TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2
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 overex...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-05-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/23242 |
| _version_ | 1811181118494343168 |
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| author | Amy T Ku Timothy M Shaver Ajay S Rao Jeffrey M Howard Christine N Rodriguez Qi Miao Gloria Garcia Diep Le Diane Yang Malgorzata Borowiak Daniel N Cohen Vida Chitsazzadeh Abdul H Diwan Kenneth Y Tsai Hoang Nguyen |
| author_facet | Amy T Ku Timothy M Shaver Ajay S Rao Jeffrey M Howard Christine N Rodriguez Qi Miao Gloria Garcia Diep Le Diane Yang Malgorzata Borowiak Daniel N Cohen Vida Chitsazzadeh Abdul H Diwan Kenneth Y Tsai Hoang Nguyen |
| author_sort | Amy T Ku |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T09:13:03Z |
| format | Article |
| id | doaj.art-b98fd3e38ef8466c89853859555a1e85 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:13:03Z |
| publishDate | 2017-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-b98fd3e38ef8466c89853859555a1e852022-12-22T04:32:26ZengeLife Sciences Publications LtdeLife2050-084X2017-05-01610.7554/eLife.23242TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2Amy T Ku0Timothy M Shaver1Ajay S Rao2Jeffrey M Howard3Christine N Rodriguez4Qi Miao5Gloria Garcia6Diep Le7Diane Yang8Malgorzata Borowiak9Daniel N Cohen10Vida Chitsazzadeh11Abdul H Diwan12Kenneth Y Tsai13Hoang Nguyen14https://orcid.org/0000-0002-1091-7483Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States; Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, United StatesStem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United StatesStem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United StatesStem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United StatesStem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United StatesStem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United StatesStem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United StatesStem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United StatesStem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United StatesStem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States; Program in Developmental Biology, Baylor College of Medicine, Houston, United States; McNair Medical Institute, Baylor College of Medicine, Houston, United StatesDepartment of Pathology and Immunology, Michael E. DeBakey VA Medical Center, Baylor College of Medicine, Houston, United StatesDepartment of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, United StatesDepartment of Dermatology, Baylor College of Medicine, Houston, United StatesDepartment of Tumor Biology, Moffitt Cancer Center, Tampa, United States; Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, United StatesStem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States; Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States; Program in Developmental Biology, Baylor College of Medicine, Houston, United States; Department of Dermatology, Baylor College of Medicine, Houston, United States; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, United StatesThe 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.https://elifesciences.org/articles/23242TCF7L1skin squamous cell carcinomacell migrationoncogene-induced senescence |
| spellingShingle | Amy T Ku Timothy M Shaver Ajay S Rao Jeffrey M Howard Christine N Rodriguez Qi Miao Gloria Garcia Diep Le Diane Yang Malgorzata Borowiak Daniel N Cohen Vida Chitsazzadeh Abdul H Diwan Kenneth Y Tsai Hoang Nguyen TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2 eLife TCF7L1 skin squamous cell carcinoma cell migration oncogene-induced senescence |
| title | TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2 |
| title_full | TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2 |
| title_fullStr | TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2 |
| title_full_unstemmed | TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2 |
| title_short | TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2 |
| title_sort | tcf7l1 promotes skin tumorigenesis independently of β catenin through induction of lcn2 |
| topic | TCF7L1 skin squamous cell carcinoma cell migration oncogene-induced senescence |
| url | https://elifesciences.org/articles/23242 |
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