Sox2 Suppresses Gastric Tumorigenesis in Mice

• Published in: Cell reports (Cambridge) Vol. 16; no. 7; pp. 1929 - 1941
• Main Authors: Sarkar, Abby, Huebner, Aaron J., Sulahian, Rita, Anselmo, Anthony, Xu, Xinsen, Flattery, Kyle, Desai, Niyati, Sebastian, Carlos, Yram, Mary Anna, Arnold, Katrin, Rivera, Miguel, Mostoslavsky, Raul, Bronson, Roderick, Bass, Adam J., Sadreyev, Ruslan, Shivdasani, Ramesh A., Hochedlinger, Konrad
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.08.2016; Elsevier
• Subjects: Adenoma - genetics; Adenoma - metabolism; Adenoma - pathology; Adenomatous Polyposis Coli Protein - deficiency; Adenomatous Polyposis Coli Protein - genetics; Animals; Base Sequence; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Epithelial Cells - metabolism; Epithelial Cells - pathology; Gene Expression Regulation, Neoplastic; Hepatocyte Nuclear Factor 1-alpha - genetics; Hepatocyte Nuclear Factor 1-alpha - metabolism; Lymphoid Enhancer-Binding Factor 1 - genetics; Lymphoid Enhancer-Binding Factor 1 - metabolism; Mice; Mice, Transgenic; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Wnt Signaling Pathway
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.07.034

Sox2 expression marks gastric stem and progenitor cells, raising important questions regarding the genes regulated by Sox2 and the role of Sox2 itself during stomach homeostasis and disease. By using ChIP-seq analysis, we have found that the majority of Sox2 targets in gastric epithelial cells are tissue specific and related to functions such as endoderm development, Wnt signaling, and gastric cancer. Unexpectedly, we found that Sox2 itself is dispensable for gastric stem cell and epithelial self-renewal, yet Sox2+ cells are highly susceptible to tumorigenesis in an Apc/Wnt-driven mouse model. Moreover, Sox2 loss enhances, rather than impairs, tumor formation in Apc-deficient gastric cells in vivo and in vitro by inducing Tcf/Lef-dependent transcription and upregulating intestinal metaplasia-associated genes, providing a mechanistic basis for the observed phenotype. Together, these data identify Sox2 as a context-dependent tumor suppressor protein that is dispensable for normal tissue regeneration but restrains stomach adenoma formation through modulation of Wnt-responsive and intestinal genes. [Display omitted] •Sox2 targets epithelial, developmental, and cancer genes in gastric progenitors•Sox2 is dispensable for gastric stem cell self-renewal and epithelial homeostasis•Sox2+ cells are potent cells of origin in Wnt-driven adenoma model•Sox2 acts as a tumor suppressor by modulating Wnt-related and intestinal genes Sarkar et al. explore the role of the stem cell factor Sox2 in gastric homeostasis and tumorigenesis. Surprisingly, they find that Sox2 is dispensable for epithelial regeneration, while it inhibits tumorigenesis in an adenoma mouse model. Mechanistically, Sox2 appears to suppress tumorigenesis by restraining Wnt/β-catenin signaling and repressing an intestinal program.