Inhibition of rhabdomyosarcoma's metastatic behavior through downregulation of MET receptor signaling.

Łukasiewicz, Ewa; Miękus, Katarzyna; Kijowski, J.; Drabik, Grażyna; Wilusz, Miroslawa; Bobis‐Wozowicz, Sylwia; Majka, Marcin

doi:10.2478/v10042-009-0108-x

Cited by 20 publications

(35 citation statements)

References 22 publications

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“…Accordingly, MET has been implicated in cytoskeletal reorganization and migration in cancer cells. In RMS cells, HGF promotes chemotaxis and invasion [33–35]. Because of these migratory effects of HGF/MET signaling, the role of this signaling pathway in tumor cell metastasis has been examined.…”

Section: Receptor Tyrosine Kinases Associated With Rhabdomyosarcomamentioning

confidence: 99%

“…Because of these migratory effects of HGF/MET signaling, the role of this signaling pathway in tumor cell metastasis has been examined. Cells derived from bone marrow secrete HGF, and RMS cells have been shown to home to bone marrow, due in part to MET expression [33, 35, 36]. Furthermore, bone marrow aspirates from RMS patients with metastatic disease have elevated MET expression [37].…”

Section: Receptor Tyrosine Kinases Associated With Rhabdomyosarcomamentioning

confidence: 99%

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Receptor Tyrosine Kinases as Therapeutic Targets in Rhabdomyosarcoma

Crose

Linardic

2011

Sarcoma

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Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas of childhood and adolescence. To date, there are no effective treatments that target the genetic abnormalities in RMS, and current treatment options for high-risk groups are not adequate. Over the past two decades, research into the molecular mechanisms of RMS has identified key genes and signaling pathways involved in disease pathogenesis. In these studies, members of the receptor tyrosine kinase (RTK) family of cell surface receptors have been characterized as druggable targets for RMS. Through small molecule inhibitors, ligand-neutralizing agents, and monoclonal receptor-blocking antibodies, RTK activity can be manipulated to block oncogenic properties associated with RMS. Herein, we review the members of the RTK family that are implicated in RMS tumorigenesis and discuss both the problems and promise of targeting RTKs in RMS.

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Section: Receptor Tyrosine Kinases Associated With Rhabdomyosarcomamentioning

confidence: 99%

Section: Receptor Tyrosine Kinases Associated With Rhabdomyosarcomamentioning

confidence: 99%

Receptor Tyrosine Kinases as Therapeutic Targets in Rhabdomyosarcoma

Crose

Linardic

2011

Sarcoma

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“…Genes involved with muscle cell differentiation and cell proliferation have been associated with RMS development and metastasis. [6][7][8][9][10][11] Gene expression profiles comparing PAX-FOXO1-positive ARMS vs translocation-negative ERMS have identified genes relevant to tumorigenic process of ARMS and ERMS. 12 microRNAs (miRNAs) have been implicated in RMS.…”

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confidence: 99%

Downregulation of microRNAs miR-1, -206 and -29 stabilizes PAX3 and CCND2 expression in rhabdomyosarcoma

