Oncotarget

Research Papers:

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

Klaudia Skrzypek, Anna Kusienicka, Barbara Szewczyk, Tomasz Adamus, Ewa Lukasiewicz, Katarzyna Miekus and Marcin Majka _

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Oncotarget. 2015; 6:31378-31398. https://doi.org/10.18632/oncotarget.5145

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Abstract

Klaudia Skrzypek1,*, Anna Kusienicka1,*, Barbara Szewczyk1, Tomasz Adamus1, Ewa Lukasiewicz1, Katarzyna Miekus2, Marcin Majka1

1Department of Transplantation, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Krakow, Poland

2Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland

*These authors have contributed equally to this work

Correspondence to:

Marcin Majka, e-mail: mmajka@cm-uj.krakow.pl

Keywords: MET, rhabdomyosarcoma (RMS), mesenchymal stem cells (MSC), differentiation, metastasis

Received: July 13, 2015     Accepted: August 27, 2015     Published: September 08, 2015

ABSTRACT

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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