title: Divergent roles of p120-catenin isoforms linked to altered cell viability, proliferation, and invasiveness in carcinogen-induced rat skin tumors.
abstract: The heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) targets multiple organs for tumorigenesis in the rat, including the colon and the skin. PhIP-induced skin tumors were subjected to mutation screening, which identified genetic changes in Hras (7/40, 17.5%) and Tp53 (2/40, 5%), but not in Ctnnb1, a commonly mutated gene in PhIP-induced colon tumors. Despite the absence of Ctnnb1 mutations, β-catenin was overexpressed in nuclear and plasma membrane fractions from PhIP-induced skin tumors, coinciding with loss of p120-catenin from the plasma membrane, and the appearance of multiple p120-catenin-associated bands in the nuclear extracts. Real-time RT-PCR revealed that p120-catenin isoforms 1 and 4 were upregulated in PhIP-induced skin tumors, whereas p120-catenin isoform 3 was expressed uniformly, compared with adjacent normal-looking tissue. In human epidermoid carcinoma and colon cancer cells, transient transfection of p120-catenin isoform 1A enhanced the viability and cell invasion index, whereas transient transfection of p120-catenin isoform 4A increased cell viability and cell proliferation. Knockdown of p120-catenin revealed a corresponding reduction in the expression of β-catenin and a transcriptionally regulated target, Ccnd1/Cyclin D1. Co-immunoprecipitation experiments identified associations of β-catenin with p120-catenin isoforms in PhIP-induced skin tumors and human cancer cell lines. The results are discussed in the context of therapeutic strategies that might target different p120-catenin isoforms, providing an avenue to circumvent constitutively active β-catenin arising via distinct mechanisms in skin and colon cancer.
authors.affiliation: Linus Pauling Institute, Oregon State University, Corvallis, Oregon.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Center for Epigenetics and Disease Prevention, Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston, Texas.
authors.forename: Ying-Shiuan
authors.initials: YS
authors.lastname: Chen
authors.affiliation: Center for Epigenetics and Disease Prevention, Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston, Texas.
authors.forename: Wan-Mohaiza
authors.initials: WM
authors.lastname: Dashwood
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Li
authors.affiliation: College of Veterinary Medicine, Oregon State University, Corvallis, Oregon.
authors.forename: Christiane V
authors.initials: CV
authors.lastname: Löhr
authors.affiliation: College of Veterinary Medicine, Oregon State University, Corvallis, Oregon.
authors.forename: Kay
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Linus Pauling Institute, Oregon State University, Corvallis, Oregon.|School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon.
authors.forename: Emily
authors.initials: E
authors.lastname: Ho
authors.affiliation: Linus Pauling Institute, Oregon State University, Corvallis, Oregon.|Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon.
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.affiliation: Center for Epigenetics and Disease Prevention, Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston, Texas.|Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.|Department of Molecular and Cellular Medicine, Texas A&M College of Medicine, College Station, Texas.|Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Roderick H
authors.identifier: 0000-0003-0351-4034
authors.initials: RH
authors.lastname: Dashwood
mesh_terms: D000818:Animals; D017209:Apoptosis; D002273:Carcinogens / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051177:Catenins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007093:Imidazoles / Q000633:toxicity; D009361:Neoplasm Invasiveness; D020033:Protein Isoforms; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D000095002:Delta Catenin
chemical_list: D002273:Carcinogens; D051177:Catenins; D007093:Imidazoles; D020033:Protein Isoforms; D034741:RNA, Small Interfering; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D000095002:Delta Catenin
keywords: CTNNB1; CTNND1; E-cadherin; adherens junction; β-catenin