Survivin and molecular pathogenesis of colorectal cancer

Lancet. 2003 Jul 19;362(9379):205-9. doi: 10.1016/S0140-6736(03)13910-4.


Background: Colorectal cancer is thought to originate in the expansion of colonic crypt cells as a result of aberrant gene expression caused by transcription factors of the T-cell factor (TCF)/beta-catenin family. Survivin is a bifunctional regulator of cell death and cell proliferation expressed during embryonic development but undetectable in healthy adult tissues and re-expressed in many cancers, including colorectal cancer.

Methods: We investigated gene expression by promoter analysis, mutagenesis, and electrophoretic mobility shift assay in colorectal cancer cells. Survivin expression in human and mouse embryonic intestine was determined by in-situ hybridisation and immunohistochemistry. Changes in apoptosis were monitored in cell lines engineered to express stabilising mutations in beta catenin.

Findings: TCF/beta catenin stimulated a six-fold to 12-fold increased expression of the survivin gene in colorectal cancer cells. Three TCF-binding elements (TBE) in the survivin promoter were occupied by nuclear factors in colorectal cancer cells, and mutagenesis of the two proximal TBE sites abolished survivin gene expression by 75-79%. Strongly expressed at the bottom of human and mouse embryonic intestinal crypts, expression of survivin was lost in TCF-4 knockout animals, and a TCF-4 dominant negative mutant blocked survivin gene transcription in colorectal cancer cells. Expression of non-destructible beta catenin mutants increased survivin expression and protected against ultraviolet-B-induced apoptosis.

Interpretation: Stimulation of survivin expression by TCF/beta catenin might impose a stem cell-like phenotype to colonic crypt epithelium coupling enhanced cell proliferation with resistance to apoptosis, and contribute to the molecular pathogenesis of colorectal cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antisense Elements (Genetics)
  • Apoptosis / physiology
  • Cell Division
  • Colorectal Neoplasms / metabolism*
  • Cytoskeletal Proteins / metabolism
  • Cytoskeletal Proteins / physiology
  • Electrophoretic Mobility Shift Assay
  • Female
  • Gene Expression
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Inhibitor of Apoptosis Proteins
  • Intestinal Mucosa / chemistry
  • Intestinal Mucosa / embryology
  • Intestinal Mucosa / metabolism
  • Mice
  • Microtubule-Associated Proteins / analysis
  • Microtubule-Associated Proteins / metabolism*
  • Mutagenesis / physiology
  • Neoplasm Proteins
  • Pregnancy
  • Promoter Regions, Genetic / physiology
  • Survivin
  • Trans-Activators / metabolism
  • Trans-Activators / physiology
  • Transcription, Genetic
  • beta Catenin


  • Antisense Elements (Genetics)
  • BIRC5 protein, human
  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • Cytoskeletal Proteins
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • Survivin
  • Trans-Activators
  • beta Catenin