Title | Divergent roles of p120-catenin isoforms linked to altered cell viability, proliferation, and invasiveness in carcinogen-induced rat skin tumors. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Wang R, Chen Y-S, Dashwood W-M, Li Q, Löhr CV, Fischer K, Ho E, Williams DE, Dashwood RH |
Journal | Mol Carcinog |
Volume | 56 |
Issue | 7 |
Pagination | 1733-1742 |
Date Published | 2017 07 |
ISSN | 1098-2744 |
Keywords | Animals, Apoptosis, Carcinogens, Carcinoma, Squamous Cell, Catenins, Cell Movement, Cell Proliferation, Colorectal Neoplasms, Humans, Imidazoles, Neoplasm Invasiveness, Protein Isoforms, Rats, RNA, Small Interfering, Skin Neoplasms, Tumor Cells, Cultured |
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. |
DOI | 10.1002/mc.22630 |
Alternate Journal | Mol. Carcinog. |
PubMed ID | 28218467 |
PubMed Central ID | PMC5479755 |
Grant List | P01 CA090890 / CA / NCI NIH HHS / United States P30 ES000210 / ES / NIEHS NIH HHS / United States P30 ES023512 / ES / NIEHS NIH HHS / United States R01 CA122959 / CA / NCI NIH HHS / United States |