HGF-Promoted Motility in Primary Human Melanocytes Depends on CD44v6 Regulated via NF-kappa B, Egr-1, and C/EBP-beta

Damm, Sabine; Koefinger, P.; Stefan, Martina; Wels, Christian; Méhes, Gábor; Richtig, Erika; Kerl, Helmut; Otte, Marcus; Schaider, Helmut

doi:10.1038/jid.2010.45

Cited by 43 publications

(39 citation statements)

References 44 publications

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“…38 The mechanism of HGF-induced motility in primary human melanocytes has been demonstrated to be dependent on this c-Met-CD44v6 interaction, and HGF-mediated transcriptional upregulation of CD44v6 presumably mediated through a complex comprising NF-kB/C/EBP-b and Egr-1. 39 Further, CD44v6 blocks Fas-mediated apoptosis; 40 its constitutive expression provides a persistent growth stimulus 41 or it interferes with PI3K/AKT pathways blocking apoptosis. 42 As a consequence, the de novo expression of v6-encoding CD44 transcripts may bring a number of biological advantages to malignant gastric cells.…”

Section: Cd44v6 In Gastric Cancermentioning

confidence: 99%

De novo expression of CD44 variants in sporadic and hereditary gastric cancer

Cunha

Oliveira

Wen

et al. 2010

Laboratory Investigation

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CD44 is the major ubiquitously expressed cell surface receptor for hyaluronate. The CD44 gene encodes several protein isoforms due to extensive alternative splicing and post-translational modifications. Some of these CD44 variable isoforms have been foreseen as key players in malignant transformation and their expression is highly restricted and highly specific, unlike the canonical CD44 standard isoform. In this study, we aimed at dissecting the mRNA splicing pattern of CD44 in normal stomach and gastric cancer (GC) cell lines (n ¼ 9) using cloning and quantitative mRNA amplification assays. Moreover, we assessed the RNA levels and protein expression pattern of relevant splicing forms in distinct premalignant and malignant gastric lesions (sporadic (n ¼ 43) and hereditary (n ¼ 3) forms) using real-time RT-PCR and immunohistochemistry. We also explored the association of CD44 and E-cadherin expression by immunohistochemistry, as E-cadherin has a pivotal functional role in GC. We established the pattern of CD44 variant forms in normal stomach and gastric malignancy. We observed that although exon v6-containing isoforms were rarely expressed in normal gastric mucosa, they became increasingly expressed both in gastric premalignant (hyperplastic polyps, complete and incomplete intestinal metaplasia, low-and high-grade dysplasia) and malignant lesions (cell lines derived from GCs, primary sporadic GCs and hereditary diffuse GCs (HDGCs)). Moreover, we verified that whenever E-cadherin expression was absent, exon v6-containing CD44 isoforms were overexpressed. The lack of expression of CD44 isoforms containing exon v6 in the surface and foveolar epithelia of normal stomach and, its de novo expression in premalignant, as well as in sporadic and hereditary malignant lesions of the stomach, pinpoint CD44 v6-containg isoforms as potential biomarkers for early transformation of the gastric mucosa. Further, our results raise the hypothesis of using CD44v6 as a marker of early invasive intramucosal carcinoma in HDGC CDH1 mutation carriers that lack CDH1 expression in their tumors.

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Section: Cd44v6 In Gastric Cancermentioning

confidence: 99%

De novo expression of CD44 variants in sporadic and hereditary gastric cancer

Cunha

Oliveira

Wen

et al. 2010

Laboratory Investigation

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“…Each experiment was repeated in triplicate. 6 cells/well, and drug resistance was induced starting at a doxorubicin concentration of 0.01 µg/ml after the cells were adherent to the flask wall. Following incubation for 24 h, the supernatant was removed and the medium was replaced with complete RPMI-1640 medium until cell recovery.…”

