Deficiency of the LIM-only protein FHL2 reduces intestinal tumorigenesis in Apc mutant mice.
BACKGROUND
The four and a half LIM-only protein 2 (FHL2) is capable of shuttling between focal adhesion and nucleus where it signals through direct interaction with a number of proteins including beta-catenin. Although FHL2 activation has been found in various human cancers, evidence of its functional contribution to carcinogenesis has been lacking.


RESULTS
Here we have investigated the role of FHL2 in intestinal tumorigenesis in which activation of the Wnt pathway by mutations in the adenomatous polyposis coli gene (Apc) or in beta-catenin constitutes the primary transforming event. In this murine model, introduction of a biallelic deletion of FHL2 into mutant Apc(Delta14/+) mice substantially reduces the number of intestinal adenomas but not tumor growth, suggesting a role of FHL2 in the initial steps of tumorigenesis. In the lesions, Wnt signalling is not affected by FHL2 deficiency, remaining constitutively active. Nevertheless, loss of FHL2 activity is associated with increased epithelial cell migration in intestinal epithelium, which might allow to eliminate more efficiently deleterious cells and reduce the risk of tumorigenesis. This finding may provide a mechanistic basis for tumor suppression by FHL2 deficiency. In human colorectal carcinoma but not in low-grade dysplasia, we detected up-regulation and enhanced nuclear localization of FHL2, indicating the activation of FHL2 during the development of malignancy.


CONCLUSIONS
Our data demonstrate that FHL2 represents a critical factor in intestinal tumorigenesis.
Labalette
Charlotte
C
Département de Virologie, Institut Pasteur, Paris, France.
Nouët
Yann
Y
Levillayer
Florence
F
Colnot
Sabine
S
Chen
Ju
J
Claude
Valere
V
Huerre
Michel
M
Perret
Christine
C
Buendia
Marie-Annick
MA
Wei
Yu
Y
D021581:Active Transport, Cell Nucleus; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D017491:Genes, APC; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007414:Intestinal Neoplasms / Q000209:etiology* / Q000235:genetics / Q000628:therapy; D060850:LIM-Homeodomain Proteins; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D009154:Mutation; D015398:Signal Transduction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000235:genetics; D051153:Wnt Proteins
C491382:Fhl2 protein, mouse; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors; D051153:Wnt Proteins