Format

Send to

Choose Destination
Elife. 2017 May 3;6. pii: e23242. doi: 10.7554/eLife.23242.

TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2.

Ku AT1,2,3, Shaver TM1,2, Rao AS1,2, Howard JM1,2, Rodriguez CN1,2,4, Miao Q1,2, Garcia G1,2, Le D1,2, Yang D1,2,4, Borowiak M1,2,4,5,6, Cohen DN7, Chitsazzadeh V8, Diwan AH9, Tsai KY10,11, Nguyen H1,2,3,4,5,9,12.

Author information

1
Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States.
2
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States.
3
Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, United States.
4
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States.
5
Program in Developmental Biology, Baylor College of Medicine, Houston, United States.
6
McNair Medical Institute, Baylor College of Medicine, Houston, United States.
7
Department of Pathology and Immunology, Michael E. DeBakey VA Medical Center, Baylor College of Medicine, Houston, United States.
8
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, United States.
9
Department of Dermatology, Baylor College of Medicine, Houston, United States.
10
Department of Tumor Biology, Moffitt Cancer Center, Tampa, United States.
11
Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, United States.
12
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, United States.

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.

KEYWORDS:

TCF7L1; cancer biology; cell biology; cell migration; human; mouse; oncogene-induced senescence; skin squamous cell carcinoma

PMID:
28467300
PMCID:
PMC5438253
DOI:
10.7554/eLife.23242
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center