TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2
| Autor: | Diane Yang, Diep Le, Gloria E. Garcia, Timothy M. Shaver, Jeffrey M. Howard, Amy T. Ku, Hoang Nguyen, Christine N Rodriguez, Daniel N Cohen, Ajay S Rao, Kenneth Y. Tsai, Abdul H. Diwan, Malgorzata Borowiak, Qi Miao, Vida Chitsazzadeh |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Skin Neoplasms Mouse cell migration Carcinogenesis QH301-705.5 Science Transcription Factor 7-Like 1 Protein Human skin Biology medicine.disease_cause General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences Lipocalin-2 Downregulation and upregulation medicine Skin Squamous Cell Carcinoma Animals Humans Biology (General) Transcription factor beta Catenin Cancer Biology General Immunology and Microbiology Gene Expression Profiling General Neuroscience oncogene-induced senescence skin squamous cell carcinoma Cell migration Cell Biology General Medicine 3. Good health Disease Models Animal TCF7L1 030104 developmental biology Catenin Carcinoma Squamous Cell Cancer research Heterografts Medicine Research Article Human |
| Zdroj: | eLife, Vol 6 (2017) eLife |
| Popis: | The transcription factor TCF7L1 is an embryonic stem cell signature gene that is upregulated in multiple aggressive cancer types, but its role in skin tumorigenesis has not yet been defined. Here we document TCF7L1 upregulation in skin squamous cell carcinoma (SCC) and demonstrate that TCF7L1 overexpression increases tumor incidence, tumor multiplicity, and malignant progression in the chemically induced mouse model of skin SCC. Additionally, we show that downregulation of TCF7L1 and its paralogue TCF7L2 reduces tumor growth in a xenograft model of human skin SCC. Using separation-of-function mutants, we show that TCF7L1 promotes tumor growth, enhances cell migration, and overrides oncogenic RAS-induced senescence independently of its interaction with β-catenin. Through transcriptome profiling and combined gain- and loss-of-function studies, we identified LCN2 as a major downstream effector of TCF7L1 that drives tumor growth. Our findings establish a tumor-promoting role for TCF7L1 in skin and elucidate the mechanisms underlying its tumorigenic capacity. DOI: http://dx.doi.org/10.7554/eLife.23242.001 |
| Databáze: | OpenAIRE |
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