Notch‐1 Promotes Stemness and Epithelial to Mesenchymal Transition in Colorectal Cancer

Abstract

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.

Activation of Notch pathway is linked with epithelial-mesenchymal transition in prostate cancer cells

“…42 Strikingly, Notch was found to promote stemness and EMT in colorectal cancer. 43 Similarly, Notch signaling triggered EMT, leading to enhanced invasion and metastasis in adenoid cystic carcinoma. 44 One study showed that aberrant expression of EMT markers E-cadherin, Vimentin, and Notch-1 was observed in prostate cancer specimen and bone metastasis tissues, suggesting that Nocth-1 could play a role in bone metastasis via regulation of EMT.…”

ATG4A promotes tumor metastasis by inducing the epithelial-mesenchymal transition and stem-like properties in gastric cells

“…EMT has been mechanistically linked to stem-like signatures regulated by Notch-1 in prostate cancer cells [48]. In colorectal cancer patient specimens, Notch-1 was found to be up-regulated in colon tumor tissue and to increase the abundance of EMT- and stemness-associated proteins, such as CD44, Slug and Smad-3 [49]. These studies indicated that the Notch pathway was associated with the EMT and acquisition of stem cell-like properties in cancer cells.…”

STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway

“…Up-regulation of NOTCH1, JAG ligands and HES1 in CRC cell lines results in the increased expression of the EMT/stemness-associated proteins: CD44, SLUG, and SMAD3 (7,8). High expression of HES1 is significantly correlated with distal metastasis at diagnosis, and unfavorable prognostic outcome for CRC patients (9).…”