Abstract
Cutaneous squamous cell carcinoma (SCC) is the second most common form of cancer in the human population, yet the underlying genetic mechanisms contributing to the disease are not well understood. We recently identified Zmiz1 as a candidate oncogene in nonmelanoma skin cancer through a transposon mutagenesis screen. Here we show that transposon-induced mutations in Zmiz1 drive expression of a truncated transcript that is similar to an alternative endogenous ZMIZ1 transcript found to be overexpressed in human SCCs relative to normal skin. We also describe an original mouse model of invasive keratoacanthoma driven by skin-specific expression of the truncated Zmiz1 transcript. Unlike most mouse models, Zmiz1-induced skin tumors develop rapidly and in the absence of promoting agents such as phorbol esters. In addition, we found that the alternative Zmiz1 isoform has greater protein stability than its full-length counterpart. Finally, we provide evidence that ZMIZ1 is overexpressed in a significant percentage of human breast, ovarian, and colon cancers in addition to human SCCs, suggesting that ZMIZ1 may play a broader role in epithelial cancers.
MeSH terms
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Carcinoma, Squamous Cell / genetics*
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Carcinoma, Squamous Cell / metabolism*
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Carcinoma, Squamous Cell / pathology
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Cell Nucleus / pathology
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology
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Disease Models, Animal
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Female
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Gene Expression Regulation, Neoplastic / genetics*
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Humans
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Intracellular Signaling Peptides and Proteins / genetics*
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Intracellular Signaling Peptides and Proteins / metabolism*
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Keratoacanthoma / genetics
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Keratoacanthoma / metabolism
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Keratoacanthoma / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mutation / genetics
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Neoplasms, Glandular and Epithelial / genetics
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Neoplasms, Glandular and Epithelial / metabolism
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Neoplasms, Glandular and Epithelial / pathology
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology
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RNA-Binding Proteins
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Skin Diseases / genetics
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Skin Diseases / metabolism
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Skin Diseases / pathology
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Skin Neoplasms / genetics*
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Skin Neoplasms / metabolism*
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Skin Neoplasms / pathology
Substances
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Intracellular Signaling Peptides and Proteins
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RNA-Binding Proteins
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Zimp10 protein, mouse