title: Concomitant expression of far upstream element (FUSE) binding protein (FBP) interacting repressor (FIR) and its splice variants induce migration and invasion of non-small cell lung cancer (NSCLC) cells.
abstract: Transcription factors integrate a variety of oncogenic input information, facilitate tumour growth and cell dissemination, and therefore represent promising therapeutic target structures. Because over-expression of DNA-interacting far upstream element binding protein (FBP) supports non-small cell lung cancer (NSCLC) migration, we asked whether its repressor, FBP-interacting repressor (FIR) is functionally inactivated and how FIR might affect NSCLC cell biology. Different FIR splice variants were highly expressed in the majority of NSCLCs, with the highest levels in tumours carrying genomic gains of chromosome 8q24.3, which contained the FIR gene locus. Nuclear FIR expression was significantly enriched at the invasion front of primary NSCLCs, but this did not correlate with tumour cell proliferation. FIR accumulation was associated with worse patient survival and tumour recurrence; in addition, FIR over-expression significantly correlated with lymph node metastasis in squamous cell carcinomas (SCCs). In vitro, we applied newly developed methods and modelling approaches for the quantitative and time-resolved description of the pro-migratory and pro-invasive capacities of SCC cells. siRNA-mediated silencing of all FIR variants significantly reduced the speed and directional movement of tumour cells in all phases of migration. Furthermore, sprouting efficiency and single cell invasiveness were diminished following FIR inhibition. Interestingly, the silencing of FIR isoforms lacking exon 2 (FIR(Δexon2)) alone was sufficient to reduce lateral migration and invasion. In summary, by using scale-spanning data derived from primary human tissues, quantitative cellular analyses and mathematical modelling, we have demonstrated that concomitant over-expression of FIR and its splice variants drives NSCLC migration and dissemination.
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Müller
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bovet
authors.affiliation: INRIA, Rocquencourt, Paris, France.|Sorbonne Universités, UPMC University Paris 6, Labortoire Jacques-Louis, Paris, France.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Centre for Modelling and Simulation in the Biosciences (BIOMS), University of Heidelberg, Germany.
authors.forename: Damian
authors.initials: D
authors.lastname: Stichel
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.
authors.forename: Mona
authors.initials: M
authors.lastname: Malz
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.
authors.forename: Margarita
authors.initials: M
authors.lastname: González-Vallinas
authors.affiliation: Centre for Modelling and Simulation in the Biosciences (BIOMS), University of Heidelberg, Germany.
authors.forename: Alistair
authors.initials: A
authors.lastname: Middleton
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Ehemann
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schmitt
authors.affiliation: Translational Research Unit, Thoraxklinik, University Hospital Heidelberg, Germany.|Translational Lung Research Centre Heidelberg (TLRC-H) [Member, German Centre for Lung Research (DZL)], Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Muley
authors.affiliation: Translational Research Unit, Thoraxklinik, University Hospital Heidelberg, Germany.|Translational Lung Research Centre Heidelberg (TLRC-H) [Member, German Centre for Lung Research (DZL)], Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Meister
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.|Tissue Bank, National Centre for Tumour Diseases (NCT), Heidelberg, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Herpel
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.|European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Singer
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.|Translational Lung Research Centre Heidelberg (TLRC-H) [Member, German Centre for Lung Research (DZL)], Heidelberg, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Warth
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: INRIA, Rocquencourt, Paris, France.|Sorbonne Universités, UPMC University Paris 6, Labortoire Jacques-Louis, Paris, France.|IZBI, University of Leipzig, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Drasdo
authors.affiliation: Centre for Modelling and Simulation in the Biosciences (BIOMS), University of Heidelberg, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Matthäus
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D008207:Lymphatic Metastasis; D018715:Microscopy, Video; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D020033:Protein Isoforms; D034622:RNA Interference; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D015398:Signal Transduction; D013997:Time Factors; D059008:Time-Lapse Imaging; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C492258:FUBP1 protein, human; D020033:Protein Isoforms; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C410595:poly-U binding splicing factor 60KDa; D004265:DNA Helicases
keywords: lung cancer; metastasis; splice variants; transcription factor