence: 99%

Proteomics-based Validation of Genomic Data

Madoz‐Gúrpide

López-Serra

Martı́nez-Torrecuadrada

et al. 2006

Molecular & Cellular Proteomics

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Multiple factors are involved in the translation of functional genomic results into proteins for proteome research and target validation on tumoral tissues. In this report, genes were selected by using DNA microarrays on a panel of colorectal cancer (CRC) paired samples. A large number of up-regulated genes in colorectal cancer patients were investigated for cellular location, and those corresponding to membrane or extracellular proteins were used for a non-biased expression in Escherichia coli. We investigated different sources of cDNA clones for protein expression as well as the influence of the protein size and the different tags with respect to protein expression levels and solubility in E. coli. From 29 selected genes, 21 distinct proteins were finally expressed as soluble proteins with, at least, one different fusion protein. In addition, seven of these potential markers (ANXA3, BMP4, LCN2, SPARC, SPP1, MMP7, and MMP11) were tested for antibody production and/or validation. Six of the seven proteins (all except SPP1) were confirmed to be overexpressed in colorectal tumoral tissues by using immunoblotting and tissue microarray analysis. Although none of them could be associated to early stages of the tumor, two of them (LCN2 and MMP11) were clearly overexpressed in late Dukes' stages (B and C). This proteomic study reveals novel clues for the assembly of a robust and highly efficient high throughput system for the validation of genomic data. Moreover it illustrates the different difficulties and bottlenecks encountered for performing a quick conversion of genomic results into clinically useful proteins.

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Lipocalin 2 Diminishes Invasiveness and Metastasis of Ras-transformed Cells

Cited by 113 publications

References 43 publications

Early diagnosis of pancreatic cancer: neutrophil gelatinase-associated lipocalin as a marker of pancreatic intraepithelial neoplasia

Early diagnosis of pancreatic cancer: neutrophil gelatinase-associated lipocalin as a marker of pancreatic intraepithelial neoplasia

Lipocalin-2 Is an Autocrine Mediator of Reactive Astrocytosis

Proteomics-based Validation of Genomic Data

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