Overexpression of SIX1 Is an Independent Prognostic Marker in Stage I-III Colorectal Cancer

Int J Cancer. 2015 Nov 1;137(9):2104-13. doi: 10.1002/ijc.29596. Epub 2015 May 21.

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.

Keywords: EMT; SIX1; colorectal cancer; prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Adenoma / metabolism*
  • Adenoma / pathology
  • Aged
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Epithelial-Mesenchymal Transition
  • Female
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Neoplasm Staging
  • Prognosis

Substances

  • Biomarkers, Tumor
  • Homeodomain Proteins
  • SIX1 protein, human