title: Overexpression of SIX1 is an independent prognostic marker in stage I-III colorectal cancer.
abstract: Epithelial-to-mesenchymal transition (EMT) contributes significantly to tumor progression and metastasis. The assessment of EMT-associated transcription factors could be a promising approach to identify biomarkers and potential therapeutic targets in colorectal cancer. In our study, we focused on the transcription factor "Sine oculis homeobox" (SIX) 1, which is a member of the superfamily of the homeobox genes and has been described to promote EMT in different types of tumors. Immunohistochemistry against SIX1 was performed on colorectal mucosa, adenomas, carcinomas-in situ and primary adenocarcinomas. An expression score was developed and subsequently assessed for its prognostic value in two independent cohorts. Cohort 1 consisted of 128 patients with stage I-III colorectal cancer; cohort 2 included 817 patients with stage I-III colorectal cancer who had participated in the DACHS study. HCT-116 cells were transfected with SIX1 plasmids and subjected to migration and colony formation assays. The expression of SIX1 increases gradually from mucosa to colorectal adenocarcinomas (p > 0.0001). Univariate and multivariate analyses reveal that high expression of SIX1 is associated with decreased overall survival (cohort 1: HR: 4.01, CI: 1.20-14.07, p = 0.025; cohort 2: HR: 1.43, CI: 1.014-2.02, p = 0.047). Overexpression of SIX1 induces a more mesenchymal-like phenotype in HCT-116 cells and enhances tumor migration. High expression of SIX1 is an independent prognostic marker in colorectal cancer. It might be a promising biomarker to stratify patients into different risk groups. Moreover, targeting SIX1 might be a novel therapeutic approach in patients with colorectal cancer.
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kahlert
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Tristan
authors.initials: T
authors.lastname: Lerbs
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Pecqueux
authors.affiliation: NCT Tissue Bank of the National Center of Tumor Diseases (NCT) Heidelberg and Institute of Pathology, INF 224, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Herpel
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoffmeister
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Lina
authors.initials: L
authors.lastname: Jansen
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.affiliation: Unit of Genetic Epidemiology, Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.affiliation: Institute of Pathology, Charité - Universitätsmedizin Berlin Campus Mitte Charitéplatz 1, Berlin, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Bläker
authors.affiliation: NCT Tissue Bank of the National Center of Tumor Diseases (NCT) Heidelberg and Institute of Pathology, INF 224, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kloor
authors.affiliation: NCT Tissue Bank of the National Center of Tumor Diseases (NCT) Heidelberg and Institute of Pathology, INF 224, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Pilarsky
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Nuh N
authors.initials: NN
authors.lastname: Rahbari
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schölch
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bork
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Reissfelder
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weitz
authors.affiliation: Institute of Pathology, Medizinische Fakultät Carl Gustav Carus, Technische Universität, Dresden, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Aust
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Koch
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000236:Adenoma / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D009367:Neoplasm Staging; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; C099236:SIX1 protein, human
keywords: EMT; SIX1; colorectal cancer; prognosis