TY - JOUR
T1 - Sox2 Suppresses Gastric Tumorigenesis in Mice
AU - Sarkar, Abby
AU - Huebner, Aaron J.
AU - Sulahian, Rita
AU - Anselmo, Anthony
AU - Xu, Xinsen
AU - Flattery, Kyle
AU - Desai, Niyati
AU - Sebastian, Carlos
AU - Yram, Mary Anna
AU - Arnold, Katrin
AU - Rivera, Miguel
AU - Mostoslavsky, Raul
AU - Bronson, Roderick
AU - Bass, Adam J.
AU - Sadreyev, Ruslan
AU - Shivdasani, Ramesh A.
AU - Hochedlinger, Konrad
N1 - Publisher Copyright:
© 2016 The Author(s)
PY - 2016/8/16
Y1 - 2016/8/16
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84997707970
U2 - 10.1016/j.celrep.2016.07.034
DO - 10.1016/j.celrep.2016.07.034
M3 - Article
C2 - 27498859
AN - SCOPUS:84997707970
SN - 2211-1247
VL - 16
SP - 1929
EP - 1941
JO - Cell Reports
JF - Cell Reports
IS - 7
ER -