title: A mechanistic study on the metastasis inducing function of FUS-CHOP fusion protein in liposarcoma.
abstract: The FUS-CHOP fusion protein has been found to be instrumental for specific oncogenic processes in liposarcoma, but its ability to induce metastasis and the underlying mechanisms by which this can be achieved remain unknown. To dissect its functional role in this context, we stably overexpressed this protein in SW872 liposarcoma and HT1080 fibrosarcoma cell lines, and were able to demonstrate that forced expression of FUS-CHOP significantly increases migration and invasion, as well as enhances lung and liver metastasis in the in vivo chicken chorioallantoic membrane (CAM) model, that is proliferation independent. Additionally, FUS-CHOP enhances the expression of matrix-metalloproteinases -2 and -9, and transactivates their promoters in vitro. Mutational analysis showed that C/EBP-β- (-769/-755), NF-κB (-525/-516) and CREB/AP-1 (-218/-207) sites were important for MMP-2 and NF-κB (-604/-598), AP-1 (-539/-532) and AP-1 (-81/-72) for MMP-9 transactivation. Moreover, a direct in vivo interaction of FUS-CHOP was observed in case of the MMP-2 promoter within region (-769/-207). siRNA data revealed that MMP-2 expression is essential in the FUS-CHOP induced metastatic phenotype. MMP-2-mRNA and protein expression correlated significantly with FUS-CHOP positivity in 46 resected patient liposarcoma tissues. We have for the first time provided substantial evidence for the FUS-CHOP oncoprotein as an inducer of metastasis that is due to the transcriptional induction of specific tumor-associated proteases. Insights gained from this study not only support a deeper understanding of the mechanistic properties of FUS-CHOP, but also open up new avenues for targeted therapy.
authors.affiliation: Department of Experimental Surgery and Molecular Oncology of Solid Tumors, Medical Faculty Mannheim, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany.
authors.forename: Nitin
authors.initials: N
authors.lastname: Patil
authors.forename: Suhail
authors.initials: S
authors.lastname: Ahmed Kabeer Rasheed
authors.forename: Mohammed
authors.initials: M
authors.lastname: Abba
authors.forename: Jörg
authors.initials: J
authors.lastname: Hendrik Leupold
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwarzbach
authors.forename: Heike
authors.initials: H
authors.lastname: Allgayer
mesh_terms: D016475:3T3 Cells; D000368:Aged; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000166:cytology / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008080:Liposarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D034702:RNA-Binding Protein FUS / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D016328:NF-kappa B; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D034702:RNA-Binding Protein FUS; C106030:TLS-CHOP fusion protein, human; D018808:Transcription Factor AP-1; D051742:Transcription Factor CHOP; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: FUS-CHOP; invasion and metastasis; migration