Section: Detection Of the 50% Inhibitory Concentration (Ic 50 ) Of Domentioning

confidence: 99%

“…NF-κB is reported to be involved in regulating the expression of MDR1 and CD44 genes in multiple cancer cells (3)(4)(5)(6)(7), and it has been found that the CD44-hyaluronan (HA) interaction induces ankyrin binding to P-gp, resulting in the efflux of chemotherapeutic drugs and development of MDR in cancer (8,9).…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin induces drug resistance and expression of the novel CD44st via NF-κB in human breast cancer MCF-7 cells

et al. 2014

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Abstract. CD44, a major receptor for hyaluronan (HA), is a member of a class of adhesion molecules of unknown classification involved in cell proliferation, differentiation, migration, angiogenesis, and the presentation of specific cytokines to the corresponding receptors as well as in cell signaling transduction. It has recently been discovered that CD44, a marker of tumor stem cells, is involved in the drug resistance and invasion of multiple types of tumors. The 20 exons in the CD44 gene that are alternatively spliced, give rise to many CD44 isoforms, possibly including tumor-specific sequences. Dozens of CD44 isoforms have been found, to date, and the standard CD44 (CD44s) isoform is the most common. We recently showed that a novel short-tail isoform of CD44 (CD44st) was expressed in multidrug-resistant human breast cancer MCF-7/Adr cells. Moreover, the novel CD44st was able to interact with HA and regulate the expression of matrix metalloproteinase (MMP)-2 and MMP-9, which increased the invasive capability of MCF-7 cells through the Ras/MAPK signaling pathway. In the present study, we verified that MCF-7 cells subjected to drug pressure develop multidrug resistance to doxorubicin, and the expression levels of multidrug resistance protein 1 (MDR1), CD44st and nuclear factor-κB (NF-κB) mRNA and protein were gradually upregulated in a dose-dependent manner in MCF-7 cells treated with doxorubicin. HA increases the secretion of MMP-2 and MMP-9 in multidrug-resistant MCF-7 cells and affected the invasive ability of MCF-7 cells through the upregulation of CD44st expression, and such an effect was blocked by the NF-κB-specific inhibitor BMS-345541.

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“…C/EBPβ is an important mediator in endothelial migration during pathological angiogenesis [18]. In addition, hepatocyte growth factor-mediated motility upregulation of human melanocyte depended on C/EBPβ [3]. Therefore, the upregulation of C/EBPb by cilostazol in HBMECs may play an important role in endothelial migration.…”

Section: Discussionmentioning

confidence: 99%

“…3). C/ EBPβ is a member of a transcription factor family that takes part in the cell migration process [3,12,18]. Induction of C/EBPβ in muscle stem cells enhanced their migration and contributed to muscle repair in dystrophic muscle [12].…”

Section: Discussionmentioning

confidence: 99%

Cilostazol Promotes the Migration of Brain Microvascular Endothelial Cells

Lee¹,

Park²,

Shin³

2016

Journal of Life Science

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Cilostazol is known to be a selective inhibitor of phosphodiesterase III and is generally used to treat stroke. Our previous findings showed that cilostazol enhanced capillary density through angiogenesis after focal cerebral ischemia. Angiogenesis is an important physiological process for promoting revascularization to overcome tissue ischemia. It is a multistep process consisting of endothelial cell proliferation, migration, and tubular structure formation. Here, we examined the modulatory effect of cilostazol at each step of the angiogenic mechanism by using human brain microvascular endothelial cells (HBMECs). We found that cilostazol increased the migration of HBMECs in a dose-dependent manner. However, it did not enhance HBMEC proliferation and capillary-like tube formation. We used a cDNA microarray to analyze the mechanisms of cilostazol in cell migration. We picked five candidate genes that were potentially related to cell migration, and we confirmed the gene expression levels by real-time PCR. The genes phosphoserine aminotransferase 1 (PSAT1) and CCAAT/enhancer binding protein β (C/EBPβ) were up-regulated. The genes tissue factor pathway inhibitor 2 (TFPI2), retinoic acid receptor responder 1 (RARRES1), and RARRES3 were down-regulated. Our observations suggest that cilostazol can promote angiogenesis by promoting endothelial migration. Understanding the cilostazol-modulated regulatory mechanisms in brain endothelial cells may help stimulate blood vessel formation for the treatment of ischemic diseases.

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HGF-Promoted Motility in Primary Human Melanocytes Depends on CD44v6 Regulated via NF-kappa B, Egr-1, and C/EBP-beta

Cited by 43 publications

References 44 publications

De novo expression of CD44 variants in sporadic and hereditary gastric cancer

De novo expression of CD44 variants in sporadic and hereditary gastric cancer

Doxorubicin induces drug resistance and expression of the novel CD44st via NF-κB in human breast cancer MCF-7 cells

Cilostazol Promotes the Migration of Brain Microvascular Endothelial Cells

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