Sarver

Alamgir

et al. 2012

Laboratory Investigation

105

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Elevated levels of PAX3 and cell proliferation genes are characteristic features of rhabdomyosarcoma (RMS). We hypothesize that the increased levels of these genes are stabilized due to downregulation of specific miRNAs. In this study, we show that downregulation of miR-1, -206 and -29 stabilizes the expression of PAX3 and CCND2 in both embryonal (ERMS) and alveolar (ARMS) RMS types. Ectopic expression of miR-1 and 206 in JR1, an ERMS cell line, show significant downregulation of PAX3 protein expression, whereas overexpression of these miRNAs in Rh30, an ARMS cell line, did not show any effect in PAX3 protein levels. In ARMS, PAX3 forms a fusion transcript with FOXO1 and the resultant loss of PAX3 3 0 UTR in the fusion transcript indicate an oncogenic mechanism to evade miRNA-mediated regulation of PAX3. Further, we show that miR-1, -206 and -29 can regulate the expression of CCND2, a cell cycle gene. In addition to CCND2, miR-29 also targets E2F7, another cell cycle regulator. Cell function analysis shows that overexpression of miR-29 downregulates the expression of these cell cycle genes, induces partial G1 arrest leading to decreased cell proliferation. Taken together our data suggest that the RMS state is stabilized by the deregulation of multiple miRNAs and their target genes, supporting a tumor suppressor role for these miRNA. KEYWORDS: cell cycle genes; miRNAs; PAX3; regulatory networks; rhabdomyosarcoma Rhabdomyosarcoma (RMS) is a malignant striated muscle tumor that accounts for B3% of all childhood cancers. 1 RMS arises from primitive muscle cells and tumors show varying degrees of skeletal muscle differentiation that serves to define their classification as either embryonal (ERMS) or alveolar (ARMS) types. 2,3 ERMS, the most common type has features of embryonic muscle and are generally associated with favorable prognosis. In contrast, ARMS display poor muscle differentiation and are associated with poor outcomes. 4 Most ARMS cases are characterized by chromosomal translocation t(2;13) or t(1;13) involving genes PAX3-FKHR or PAX7-FKHR, respectively. 5 Regulatory disruptions in growth and differentiation pathways of myogenic precursor cells have been implicated in RMS development. Genes involved with muscle cell differentiation and cell proliferation have been associated with RMS development and metastasis. 6-11 Gene expression profiles comparing PAX-FOXO1-positive ARMS vs translocation-negative ERMS have identified genes relevant to tumorigenic process of ARMS and ERMS. 12 microRNAs (miRNAs) have been implicated in RMS. [13][14][15] miRNAs are small (18-22 nucleotides) evolutionarily conserved, non-coding RNAs that post-transcriptionally regulate gene expression through mRNA degradation, translation inhibition or chromatin-based silencing mechanisms. 16 Each miRNA can potentially regulate hundreds of targets either directly or indirectly. miRNAs have been shown to be deregulated in many types of cancers. 17 As a consequence, miRNAs from tumor tissue have been proposed for use in the diagnosis, classif...

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“…Recently, cell proliferation in vitro and tumor burden in mouse xenograft models were decreased by targeted knockdown of c-Met using siRNA in human RMS cell lines [34,35]. In order to improve clinical application of this concept, several different strategies are being explored, including the development of competitors of c-Met/HGF, monoclonal antibodies directed against HGF and c-Met, and small-molecule tyrosine kinase inhibitors directed against c-Met [8].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of phosphorylated c-Met in rhabdomyosarcoma cell lines by a small molecule inhibitor SU11274

et al. 2011

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Backgroundc-Met is a receptor tyrosine kinase (RTK) that is over-expressed in a variety of cancers and involved in cell growth, invasion, metastasis and angiogenesis. In this study, we investigated the role of c-Met in rhabdomyosarcoma (RMS) using its small molecule inhibitor SU11274, which has been hypothesized to be a potential therapeutic target for RMS.MethodsThe expression level of phosphorylated c-Met in RMS cell lines (RD, CW9019 and RH30) and tumor tissues was assessed by phospho-RTK array and immunohistochemistry, respectively. The inhibition effects of SU11274 on RMS cells were studied with regard to intracellular signaling, cell proliferation, cell cycle and cell migration.ResultsA high level of phosphorylated c-Met was detected in 2 alveolar RMS cell lines (CW9019 and RH30) and 14 out of 24 RMS tissue samples, whereas relatively low levels of phospho-c-Met were observed in the embryonic RMS cell line (RD). The small molecule SU11274 could significantly reduce the phosphorylation of c-Met, resulting in inhibition of cell proliferation, G1 phase arrest of cell cycle and blocking of cell migration in CW9019 and RH30 cell lines.ConclusionThese results might support the role of c-Met in the development and progression of RMS. Furthermore, the inhibitor of c-Met, SU11274, could be an effective targeting therapy reagent for RMS, especially alveolar RMS.

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Inhibition of rhabdomyosarcoma's metastatic behavior through downregulation of MET receptor signaling.

Cited by 20 publications

References 22 publications

Receptor Tyrosine Kinases as Therapeutic Targets in Rhabdomyosarcoma

Receptor Tyrosine Kinases as Therapeutic Targets in Rhabdomyosarcoma

Downregulation of microRNAs miR-1, -206 and -29 stabilizes PAX3 and CCND2 expression in rhabdomyosarcoma

Inhibition of phosphorylated c-Met in rhabdomyosarcoma cell lines by a small molecule inhibitor SU11274

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