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Evidence for Changes in RREB-1, ZIP3, and Zinc in the Early Development of Pancreatic Adenocarcinoma

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Abstract

Purpose

Pancreatic adenocarcinoma is an untreatable cancer with a 5-year survival rate of about 6 % or less for the past 35 years. This lack of significant progress is largely due to the lack of elucidation and understanding of the factors involved in the development of this cancer. Recent studies identified and implicated zinc in the development and progression of pancreatic cancer. This study was conducted to establish the changes in zinc, ZIP3 zinc transporter, and Ras-responsive element-binding protein 1 (RREB-1) transcription factor as early events in the development of malignancy.

Methods

In situ relative zinc determination and immunohistochemical analysis of ZIP3 and RREB-1 were performed on archived human pancreatic tissue sections and tissue microarrays. Normal/benign versus adenocarcinoma pancreas was compared. Panc1 cells were employed to determine the influence of RREB-1 on ZIP3 expression.

Results

Zinc levels of normal ductal and acinar epithelium were markedly and consistently decreased in adenocarcinoma. Pancreatic intraepithelial neoplasia (PanIN) lesions also exhibited a loss of zinc. ZIP3 and RREB-1 were also markedly downregulated. Initial results indicate that RREB-1 regulates ZIP3 expression.

Conclusions

These results corroborate the earlier report that zinc, ZIP3, and RREB-1 are markedly decreased in early stage adenocarcinoma. Additionally and most importantly, these changes occur in PanIN, which are thought to be precancerous lesions leading to ductal adenocarcinoma. These results support a concept that downregulation of RREB-1 causes downregulation of ZIP3, which results in decreased zinc in premalignant and carcinoma cells. The decrease in zinc is essential to remove its cytotoxic effects on malignant cells. This relationship constitutes a new concept of early genetic/metabolic events in the progressive transformation of normal cells to premalignant cells to malignant cells in the development of pancreatic cancer.

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Acknowledgments

We thank Lippincott Williams and Wilkins for granting permission to reproduce and modify Fig. 13 taken from Scarlett et al. [3].

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650 West Baltimore Street, Baltimore, MD, 21201, USA

    Leslie C. Costello & Renty B. Franklin

  2. The University of Maryland Greenebaum Cancer Center, Baltimore, MD, 21201, USA

    Leslie C. Costello & Renty B. Franklin

  3. Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, MD, 21201, USA

    Jing Zou

  4. Department of Pathology (Division of Breast/Ob/Gyn), Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Mohamed Mokhtar Desouki

Authors
  1. Leslie C. Costello
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  2. Jing Zou
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  3. Mohamed Mokhtar Desouki
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  4. Renty B. Franklin
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Corresponding author

Correspondence to Leslie C. Costello.

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Costello, L.C., Zou, J., Desouki, M.M. et al. Evidence for Changes in RREB-1, ZIP3, and Zinc in the Early Development of Pancreatic Adenocarcinoma. J Gastrointest Canc 43, 570–578 (2012). https://doi.org/10.1007/s12029-012-9378-1

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  • DOI: https://doi.org/10.1007/s12029-012-9378-1

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