Targeting Notch1 and IKKα Enhanced NF-κB Activation in CD133+ Skin Cancer Stem Cells
| Autor: | Nga Voong Hawk, Zhong Chen, David Petersen, Paul S. Meltzer, Carter Van Waes, Andrew Montemarano, Weiping Chen, Xin Xin Quan, Jamie Coupar, Martin Braun, Steven Lee |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Regulation of gene expression Cancer Research education.field_of_study RELB Population Wnt signaling pathway Biology Gene expression profiling 03 medical and health sciences Transactivation 030104 developmental biology Oncology embryonic structures Cancer research Stem cell education PI3K/AKT/mTOR pathway |
| Zdroj: | Molecular Cancer Therapeutics. 17:2034-2048 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-17-0421 |
| Popis: | Cancer stem–like cells are hypothesized to be the major tumor-initiating cell population of human cutaneous squamous cell carcinoma (cSCC), but the landscape of molecular alterations underpinning their signaling and cellular phenotypes as drug targets remains undefined. In this study, we developed an experimental pipeline to isolate a highly enriched CD133+CD31−CD45−CD61−CD24− (CD133+) cell population from primary cSCC specimens by flow cytometry. The CD133+ cells show enhanced stem–like phenotypes, which were verified by spheroid and colony formation in vitro and tumor generation in vivo. Gene expression profiling of CD133+/− cells was compared and validated, and differentially expressed gene signatures and top pathways were identified. CD133+ cells expressed a repertoire of stemness and cancer-related genes, including NOTCH and NOTCH1-mediated NF-κB pathway signaling. Other cancer-related genes from WNT, growth factor receptors, PI3K/mTOR, STAT pathways, and chromatin modifiers were also identified. Pharmacologic and genetic targeting of NOTCH1, IKKα, RELA, and RELB modulated NF-κB transactivation, the CD133+ population, and cellular and stemness phenotypes. Immunofluorescent staining confirmed colocalization of CD133+ and IKKα expression in SCC tumor specimens. Our functional, genetic, and pharmacologic studies uncovered a novel linkage between NOTCH1, IKKα, and NF-κB pathway activation in maintaining the CD133+ stem SCC phenotypes. Studies investigating markers of activation and modulators of NOTCH, IKK/NF-κB, and other pathways regulating these cancer stem gene signatures could further accelerate the development of effective therapeutic strategies to treat cSCC recurrence and metastasis. Mol Cancer Ther; 17(9); 2034–48. ©2018 AACR. |
| Databáze: | OpenAIRE |
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