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Ectopic expression of Zmiz1 induces cutaneous squamous cell malignancies in a mouse model of cancer.

Rogers LM, Riordan JD, Swick BL, Meyerholz DK, Dupuy AJ - J. Invest. Dermatol. (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.

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.

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Aberrant nuclear accumulation of Zmiz1 in tumor tissue(a) Immunohistochemistry (IHC) analysis reveals overexpression of Zmiz1 in SB. induced tumors with transposon insertions in intron 8. (b) Zmiz1 expression is undetectable by IHC in normal mouse skin. Scale bars, 50μm. Similarly, nuclear accumulation was observed in K14-CreTg/+; Zmiz1Δ1-185 Tg/+ double transgenic tumors (c), but not normal skin from double transgenic mice (d). Scale bars, 100μm. (e) Strong nuclear ZMIZ1 expression was observed in 14 of 19 human cutaneous SCCs when analyzed by IHC. (f) Example of a human SCC without ZMIZ1 overexpression. Scale bars, 100μm.
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Figure 3: Aberrant nuclear accumulation of Zmiz1 in tumor tissue(a) Immunohistochemistry (IHC) analysis reveals overexpression of Zmiz1 in SB. induced tumors with transposon insertions in intron 8. (b) Zmiz1 expression is undetectable by IHC in normal mouse skin. Scale bars, 50μm. Similarly, nuclear accumulation was observed in K14-CreTg/+; Zmiz1Δ1-185 Tg/+ double transgenic tumors (c), but not normal skin from double transgenic mice (d). Scale bars, 100μm. (e) Strong nuclear ZMIZ1 expression was observed in 14 of 19 human cutaneous SCCs when analyzed by IHC. (f) Example of a human SCC without ZMIZ1 overexpression. Scale bars, 100μm.

Mentions: Zmiz1 protein expression was evaluated in SB-induced KAs by immunohistochemical (IHC) staining of formalin-fixed paraffin-embedded skin sections. As predicted, tumors with transposon insertions in the Zmiz1 locus displayed high levels Zmiz1 expression (Figure 3a). Conversely, Zmiz1 protein was undetectable in normal mouse skin (Figure 3b), although the endogenous full-length transcript is expressed (Dupuy et al., 2009). Based on these findings, we conclude that the majority of Zmiz1 protein detected in SB-induced tumors is derived from the truncated Zmiz1 transcript.


Ectopic expression of Zmiz1 induces cutaneous squamous cell malignancies in a mouse model of cancer.

Rogers LM, Riordan JD, Swick BL, Meyerholz DK, Dupuy AJ - J. Invest. Dermatol. (2013)

Aberrant nuclear accumulation of Zmiz1 in tumor tissue(a) Immunohistochemistry (IHC) analysis reveals overexpression of Zmiz1 in SB. induced tumors with transposon insertions in intron 8. (b) Zmiz1 expression is undetectable by IHC in normal mouse skin. Scale bars, 50μm. Similarly, nuclear accumulation was observed in K14-CreTg/+; Zmiz1Δ1-185 Tg/+ double transgenic tumors (c), but not normal skin from double transgenic mice (d). Scale bars, 100μm. (e) Strong nuclear ZMIZ1 expression was observed in 14 of 19 human cutaneous SCCs when analyzed by IHC. (f) Example of a human SCC without ZMIZ1 overexpression. Scale bars, 100μm.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3672356&req=5

Figure 3: Aberrant nuclear accumulation of Zmiz1 in tumor tissue(a) Immunohistochemistry (IHC) analysis reveals overexpression of Zmiz1 in SB. induced tumors with transposon insertions in intron 8. (b) Zmiz1 expression is undetectable by IHC in normal mouse skin. Scale bars, 50μm. Similarly, nuclear accumulation was observed in K14-CreTg/+; Zmiz1Δ1-185 Tg/+ double transgenic tumors (c), but not normal skin from double transgenic mice (d). Scale bars, 100μm. (e) Strong nuclear ZMIZ1 expression was observed in 14 of 19 human cutaneous SCCs when analyzed by IHC. (f) Example of a human SCC without ZMIZ1 overexpression. Scale bars, 100μm.
Mentions: Zmiz1 protein expression was evaluated in SB-induced KAs by immunohistochemical (IHC) staining of formalin-fixed paraffin-embedded skin sections. As predicted, tumors with transposon insertions in the Zmiz1 locus displayed high levels Zmiz1 expression (Figure 3a). Conversely, Zmiz1 protein was undetectable in normal mouse skin (Figure 3b), although the endogenous full-length transcript is expressed (Dupuy et al., 2009). Based on these findings, we conclude that the majority of Zmiz1 protein detected in SB-induced tumors is derived from the truncated Zmiz1 transcript.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.

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.

Show MeSH
Related in: MedlinePlus