TY - JOUR
T1 - RhoA downregulation in the murine intestinal epithelium results in chronic Wnt activation and increased tumorigenesis
AU - Dopeso, Higinio
AU - Rodrigues, Paulo
AU - Cartón-García, Fernando
AU - Macaya, Irati
AU - Bilic, Josipa
AU - Anguita, Estefanía
AU - Jing, Li
AU - Brotons, Bruno
AU - Vivancos, Núria
AU - Beà, Laia
AU - Sánchez-Martín, Manuel
AU - Landolfi, Stefania
AU - Hernandez-Losa, Javier
AU - Ramon y Cajal, Santiago
AU - Nieto, Rocío
AU - Vicario, María
AU - Farre, Ricard
AU - Schwartz, Simo
AU - van Ijzendoorn, Sven C.D.
AU - Kobayashi, Kazuto
AU - Martinez-Barriocanal, Águeda
AU - Arango, Diego
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/4/19
Y1 - 2024/4/19
N2 - Rho GTPases are molecular switches regulating multiple cellular processes. To investigate the role of RhoA in normal intestinal physiology, we used a conditional mouse model overexpressing a dominant negative RhoA mutant (RhoAT19N) in the intestinal epithelium. Although RhoA inhibition did not cause an overt phenotype, increased levels of nuclear β-catenin were observed in the small intestinal epithelium of RhoAT19N mice, and the overexpression of multiple Wnt target genes revealed a chronic activation of Wnt signaling. Elevated Wnt signaling in RhoAT19N mice and intestinal organoids did not affect the proliferation of intestinal epithelial cells but significantly interfered with their differentiation. Importantly, 17-month-old RhoAT19N mice showed a significant increase in the number of spontaneous intestinal tumors. Altogether, our results indicate that RhoA regulates the differentiation of intestinal epithelial cells and inhibits tumor initiation, likely through the control of Wnt signaling, a key regulator of proliferation and differentiation in the intestine.
AB - Rho GTPases are molecular switches regulating multiple cellular processes. To investigate the role of RhoA in normal intestinal physiology, we used a conditional mouse model overexpressing a dominant negative RhoA mutant (RhoAT19N) in the intestinal epithelium. Although RhoA inhibition did not cause an overt phenotype, increased levels of nuclear β-catenin were observed in the small intestinal epithelium of RhoAT19N mice, and the overexpression of multiple Wnt target genes revealed a chronic activation of Wnt signaling. Elevated Wnt signaling in RhoAT19N mice and intestinal organoids did not affect the proliferation of intestinal epithelial cells but significantly interfered with their differentiation. Importantly, 17-month-old RhoAT19N mice showed a significant increase in the number of spontaneous intestinal tumors. Altogether, our results indicate that RhoA regulates the differentiation of intestinal epithelial cells and inhibits tumor initiation, likely through the control of Wnt signaling, a key regulator of proliferation and differentiation in the intestine.
KW - Cancer
KW - Cell biology
UR - http://www.scopus.com/inward/record.url?scp=85187722643&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2024.109400
DO - 10.1016/j.isci.2024.109400
M3 - Article
C2 - 38523777
AN - SCOPUS:85187722643
SN - 2589-0042
VL - 27
JO - Iscience
JF - Iscience
IS - 4
M1 - 109400
ER -