RAGE Expression in Rhabdomyosarcoma Cells Results in Myogenic Differentiation and Reduced Proliferation, Migration, Invasiveness, and Tumor Growth

Riuzzi, Francesca; Sorci, Guglielmo; Donato, Rosario

doi:10.2353/ajpath.2007.070049

Cited by 54 publications

(55 citation statements)

References 67 publications

(73 reference statements)

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“…15,23 Moreover, one study reported that RAGE expression in rhabdomyosarcoma reduced proliferation, migration, invasiveness and tumor growth, and functional inactivation of RAGE in L6 myoblasts resulted in increased proliferation and tumor formation in vivo. 19,24 These data are also consistent with our results and suggest that a decrease in RAGE signaling is associated with tumor progression. However, our observations are at variance with the data obtained with glioma, gastric cancer, colon cancer, biliary cancer, and human pancreatic carcinoma cells, in which a positive correlation was found between RAGE expression, tumor progression, and metastasis.…”

Section: Discussionsupporting

confidence: 82%

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Expression of Receptor for Advanced Glycation End Products (RAGE) is Related to Prognosis in Patients with Esophageal Squamous Cell Carcinoma

et al. 2008

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The receptor for advanced glycation end products (RAGE), known as a multiligand receptor for certain stress-associated factors, has been considered to affect the characteristic differences of various cancer cells. We analyzed the expression and clinicopathological significance of RAGE in esophageal squamous cell carcinoma. We investigated immunohistochemically the relationship between RAGE expression and clinicopathological factors, including prognosis, in surgical specimens of primary tumors in 216 patients with esophageal squamous cell carcinoma. Prognostic factors were examined by univariate and multivariate analyses (Cox proportional hazard regression model). The positive expression rate of RAGE was 50%. RAGE expression was negatively correlated with depth of invasion and venous invasion. Moreover, tumors with positive RAGE expression exhibited better prognosis than those with negative RAGE expression (5-year survival, 52% vs. 32%, respectively). Multivariate analysis indicated that the positive expression of RAGE was an independent prognostic factor, along with tumor depth and nodal metastasis. Our findings suggest that loss of RAGE expression may play an important role in the progression of esophageal squamous cell carcinoma. Evaluation of the expression of RAGE could be useful for determining the tumor properties, including those associated with prognosis, in patients with esophageal squamous cell carcinoma.The receptor for advanced glycation end products (RAGE) is a multiligand receptor classified as an immunoglobulin superfamily cell surface molecule; it acts as a counterreceptor for high-mobility group box 1 (HMGB1) proteins, RAGEs, S100/calgranulins, and amyloid-b peptides.1-3 These interactions trigger the activation of key cell signaling pathways (e.g., p38 and p44/42 MAP kinase, NFjB, cdc42/rac, and the generation of reactive oxygen species) and result in the production of proinflammatory cytokines.4-7 RAGE-mediated proinflammatory processes are now considered to contribute to the progression of many chronic diseases, such as neuropathy, nephropathy, macrovascular disease, amyloidoses, inflammatory conditions (e.g., rheumatoid arthritis and inflammatory bowel disease), and sepsis. [7][8][9] In addition to RAGE-mediated proinflammatory events, recent studies have revealed that the interaction of RAGE and its ligands and the resultant signaling play a causative role in the characteristic modulation of cancer cell functions, i.e., increasing tumor invasion and metastasis. 10 Furthermore, several clinical studies have demonstrated a strong association of RAGE expression with the malignant potential of various cancers such as gastric cancer, colon cancer, biliary cancer, pancreatic cancer, and prostate cancer, although several reports showed a reverse correlation between RAGE expression and tumor progression.

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Section: Discussionsupporting

confidence: 82%

“…[11][12][13][14][15][16][17][18][19] We previously reported a change in RAGE expression according to the sequential change of liver tissue. 20 The RAGE expression was higher in the early or prestages of cancer than in the normal liver or advanced hepatocellular carcinoma (HCC).…”

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confidence: 99%

Expression of Receptor for Advanced Glycation End Products (RAGE) is Related to Prognosis in Patients with Esophageal Squamous Cell Carcinoma

et al. 2008

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“…Extracellular factors, acting via cell-surface receptors, and adhesion molecules control cell proliferation arrest and differentiation of myoblasts through regulation of signalling pathways for the expression of muscle-specific transcription factors. This, in turn, coordinates the expression and activity of a cohort of factors that are responsible for phenotypic changes, including myoblast fusion into myotubes, the precursors of the mature myofibres [50]. Our data demonstrate the specific role of GTP as an enhancer of the myogenic process; indeed, the data in Fig.…”

Section: Discussionsupporting

confidence: 60%

Transcriptional profile of GTP-mediated differentiation of C2C12 skeletal muscle cells

