Overexpression of regenerating islet-derived 1 alpha and 3 alpha genes in human primary liver tumors with beta-catenin mutations.
The Wnt/beta-catenin signaling pathway is activated in many human hepatocellular carcinomas (HCC). We tried to identify the genes involved in carcinogenesis and progression of HCC with beta-catenin mutations. We used PCR-based subtractive hybridization to compare gene expression between malignant and benign components of a human HCC occurring in pre-existing adenoma activated for beta-catenin. Two of the genes identified belong to the Regenerating gene (REG) family. They encode the Regenerating islet-derived 3 alpha (REG3A/HIP/PAP/REG-III) and 1 alpha (REG1A) proteins, both involved in liver and pancreatic regeneration and proliferation. Using siRNA directed against beta-catenin, we demonstrated that REG3A is a target of beta-catenin signaling in Huh7 hepatoma cells. The upregulation of REG3A and REG1A expression is significantly correlated to the beta-catenin status in 42 HCC and 28 hepatoblastomas characterized for their beta-catenin status. Thus, we report strong evidence that both genes are downstream targets of the Wnt pathway during liver tumorigenesis.
Cavard
C
C
Département GDPM, INSERM U-567, CNRS UMR 8104, Institut Cochin, Université Paris 5, France. cavard@cochin.inserm.fr
Terris
B
B
Grimber
G
G
Christa
L
L
Audard
V
V
Radenen-Bussiere
B
B
Simon
M-T
MT
Renard
C-A
CA
Buendia
M-A
MA
Perret
C
C
D000236:Adenoma / Q000235:genetics; D000328:Adult; D000951:Antigens, Neoplasm / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018197:Hepatoblastoma / Q000235:genetics; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics*; D051847:Lithostathine / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D009154:Mutation; D000073718:Pancreatitis-Associated Proteins; D015398:Signal Transduction; D051176:beta Catenin / Q000235:genetics*
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D037181:Lectins, C-Type; D051847:Lithostathine; D000073718:Pancreatitis-Associated Proteins; C497617:REG1A protein, human; C000612141:REG3A protein, human; D051176:beta Catenin