NOTCH3 knockdown in non-transformed human esophageal cells
Transcriptomics Dataset
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| Accession | GSE27424 |
| Title | NOTCH3 knockdown in non-transformed human esophageal cells |
| Description | To determine the role of NOTCH3 in human esophageal epitheila homeostasis/squamous cell differentiation Zinc finger E-box binding (ZEB) proteins ZEB1 and ZEB2 are transcription factors essential in transforming growth factor (TGF)--mediated epithelial to mesenchymal transition (EMT), senescence and cancer stem cell maintenance through mutual negative regulation of the microRNA (miR)-200 family members. However, little is known as to how ZEB expressing tumor cells may emerge during invasive growth. We find that canonical Notch signaling prevents expansion of a unique subset of cells expressing ZEBs through NOTCH3 (N3). In primary esophageal squamous cell carcinoma (ESCC), ZEB1 is induced in tumor cells displaying EMT-like dedifferentiation at the invasive front of tumor nests with reciprocal downregulation of the miR-200. ZEB expression was associated with the lack of cellular capability of undergoing squamous differentiation through dysfunction of N3, implicated at the onset of normal esophageal squamous differentiation. Dominant-negative Mastermind-like1 (DNMAML1), a genetic pan-notch inhibitor, prevented CSL-dependent transcription, resulting in suppression of N3 expression and squamous differentiation while enriching EMT competent cells with robust upregulation of ZEBs and downregulation of the miR-200. Such a cell population demonstrated enhanced anchorage independent growth as well as tumor formation in nude mice. RNA interference (RNAi) experiments documented the requirement of ZEBs in TGF--mediated EMT. Invasive growth and impaired squamous differentiation was recapitulated upon Notch inhibition in organotypic 3D culture, a form of human tissue engineering. Finally, RNAi experiments revealed N3 as a key factor limiting the expansion of the ZEB expressing cells, providing novel mechanistic insights into the role of Notch signaling in ESCC cell fate regulation and disease progression. |
| Landing Page | https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE27424 |
| Repository | Gene Expression Omnibus |
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