Notch-1 promotes stemness and epithelial to mesenchymal transition in colorectal cancer.
Colorectal cancer (CRC) is the third leading cause of cancer death in the United States, resulting in an average of 50,000 deaths per year. Surgery and combination chemotherapy comprise current treatment strategies. However, curative options are limited if surgery and chemotherapy are unsuccessful. Several studies have indicated that CRC aggressiveness and potential for metastatic spread are associated with the acquisition of stem cell like properties. The Notch-1 receptor and its cognate signaling pathway is well known for controlling cell fate decisions and stem-cell phenotypes. Alterations in Notch receptors and Notch signaling has been reported for some colon cancers. Herein, we examine a potential role for Notch-1 signaling in CRC. In CRC patient samples, Notch-1 expression was increased in colon tumor tissue as compared with normal colon tissue. Retroviral transduction of constitutively active Notch-1 (ICN1) into the colon tumor cell line HCT-116 resulted in increased expression of the EMT/stemness associated proteins CD44, Slug, Smad-3, and induction of Jagged-1 expression. These changes in ICN1 expressing cells were accompanied by increased migration and increased anchorage independent growth by 2.5-fold and 23%, respectively. Experiments with the pan-Notch inhibitor DAPT, and soluble Jagged-1-Fc protein provided evidence that Notch-1 signaling activates CD44, Slug, and Smad-3 via a cascade of other Notch-receptors through induction of Jagged-1 expression. These data indicate a key role for Notch signaling in the phenotype of CRC and suggest that targeting of Notch signaling may be of therapeutic value in colon cancers.
Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, North Carolina.|Department of Oncology, Brody School of Medicine, East Carolina University, Greenville, North Carolina.
Alexander W
AW
Fender
Department of Oncology, Brody School of Medicine, East Carolina University, Greenville, North Carolina.
Jennifer M
JM
Nutter
Department of Surgery, Brody School of Medicine, East Carolina University, Greenville, North Carolina.
Timothy L
TL
Fitzgerald
Department of Oncology, Brody School of Medicine, East Carolina University, Greenville, North Carolina.|Department of Clinical and Diagnostic Sciences, Department of Nutrition Sciences, School of Health Professions, University of Alabama, Birmingham, Alabama.
Fred E
FE
Bertrand
Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, North Carolina.|Department of Oncology, Brody School of Medicine, East Carolina University, Greenville, North Carolina.
George
G
Sigounas
D014408:Biomarkers, Tumor / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D045325:HCT116 Cells; D006801:Humans; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
D014408:Biomarkers, Tumor; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1
COLON CANCER; EMT; NOTCH SIGNALING; STEMNESS