Expression of potential beta-catenin targets, cyclin D1, c-Jun, c-Myc, E-cadherin, and EGFR in chemically induced hepatocellular neoplasms from B6C3F1 mice.
In this study we used liver neoplasms induced by several chemical carcinogens to investigate potential nuclear targets associated with beta-catenin/Wnt signaling and potential membrane-associated beta-catenin binding partners. Strong expression of cyclin D1, in a pattern similar to that observed previously for beta-catenin, was observed by Western analysis for all five hepatoblastomas examined regardless of treatment. Increased expression of cyclin D1 was also detected in 12 of 35 (34%) hepatocellular neoplasms. Ten of 15 tumors (67%) that had mutations in the Catnb gene had upregulation of cyclin D1, while only 2 of 20 tumors (10%) without Catnb mutations had increased cyclin D1 expression. Immunohistochemical analysis confirmed strong expression of cyclin D1 in most nuclei of hepatoblastomas and scattered nuclear staining in hepatocellular tumors that had Catnb mutations. Increased c-Jun expression was observed in 19 of 30 (63%) hepatocellular tumors and all hepatoblastomas, although upregulation was not completely correlated with Catnb mutation. C-Myc expression was not increased in the tumors. Reduced expression of E-cadherin, which interacts with beta-catenin at the membrane, was observed in some tumors, but this did not correlate with Catnb mutation. Expression of the epidermal growth factor receptor, which may have a role in beta-catenin tyrosine phosphorylation, was lower in some tumors than in normal tissue depending on chemical treatment. The results provide evidence that increased expression of cyclin D1 and c-Jun may provide an advantage during tumor progression and in the transition from hepatocellular neoplasms to hepatoblastomas. Moreover, it is likely increased cyclin D1 expression results at least in part from Catnb mutation, beta-catenin accumulation, and increased Wnt signaling.
Anna
Colleen H
CH
Laboratory of Molecular Carcinogenesis NIEHS, NIH, Research Triangle Park, NC 27709, USA.
Iida
Mari
M
Sills
Robert C
RC
Devereux
Theodora R
TR
D018248:Adenoma, Liver Cell / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics*; D066246:ErbB Receptors / Q000378:metabolism; D011905:Genes, ras / Q000235:genetics; D018197:Hepatoblastoma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
D014408:Biomarkers, Tumor; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D019938:Cyclin D1; D066246:ErbB Receptors