Abstract:
: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.
journal_name
Elifejournal_title
eLifeauthors
Ku AT,Shaver TM,Rao AS,Howard JM,Rodriguez CN,Miao Q,Garcia G,Le D,Yang D,Borowiak M,Cohen DN,Chitsazzadeh V,Diwan AH,Tsai KY,Nguyen Hdoi
10.7554/eLife.23242subject
Has Abstractpub_date
2017-05-03 00:00:00issn
2050-084Xjournal_volume
6pub_type
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