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FUS-DDIT3 Fusion Pr...
FUS-DDIT3 Fusion Protein-Driven IGF-IR Signaling is a Therapeutic Target in Myxoid Liposarcoma
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Trautmann, M. (författare)
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Menzel, J. (författare)
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Bertling, C. (författare)
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Cyra, M. (författare)
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Isfort, I. (författare)
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Steinestel, K. (författare)
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Elges, S. (författare)
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Gunewald, I. (författare)
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Altvater, B. (författare)
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Rossig, C. (författare)
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Frohling, S. (författare)
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Hafner, S. (författare)
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Simmet, T. (författare)
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- Åman, Pierre, 1953 (författare)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center
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Wardelmann, E. (författare)
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Huss, S. (författare)
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Hartmann, W. (författare)
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(creator_code:org_t)
- 2017-10-12
- 2017
- Engelska.
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Ingår i: Clinical Cancer Research. - : American Association for Cancer Research (AACR). - 1078-0432 .- 1557-3265. ; 23:20, s. 6227-6238
- Relaterad länk:
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Purpose: Myxoid liposarcoma is an aggressive disease with particular propensity to develop hematogenic metastases. Over 90% of myxoid liposarcoma are characterized by a reciprocal t(12;16)(q13;p11) translocation. The resulting chimeric FUS-DDIT3 fusion protein plays a crucial role in myxoid liposarcoma pathogenesis; however, its specific impact on oncogenic signaling pathways remains to be substantiated. We here investigate the functional role of FUS-DDIT3 in IGF-IR/PI3K/Akt signaling driving myxoid liposarcoma pathogenesis. Experimental Design: Immunohistochemical evaluation of key effectors of the IGF-IR/PI3K/Akt signaling axis was performed in a comprehensive cohort of myxoid liposarcoma specimens. FUS-DDIT3 dependency and biological function of the IGF-IR/PI3K/Akt signaling cascade were analyzed using a HT1080 fibrosarcoma-based myxoid liposarcoma tumor model and multiple tumor-derived myxoid liposarcoma cell lines. An established myxoid liposarcoma avian chorioallantoic membrane model was used for in vivo confirmation of the preclinical in vitro results. Results: A comprehensive subset of myxoid liposarcoma specimens showed elevated expression and phosphorylation levels of various IGF-IR/PI3K/Akt signaling effectors. In HT1080 fibrosarcoma cells, overexpression of FUS-DDIT3 induced aberrant IGF-IR/PI3K/Akt pathway activity, which was dependent on transcriptional induction of the IGF2 gene. Conversely, RNAi-mediated FUS-DDIT3 knockdown in myxoid liposarcoma cells led to an inactivation of IGF-IR/PI3K/Akt signaling associated with diminished IGF2 mRNA expression. Treatment of myxoid liposarcoma cell lines with several IGF-IR inhibitors resulted in significant growth inhibition in vitro and in vivo. Conclusions: Our preclinical study substantiates the fundamental role of the IGF-IR/PI3K/Akt signaling pathway in myxoid liposarcoma pathogenesis and provides a mechanism-based rationale for molecular-targeted approaches in myxoid liposarcoma cancer therapy. (C)2017 AACR.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- refractory ewing sarcoma
- soft-tissue sarcoma
- cell liposarcoma
- synovial sarcoma
- human cancer
- in-vivo
- growth
- receptor
- chop
- pathway
- Oncology
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Trautmann, M.
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Menzel, J.
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Bertling, C.
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Cyra, M.
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Isfort, I.
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Steinestel, K.
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visa fler...
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Elges, S.
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Gunewald, I.
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Altvater, B.
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Rossig, C.
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Frohling, S.
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Hafner, S.
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Simmet, T.
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Åman, Pierre, 19 ...
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Wardelmann, E.
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Huss, S.
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Hartmann, W.
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visa färre...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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Clinical Cancer ...
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Göteborgs universitet