Survivin and molecular pathogenesis of colorectal cancer.
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.


RESULTS
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.


CONCLUSIONS
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.
Kim
Paul J
PJ
Department of Cancer Biology and the Cancer Center, University of Massachusetts, Medical School, Worcester, MA, USA.
Plescia
Janet
J
Clevers
Hans
H
Fearon
Eric R
ER
Altieri
Dario C
DC
D000818:Animals; D016375:Antisense Elements (Genetics); D017209:Apoptosis / Q000502:physiology; D002455:Cell Division; D015179:Colorectal Neoplasms / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051034:Inhibitor of Apoptosis Proteins; D007413:Intestinal Mucosa / Q000737:chemistry / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000378:metabolism*; D016296:Mutagenesis / Q000502:physiology; D009363:Neoplasm Proteins; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000502:physiology; D000077022:Survivin; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology; D014158:Transcription, Genetic; D051176:beta Catenin
D016375:Antisense Elements (Genetics); C107489:BIRC5 protein, human; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D015534:Trans-Activators; D051176:beta Catenin