Divergent roles of p120-catenin isoforms linked to altered cell viability, proliferation, and invasiveness in carcinogen-induced rat skin tumors

Rong Wang, Ying Shiuan Chen, Wan Mohaiza Dashwood, Qingjie Li, Christiane V. Löhr, Kay Fischer, Emily Ho, David E. Williams, Roderick H. Dashwood

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1733-1742
Number of pages10
JournalMolecular Carcinogenesis
Volume56
Issue number7
DOIs
StatePublished - Jul 2017

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Keywords

  • CTNNB1
  • CTNND1
  • E-cadherin
  • adherens junction
  • β-catenin

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Wang, R., Chen, Y. S., Dashwood, W. M., Li, Q., Löhr, C. V., Fischer, K., Ho, E., Williams, D. E., & Dashwood, R. H. (2017). Divergent roles of p120-catenin isoforms linked to altered cell viability, proliferation, and invasiveness in carcinogen-induced rat skin tumors. Molecular Carcinogenesis, 56(7), 1733-1742. https://doi.org/10.1002/mc.22630