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: Rong Wang, Ying-Shiuan Chen, Wan-Mohaiza Dashwood, Qingjie Li, Christiane V Löhr, Kay Fischer, Emily Ho, David E Williams, Roderick H Dashwood
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 56 Issue 7 Pg. 1733-1742 (07 2017) ISSN: 1098-2744 [Electronic] United States
• PMID: 28218467 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2017 Wiley Periodicals, Inc.

Chemical References

• Carcinogens
• Catenins
• Imidazoles
• Protein Isoforms
• RNA, Small Interfering
• 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
• Delta Catenin

Topics

• Animals
• Apoptosis
• Carcinogens (toxicity)
• Carcinoma, Squamous Cell (genetics, metabolism, pathology)
• Catenins (antagonists & inhibitors, genetics, metabolism)
• Cell Movement
• Cell Proliferation
• Colorectal Neoplasms (genetics, metabolism, pathology)
• Humans
• Imidazoles (toxicity)
• Neoplasm Invasiveness
• Protein Isoforms
• RNA, Small Interfering (genetics)
• Rats
• Skin Neoplasms (chemically induced, metabolism, pathology)
• Tumor Cells, Cultured
• Delta Catenin