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Notch‐1 Promotes Stemness and Epithelial to Mesenchymal Transition in Colorectal Cancer
Author(s) -
Fender Alexander W.,
Nutter Jennifer M.,
Fitzgerald Timothy L.,
Bertrand Fred E.,
Sigounas George
Publication year - 2015
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.25196
Subject(s) - epithelial–mesenchymal transition , colorectal cancer , mesenchymal stem cell , cancer research , notch signaling pathway , microbiology and biotechnology , biology , cancer , medicine , metastasis , signal transduction
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. J. Cell. Biochem. 116: 2517–2527, 2015. © 2015 Wiley Periodicals, Inc.