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STAT3 and Importins Are Novel Mediators of Early Molecular and Cellular Responses in Experimental Duodenal Ulceration

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Abstract

Objectives

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that directly upregulates VEGF, Ref-1, p21, and anti-apoptotic genes such as Bcl-xL. In this study, we hypothesized that STAT3 signaling is activated and provides a critical protective role that is required for enterocyte survival during the early phases of cysteamine-induced duodenal ulcers.

Methods

We studied the effect of inhibition of STAT3 activity on cysteamine-induced duodenal ulcers in rats and egr-1 knockout mice using STAT3/DNA binding assay, immunohistochemistry, immunoblot, and quantitative reverse transcriptase PCR analyses.

Results

We found that G-quartet oligodeoxynucleotides T40214, a specific inhibitor of STAT3/DNA binding, aggravated cysteamine-induced duodenal ulcers in rats 2.8-fold (p < 0.05). In the pre-ulcerogenic stage, cysteamine induced STAT3 tyrosine phosphorylation, its translocation to nuclei, an increased expression and nuclear translocation of importin α and β in the rat duodenal mucosa. Cysteamine enhanced the binding of STAT3 to its DNA consensus sequences at 6, 12, and 24 h after cysteamine by 1.5-, 1.8-, and 3.5-fold, respectively, and activated the expression of STAT3 target genes such as VEGF, Bcl-xL, Ref-1, and STAT3-induced feedback inhibitor, a suppressor of cytokine signaling 3. We also demonstrated that egr-1 knockout mice, which are more susceptible to cysteamine-induced duodenal ulcers, had lower levels of STAT3 expression, its phosphorylation, expression of importin α or β, and STAT3/DNA binding than wild-type mice in response to cysteamine.

Conclusions

Thus, STAT3 represents an important new molecular mechanism in experimental duodenal ulceration.

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Acknowledgments

The present study was supported by funds from the Department of Veterans Affairs, Medical Research Service Merit Review.

Conflict of interest

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Authors and Affiliations

  1. VA Medical Center, (05/113) 5901 East 7th Street, Long Beach, CA, 90822-5201, USA

    Tetyana Khomenko, Xiaoming Deng, Amrita Ahluwalia, Andrzej Tarnawski, Khushin N. Patel, Zsuzsanna Sandor & Sandor Szabo

  2. Department of Pathology, University of California, Irvine, CA, USA

    Tetyana Khomenko, Xiaoming Deng & Sandor Szabo

  3. Department of Pharmacology, University of California, Irvine, CA, USA

    Sandor Szabo

  4. Department of Medicine, School of Medicine, University of California, Irvine, CA, USA

    Andrzej Tarnawski & Zsuzsanna Sandor

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  1. Tetyana Khomenko
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  2. Xiaoming Deng
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  3. Amrita Ahluwalia
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  4. Andrzej Tarnawski
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  6. Zsuzsanna Sandor
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  7. Sandor Szabo
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Correspondence to Sandor Szabo.

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Khomenko, T., Deng, X., Ahluwalia, A. et al. STAT3 and Importins Are Novel Mediators of Early Molecular and Cellular Responses in Experimental Duodenal Ulceration. Dig Dis Sci 59, 297–306 (2014). https://doi.org/10.1007/s10620-013-2807-6

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  • DOI: https://doi.org/10.1007/s10620-013-2807-6

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