title: Loss of SOX2 expression induces cell motility via vimentin up-regulation and is an unfavorable risk factor for survival of head and neck squamous cell carcinoma.
abstract: Recurrent gain on chromosome 3q26 encompassing the gene locus for the transcription factor SOX2 is a frequent event in human squamous cell carcinoma, including head and neck squamous cell carcinoma (HNSCC). Numerous studies demonstrated that SOX2 expression and function is related to distinct aspects of tumor cell pathophysiology. However, the underlying molecular mechanisms are not well understood, and the correlation between SOX2 expression and clinical outcome revealed conflicting data. Transcriptional profiling after silencing of SOX2 expression in a HNSCC cell line identified a set of up-regulated genes related to cell motility (e.g. VIM, FN1, CDH2). The inverse regulation of SOX2 and aforementioned genes was validated in 18 independent HNSCC cell lines from different anatomical sites. The inhibition of cell migration and invasion by SOX2 was confirmed by constant or conditional gene silencing and accelerated motility of HNSCC cells after SOX2 silencing was partially reverted by down-regulation of vimentin. In a retrospective study, SOX2 expression was determined by immunohistochemical staining on tissue microarrays containing primary tumor specimens of two independent HNSCC patient cohorts. Low SOX2 expression was found in 19.3% and 44.9% of primary tumor specimens, respectively. Univariate analysis demonstrated a statistically significant correlation between low SOX2 protein levels and reduced progression-free survival (Cohort I 51 vs. 16 months; Cohort II 33 vs. 12 months) and overall survival (Cohort I 150 vs. 37 months; Cohort II 33 vs. 16 months). Multivariate Cox proportional hazard model analysis confirmed that low SOX2 expression serves as an independent prognostic marker for HNSCC patients. We conclude that SOX2 inhibits tumor cell motility in HNSCC cells and that low SOX2 expression serves as a prognosticator to identify HNSCC patients at high risk for treatment failure.
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, D-69120, Germany; Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, D-69120, Germany. Electronic address: pilarbz@gmail.com.
authors.forename: Pilar
authors.initials: P
authors.lastname: Bayo
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Heidelberg, D-69120, Germany; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, D-69120, Germany; Oral Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, CEP: 90035-003, Brazil. Electronic address: a.jou@Dkfz-Heidelberg.de.
authors.forename: Adriana
authors.initials: A
authors.lastname: Jou
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, D-69120, Germany. Electronic address: albrecht.stenzinger@med.uni-heidelberg.de.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.affiliation: Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, D-69120, Germany. Electronic address: c.shao@Dkfz-Heidelberg.de.
authors.forename: Chunxuan
authors.initials: C
authors.lastname: Shao
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Heidelberg, D-69120, Germany; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, D-69120, Germany. Electronic address: MadeleineGross@gmx.de.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Gross
authors.affiliation: Department of Radiation Oncology, University Hospital Heidelberg, D-69120, Germany. Electronic address: alexandra.jensen@med.uni-heidelberg.de.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Jensen
authors.affiliation: Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, Heidelberg, D-69120, Germany; Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany. Electronic address: niels.grabe@bioquant.uni-heidelberg.de.
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
authors.affiliation: Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany; Molecular Cell Biology Group, Department of Otorhinolaryngology, Head and Neck Surgery, Heidelberg, Germany. Electronic address: h.mende@med.uni-heidelberg.de.
authors.forename: Christel Herold
authors.initials: CH
authors.lastname: Mende
authors.affiliation: Oral Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, CEP: 90035-003, Brazil. Electronic address: pantelis@ufrgs.br.
authors.forename: Pantelis Varvaki
authors.initials: PV
authors.lastname: Rados
authors.affiliation: Department of Radiation Oncology, University Hospital Heidelberg, D-69120, Germany. Electronic address: juergen.debus@med.uni-heidelberg.de.
authors.forename: Juergen
authors.initials: J
authors.lastname: Debus
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, D-69120, Germany. Electronic address: wilko.weichert@med.uni-heidelberg.de.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, D-69120, Germany. Electronic address: peter_plinkert@med.uni-heidelberg.de.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Plinkert
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, D-69120, Germany. Electronic address: Peter.Lichter@Dkfz-Heidelberg.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Heidelberg, D-69120, Germany. Electronic address: kolja.freier@med.uni-heidelberg.de.
authors.forename: Kolja
authors.initials: K
authors.lastname: Freier
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, D-69120, Germany; Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, D-69120, Germany. Electronic address: j.hess@dkfz-heidelberg.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hess
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D015536:Down-Regulation; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D055748:SOXB1 Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000077195:Squamous Cell Carcinoma of Head and Neck; D016019:Survival Analysis; D014746:Vimentin / Q000235:genetics* / Q000378:metabolism
chemical_list: C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D014746:Vimentin
keywords: Cell motility; Gene expression profiling; Immunohistochemistry; Prognostic biomarker; Tissue microarray