SEMA4C is a novel target to limit osteosarcoma growth, progression, and metastasis.

Autor: Smeester BA; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA., Slipek NJ; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA., Pomeroy EJ; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA., Bomberger HE; Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA., Shamsan GA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.; Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA., Peterson JJ; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA., Crosby MR; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA., Draper GM; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA., Becklin KL; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA., Rahrmann EP; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK., McCarthy JB; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA., Odde DJ; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.; Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA., Wood DK; Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA., Largaespada DA; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA., Moriarity BS; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA. mori0164@umn.edu.; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA. mori0164@umn.edu.; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. mori0164@umn.edu.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2020 Jan; Vol. 39 (5), pp. 1049-1062. Date of Electronic Publication: 2019 Oct 03.
DOI: 10.1038/s41388-019-1041-x
Abstrakt: Semaphorins, specifically type IV, are important regulators of axonal guidance and have been increasingly implicated in poor prognoses in a number of different solid cancers. In conjunction with their cognate PLXNB family receptors, type IV members have been increasingly shown to mediate oncogenic functions necessary for tumor development and malignant spread. In this study, we investigated the role of semaphorin 4C (SEMA4C) in osteosarcoma growth, progression, and metastasis. We investigated the expression and localization of SEMA4C in primary osteosarcoma patient tissues and its tumorigenic functions in these malignancies. We demonstrate that overexpression of SEMA4C promotes properties of cellular transformation, while RNAi knockdown of SEMA4C promotes adhesion and reduces cellular proliferation, colony formation, migration, wound healing, tumor growth, and lung metastasis. These phenotypic changes were accompanied by reductions in activated AKT signaling, G1 cell cycle delay, and decreases in expression of mesenchymal marker genes SNAI1, SNAI2, and TWIST1. Lastly, monoclonal antibody blockade of SEMA4C in vitro mirrored that of the genetic studies. Together, our results indicate a multi-dimensional oncogenic role for SEMA4C in metastatic osteosarcoma and more importantly that SEMA4C has actionable clinical potential.
Databáze: MEDLINE
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