Mancinelli

Pietrangelo

Burnstock³

et al. 2011

Purinergic Signalling

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Several purine receptors have been localised on skeletal muscle membranes. Previous data support the hypothesis that extracellular guanosine 5′-triphosphate (GTP) is an important regulatory factor in the development and function of muscle tissue. We have previously described specific extracellular binding sites for GTP on the plasma membrane of mouse skeletal muscle (C2C12) cells. Extracellular GTP induces an increase in intracellular Ca 2+ concentrations that results in membrane hyperpolarisation through Ca 2+ -activated K + channels, as has been demonstrated by patch-clamp experiments. This GTPevoked increase in intracellular Ca 2+ is due to release of Ca 2+ from intracellular inositol-1,4,5-trisphosphate-sensitive stores. This enhances the expression of the myosin heavy chain in these C2C12 myoblasts and commits them to fuse into multinucleated myotubes, probably via a phosphoinositide-3-kinase-dependent signal-transduction mechanism. To define the signalling of extracellular GTP as an enhancer or modulator of myogenesis, we investigated whether the gene-expression profile of differentiated C2C12 cells (4 and 24 h in culture) is affected by extracellular GTP. To investigate the nuclear activity and target genes modulated by GTP, transcriptional profile analysis and realtime PCR were used. We demonstrate that in the early stages of differentiation, GTP up-regulates genes involved in different pathways associated with myogenic processes, including cytoskeleton structure, the respiratory chain, myogenesis, chromatin reorganisation, cell adhesion, and the Jak/Stat pathway, and down-regulates the mitogenactivated protein kinase pathway. GTP also increases the expression of three genes involved in myogenesis, Pp3ca, Gsk3b, and Pax7. Our data suggests that in the myogenic C2C12 cell line, extracellular GTP acts as a differentiative factor in the induction and sustaining of myogenesis.

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“…Total Src, ERK1/2, p38 MAPK, Akt, and p65 NF-B were detected using a polyclonal anti-Src (1:1,000; Cell Signaling Technology), anti-ERK1/2 antibody (1:20,000; Sigma), a polyclonal anti-p38 MAPK antibody (1:2,000; Cell Signaling Technology), polyclonal anti-Akt (1:1000; Cell Signaling Technology), and a polyclonal anti-p65 NF-B antibody (1:1,000; Santa Cruz Biotechnology), respectively. Analysis of culture medium HMGB1 was performed as described (50). Briefly, culture media were clarified by centrifugation, added with 1/100 volume of 2% sodium deoxycholate, and subjected to precipitation with 1/10 volume of 100% trichloroacetic acid.…”

Section: Methodsmentioning

confidence: 99%

S100B Protein Stimulates Microglia Migration via RAGE-dependent Up-regulation of Chemokine Expression and Release

Bianchi

Kastrisianaki

Giambanco

et al. 2011

Journal of Biological Chemistry

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205

173

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The Ca 2؉ -binding protein of the EF-hand type, S100B, is abundantly expressed in and secreted by astrocytes, and release of S100B from damaged astrocytes occurs during the course of acute and chronic brain disorders. Thus, the concept has emerged that S100B might act an unconventional cytokine or a damage-associated molecular pattern protein playing a role in the pathophysiology of neurodegenerative disorders and inflammatory brain diseases. S100B proinflammatory effects require relatively high concentrations of the protein, whereas at physiological concentrations S100B exerts trophic effects on neurons. Most if not all of the extracellular (trophic and toxic) effects of S100B in the brain are mediated by the engagement of RAGE (receptor for advanced glycation end products). We show here that high S100B stimulates murine microglia migration in Boyden chambers via RAGE-dependent activation of Src kinase, Ras, PI3K, MEK/ERK1/2, RhoA/ROCK, Rac1/JNK/AP-1, Rac1/ NF-B, and, to a lesser extent, p38 MAPK. Recruitment of the adaptor protein, diaphanous-1, a member of the formin protein family, is also required for S100B/RAGE-induced migration of microglia. The S100B/RAGE-dependent activation of diaphanous-1/Rac1/JNK/AP-1, Ras/Rac1/NF-B and Src/Ras/PI3K/ RhoA/diaphanous-1 results in the up-regulation of expression of the chemokines, CCL3, CCL5, and CXCL12, whose release and activity are required for S100B to stimulate microglia migration. Lastly, RAGE engagement by S100B in microglia results in up-regulation of the chemokine receptors, CCR1 and CCR5. These results suggests that S100B might participate in the pathophysiology of brain inflammatory disorders via RAGEdependent regulation of several inflammation-related events including activation and migration of microglia. S100B is a Ca 2ϩ -binding protein of the EF-hand type abundantly expressed in astrocytes (1). S100B has been implicated in the regulation of astrocyte shape, migration, proliferation and differentiation via activation of the Src/PI3K module and PI3K-dependent stimulation of Akt and RhoA activities and hence of the supramolecular organization of F-actin (2). S100B also regulates the state of assembly of microtubules and type III intermediate filaments (3) and the cytosolic Ca 2ϩ concentration (4). In addition to having intracellular regulatory activities, S100B also exerts extracellular effects. Indeed, astrocytes secrete the protein constitutively and to a larger extent under the action of several stimuli including the proinflammatory cytokine, TNF-␣ (see for review Ref. 1). Moreover, levels of brain S100B are elevated in the aging brain and in several pathological conditions such as Alzheimer disease, brain infarct, epilepsy, and infectious diseases, as well as in Down syndrome (5, 6) in consequence of S100B human gene mapping to chromosome 21q22.3 (7). For example, hypertrophic astrocytes in peri-infarct areas and in neuritic plaques in Alzheimer disease and Down syndrome show elevated expression levels of S100B, and S100B can be detected outside hypert...

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RAGE Expression in Rhabdomyosarcoma Cells Results in Myogenic Differentiation and Reduced Proliferation, Migration, Invasiveness, and Tumor Growth

Cited by 54 publications

References 67 publications

Expression of Receptor for Advanced Glycation End Products (RAGE) is Related to Prognosis in Patients with Esophageal Squamous Cell Carcinoma

Expression of Receptor for Advanced Glycation End Products (RAGE) is Related to Prognosis in Patients with Esophageal Squamous Cell Carcinoma

Transcriptional profile of GTP-mediated differentiation of C2C12 skeletal muscle cells

S100B Protein Stimulates Microglia Migration via RAGE-dependent Up-regulation of Chemokine Expression and Release

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