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Differentially expressed genes execute zinc-induced apoptosis in precancerous esophageal epithelium of zinc-deficient rats

Oncogene volume 23, pages 8040–8048 (2004)Cite this article

Abstract

Zinc deficiency (ZD) in rats increases esophageal cell proliferation and the incidence of N-nitrosomethylbenzylamine-induced esophageal tumors. Conversely, zinc replenishment (ZR) rapidly induces apoptosis in esophageal epithelia and reverses cancer development. We investigated gene expression changes in ZR versus ZD esophageal epithelia to identify differentially expressed genes associated with the antitumor effect of ZR. Weanling rats were fed a ZD diet for 6 weeks to establish esophageal cell proliferation or a zinc-sufficient (ZS) diet. Then, 10 ZD rats were treated with zinc gluconate intragastrically and switched to ZS diet; the remaining 10 ZD and ZS animals were treated with saline. All animals were killed 26–28 h later. Using cDNA microarrays, real-time polymerase chain reaction amplification and RNA hybridization techniques, we identified novel differentially expressed genes, including a RNA-binding protein with two RNA recognition motifs and a zinc knuckle (ZD7), and a DNA/RNA helicase with a DEAD box (ZD10) with two splice variants, ZD10a and ZD10b. In situ hybridization detected increased mRNA expression of ZD7, ZD10a and ZD10b in ZR esophageal epithelia, which displayed markedly increased occurrence of apoptotic cells, relative to ZD epithelia. Overexpression of ZD7 in human esophageal cancer cells resulted in induction of apoptosis and activation of caspase-3 and -7, activities that were inhibited by caspase-specific inhibitors. In addition, ZD7 mRNA levels and zinc-induced apoptosis in rat squamous carcinoma cells were reduced by specific small interfering ribonucleic acids. Thus, ZR rapidly induces ZD7 and ZD10 expression, which in turn stimulates apoptosis. These results provide the beginnings of a molecular pathway for zinc-induced apoptosis under conditions that reverse esophageal tumor initiation.

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Acknowledgements

This work was supported by Grants: 02A025-REV from the American Institute for Cancer Research (LYYF), NIH P01 DE12467, CA56036 (CMC), and CA77738 (KH) from the US National Institutes of Health; and funds from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Kato Memorial Bioscience Foundation, the Chiyoda Health Foundation, and the Suzuken Memorial Foundation, Japan (HI, YF).

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Authors and Affiliations

  1. Kimmel Cancer Center, Jefferson Medical College, 1020 Locust Street, Philadelphia, 19107, PA, USA

    Hideshi Ishii, Andrea Vecchione, Carlo M Croce, Kay Huebner & Louise YY Fong

  2. Center for Molecular Medicine, Jichi Medical School, Tochigi, 329-0498, Japan

    Hideshi Ishii & Yusuke Furukawa

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  1. Hideshi Ishii
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  2. Andrea Vecchione
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  3. Yusuke Furukawa
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  4. Carlo M Croce
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  5. Kay Huebner
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Correspondence to Louise YY Fong.

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GenBank Accession number

The accession numbers for the sequences described in this paper are AY303540 and AY303541.

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Ishii, H., Vecchione, A., Furukawa, Y. et al. Differentially expressed genes execute zinc-induced apoptosis in precancerous esophageal epithelium of zinc-deficient rats. Oncogene 23, 8040–8048 (2004). https://doi.org/10.1038/sj.onc.1207974

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