NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer.
NOTCH signaling is critical for specifying the intestinal epithelial cell lineage and for initiating colorectal adenomas and colorectal cancers (CRC). Based on evidence that NOTCH is important for the maintenance and self-renewal of cancer-initiating cells in other malignancies, we studied the role of NOTCH signaling in colon cancer-initiating cells (CCIC). Tumors formed by CCICs maintain many properties of the primary CRCs from which they were derived, such as glandular organization, cell polarity, gap junctions, and expression of characteristic CRC molecular markers. Furthermore, CCICs have the property of self-renewal. In this study, we show that NOTCH signaling is 10- to 30-fold higher in CCIC compared with widely used colon cancer cell lines. Using small-molecule inhibition and short hairpin RNA knockdown, we show that NOTCH prevents CCIC apoptosis through repression of cell cycle kinase inhibitor p27 and transcription factor ATOH1. NOTCH is also critical to intrinsic maintenance of CCIC self-renewal and the repression of secretory cell lineage differentiation genes such as MUC2. Our findings describe a novel human cell system to study NOTCH signaling in CRC tumor initiation and suggest that inhibition of NOTCH signaling may improve CRC chemoprevention and chemotherapy.
Department of Biological Chemistry, School of Medicine, University of California, Irvine, California, USA.
Shaheen S
SS
Sikandar
Kira T
KT
Pate
Scott
S
Anderson
Diana
D
Dizon
Robert A
RA
Edwards
Marian L
ML
Waterman
Steven M
SM
Lipkin
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D019858:Enteroendocrine Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; C497761:NOTCH1 protein, human; D034741:RNA, Small Interfering; D051881:Receptor, Notch1