Autocrine role for Gas6 with Tyro3 and Axl in leiomyosarcomas
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- 作者：Hiba el Sayadi (1)
Daniel Pissaloux (1)
Laurent Alberti (1)
Severine Tabone-Eglinger (1)
Dominique Ranchere (2)
Anne Valie Decouvelaere (2)
Eric Tabone (2)
Isabelle Ray-Coquard (3)
Christophe Caux (1)
Jome Fayette (3)
Jean-Yves Blay (1) (3) (4) - 关键词：Leiomyosarcomas ; Tyrosine kinase ; Tyro3 ; Gas6 ; Targeted therapy ; Sarcoma ; FAK
- 刊名：Targeted Oncology
- 出版年：2013
- 出版时间：December 2013
- 年：2013
- 卷：8
- 期：4
- 页码：261-269
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- 作者单位：Hiba el Sayadi (1)
Daniel Pissaloux (1)
Laurent Alberti (1)
Severine Tabone-Eglinger (1)
Dominique Ranchere (2)
Anne Valie Decouvelaere (2)
Eric Tabone (2)
Isabelle Ray-Coquard (3)
Christophe Caux (1)
Jome Fayette (3)
Jean-Yves Blay (1) (3) (4)
1. Pole des Sciences Cliniques & Centre de Recherche en Cancerologie de Lyon, INSERM UMR5286 Equipe 11, Centre Ln Bard, Lyon, France
2. Service dnatomie pathologique, Centre Ln Bard, Lyon, France
3. Dartement de Mecine Centre Ln Bard, 28 rue Lannec, 69373, Lyon cedex 08, France
4. UniversitClaude Bernard Lyon 1, Lyon, France - ISSN：1776-260X
文摘
Leiomyosarcoma (LMS) represent 15% of adult sarcomas. The aim of this work was to identify novel altered pathways in LMS, which may be of therapeutic value for patients. Thirteen fresh frozen samples of soft tissue and visceral LMS were analyzed and compared with normal smooth muscle uterine tissue (NSM) for phosphoproteomic profile. Four proteins were found differentially expressed including Tyro3. The functional role of Tyro3 and its ligand Gas6 was investigated in two LMS cell lines, SK-LMS-1 and CNIO-AA. Four proteins and phosphoproteins were differentially expressed in LMS samples vs NSM: A loss of FAK Y397 phosphorylation was observed in all LMSs, while Tyro3, MSH2 and PKC theta were consistently overexpressed. Gas6, the major ligand of Tyro3, was expressed in 8 of the 13 LMS samples, and Gas6 expression highly correlated to Akt Y473 phosphorylation and to a lesser extent to Erk1/2 phosphorylation. SK-LMS-1 and CNIO-AA LMS expressed Tyro3, Axl and Gas6 at high level in CNIO-AA while at low levels in SK-LMS-1. Exposure of both cell lines to foretinib, a tyrosine kinase inhibitor of Met, Axl and Tyro3, reduced cell viability and induced caspase 3/7 activation. Transfection of CNIO-AA with small interfering RNA directed against Tyro3 and Axl genes induced a reduction of the expression of the specific proteins and, when combined, significantly reduced CNIO-AA cell viability. Leiomyosarcomas overexpress Tyro3. Gas6, a ligand of Tyro3, exerts an autocrine activities though Tyro3 and Axl in a subgroup of LMS.