Differential expression of Snail1 transcription factor and Snail1-related genes in alveolar and embryonal rhabdomyosarcoma subtypes.

PĂźskĂźllĂźoglu, Mirosława; Łukasiewicz, Ewa; Miękus, Katarzyna; Jarocha, Danuta; Majka, Marcin

doi:10.2478/v10042-010-0046-7

Cited by 6 publications

(7 citation statements)

References 32 publications

(31 reference statements)

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“…Our previous study [ 19 ] and current analysis of new rhabdomyosarcoma tumor samples demonstrated that expression of MET mRNA is lower in embryonal (ERMS) than in alveolar (ARMS) subtype (Figure 1A ), which is usually associated with more malignant phenotype [ 3 ]. Moreover, in those samples MET level positively correlated with MyoD expression ( Supplementary Table 1 ), suggesting association of MET with a defect in myogenic differentiation in those tumors.…”

Section: Resultsmentioning

confidence: 99%

“…Increased level of the MET receptor in tumors of mesenchymal origin is usually associated with higher aggressiveness. For example in RMS tumors more aggressive ARMS cells display higher expression of MET than ERMS cell lines [ 19 ]. Increased level of the MET receptor in RMS may be explained by the defects in posttranscriptional regulation of its expression by miR-206 [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Constitutive activation of MET signaling impairs myogenic differentiation of rhabdomyosarcoma and promotes its development and progression

et al. 2015

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Rhabdomyosarcoma (RMS) is a soft tissue sarcoma, which may originate from impaired differentiation of mesenchymal stem cells (MSC). Expression of MET receptor is elevated in alveolar RMS subtype (ARMS) which is associated with worse prognosis, compared to embryonal RMS (ERMS). Forced differentiation of ARMS cells diminishes MET level and, as shown previously, MET silencing induces differentiation of ARMS. In ERMS cells introduction of TPR-MET oncogene leads to an uncontrolled overstimulation of the MET receptor downstream signaling pathways. In vivo, tumors formed by those cells in NOD-SCID mice display inhibited differentiation, enhanced proliferation, diminished apoptosis and increased infiltration of neutrophils. Consequently, tumors grow significantly faster and they display enhanced ability to metastasize to lungs and to vascularize due to elevated VEGF, MMP9 and miR-378 expression. In vitro, TPR-MET ERMS cells display enhanced migration, chemotaxis and invasion toward HGF and SDF-1. Introduction of TPR-MET into MSC increases survival and may induce expression of early myogenic factors depending on the genetic background, and it blocks terminal differentiation of skeletal myoblasts. To conclude, our results suggest that activation of MET signaling may cause defects in myogenic differentiation leading to rhabdomyosarcoma development and progression.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Constitutive activation of MET signaling impairs myogenic differentiation of rhabdomyosarcoma and promotes its development and progression

et al. 2015

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“…In our previous work, we observed that aggressive ARMS tumors display higher expression of the SNAIL gene and that SNAIL expression positively correlates with PAX3/7-FOXO1 9 . SNAIL (snail family zinc finger 1; SNAI1) is a member of the group of zinc finger transcription factors.…”

Section: Introductionmentioning

confidence: 87%

“…The repressive complex of SNAIL with HDACs binds and excludes MYOD from G/C-rich E-box motifs in murine satellite cells, thereby inhibiting myogenic differentiation. In RMS SNAIL expression is higher in ARMS tumor 9 that is associated with worse prognosis and SNAIL is a mediator of NOTCH pathway in ERMS subtype 19 .…”

Section: Introductionmentioning

confidence: 99%

SNAIL is a key regulator of alveolar rhabdomyosarcoma tumor growth and differentiation through repression of MYF5 and MYOD function

et al. 2018

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Rhabdomyosarcoma (RMS) is a mesenchymal tumor of soft tissue in children that originates from a myogenic differentiation defect. Expression of SNAIL transcription factor is elevated in the alveolar subtype of RMS (ARMS), characterized by a low myogenic differentiation status and high aggressiveness. In RMS patients SNAIL level increases with higher stage. Moreover, SNAIL level negatively correlates with MYF5 expression. The differentiation of human ARMS cells diminishes SNAIL level. SNAIL silencing in ARMS cells inhibits proliferation and induces differentiation in vitro, and thereby completely abolishes the growth of human ARMS xenotransplants in vivo. SNAIL silencing induces myogenic differentiation by upregulation of myogenic factors and muscle-specific microRNAs, such as miR-206. SNAIL binds to the MYF5 promoter suppressing its expression. SNAIL displaces MYOD from E-box sequences (CANNTG) that are associated with genes expressed during differentiation and G/C rich in their central dinucleotides. SNAIL silencing allows the re-expression of MYF5 and canonical MYOD binding, promoting ARMS cell myogenic differentiation. In differentiating ARMS cells SNAIL forms repressive complex with histone deacetylates 1 and 2 (HDAC1/2) and regulates their expression. Accordingly, in human myoblasts SNAIL silencing induces differentiation by upregulation of myogenic factors. Our data clearly point to SNAIL as a key regulator of myogenic differentiation and a new promising target for future ARMS therapies.

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“…We discovered noncanonical action mechanisms of SNAIL in RMS [ 9 ]. Importantly, the SNAIL level has been shown to be elevated in the ARMS tumor subtype, which is usually associated with a worse prognosis [ 11 ]. Moreover, the SNAIL level was significantly increased in RMS samples from patients displaying stages 2, 3, and 4 of the disease compared to those from patients with stage 1, suggesting an important role of SNAIL in RMS progression [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

SNAIL Promotes Metastatic Behavior of Rhabdomyosarcoma by Increasing EZRIN and AKT Expression and Regulating MicroRNA Networks

Skrzypek

Kot

Konieczny

et al. 2020

Cancers

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Rhabdomyosarcoma (RMS) is a predominant soft tissue tumor in children and adolescents. For high-grade RMS with metastatic involvement, the 3-year overall survival rate is only 25 to 30%. Thus, understanding the regulatory mechanisms involved in promoting the metastasis of RMS is important. Here, we demonstrate for the first time that the SNAIL transcription factor regulates the metastatic behavior of RMS both in vitro and in vivo. SNAIL upregulates the protein expression of EZRIN and AKT, known to promote metastatic behavior, by direct interaction with their promoters. Our data suggest that SNAIL promotes RMS cell motility, invasion and chemotaxis towards the prometastatic factors: HGF and SDF-1 by regulating RHO, AKT and GSK3b activity. In addition, miRNA transcriptome analysis revealed that SNAIL-miRNA axis regulates processes associated with actin cytoskeleton reorganization. Our data show a novel role of SNAIL in regulating RMS cell metastasis that may also be important in other mesenchymal tumor types and clearly suggests SNAIL as a promising new target for future RMS therapies.

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Differential expression of Snail1 transcription factor and Snail1-related genes in alveolar and embryonal rhabdomyosarcoma subtypes.

Cited by 6 publications

References 32 publications

Constitutive activation of MET signaling impairs myogenic differentiation of rhabdomyosarcoma and promotes its development and progression

Constitutive activation of MET signaling impairs myogenic differentiation of rhabdomyosarcoma and promotes its development and progression

SNAIL is a key regulator of alveolar rhabdomyosarcoma tumor growth and differentiation through repression of MYF5 and MYOD function

SNAIL Promotes Metastatic Behavior of Rhabdomyosarcoma by Increasing EZRIN and AKT Expression and Regulating MicroRNA Networks

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