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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: Our data demonstrate that FHL2 represents a critical factor in intestinal tumorigenesis

Hepatic Stem-like Phenotype and Interplay of Wnt/β-Catenin and Myc Signaling in Aggressive Childhood Liver Cancer

SummaryHepatoblastoma, the most common pediatric liver cancer, is tightly linked to excessive Wnt/β-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of liver development and a discriminating 16-gene signature. β-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy

Etude des propriétés oncogéniques de la beta-caténine (activité transcriptionnelle et gènes cibles)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Pathogenèse moléculaire du carcinome hépatocellulaire (rôle de facteurs viraux et mécanismes génétiques)

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Identification de nouveaux partenaires de la protéine HBx du virus de l'hépatite B et étude fonctionnelle de leur interaction avec HBx dans la réplication virale

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Etude fonctionnelle du rôle de l'interaction de la proteine HBx du virus de l'hépatite B avec les histones acétyltransférases dans la réplication virale et l'hépatocarcinogenèse

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Studies of genetic defects in hepatocellular carcinoma: recent outcomes and new challenges

Comment on : New target region of allelic loss in hepatocellular carcinomas within a 1-cM interval on chromosome 6q23./Koyama M, Nagai H, Bando K, Matsumoto S, Tajiri T, Onda M, Ito M, Moriyama Y, Emi M. J Hepatol. 2000 Jul;33(1):85-90. doi: 10.1016/s0168-8278(00)80163-4. PMID: 10905590International audienceEditoria