Research Article

The microRNAs, MiR-31 and MiR-375, as candidate markers in Barrett's esophageal carcinogenesis

  1. Rom S. Leidner1,2,3,
  2. Lakshmeswari Ravi1,
  3. Patrick Leahy3,4,
  4. Yanwen Chen3,
  5. Beth Bednarchik5,6,
  6. Mirte Streppel7,8,9,
  7. Marcia Canto10,
  8. Jean S.Wang11,
  9. Anirban Maitra7,12,
  10. Joseph Willis3,6,13,
  11. Sanford D. Markowitz1,3,
  12. Jill Barnholtz-Sloan3,
  13. Mark D. Adams14,
  14. Amitabh Chak3,5,6,
  15. Kishore Guda3,4,†,*

Article first published online: 3 FEB 2012

DOI: 10.1002/gcc.21934

Issue

Genes, Chromosomes and Cancer

Genes, Chromosomes and Cancer

Volume 51, Issue 5, pages 473–479, May 2012

Additional Information

How to Cite

Leidner, R. S., Ravi, L., Leahy, P., Chen, Y., Bednarchik, B., Streppel, M., Canto, M., S.Wang, J., Maitra, A., Willis, J., Markowitz, S. D., Barnholtz-Sloan, J., Adams, M. D., Chak, A. and Guda, K. (2012), The microRNAs, MiR-31 and MiR-375, as candidate markers in Barrett's esophageal carcinogenesis. Genes Chromosom. Cancer, 51: 473–479. doi: 10.1002/gcc.21934

Author Information

  1. 1

    Division of Hematology and Oncology, Case Western Reserve University School of Medicine, Cleveland, OH

  2. 2

    Department of Veterans Affairs Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio

  3. 3

    Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH

  4. 4

    Division of General Medical Sciences–Oncology, Case Western Reserve University School of Medicine, Cleveland, OH

  5. 5

    Division of Gastroenterology, Case Western Reserve University School of Medicine, Cleveland, OH

  6. 6

    University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH

  7. 7

    Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland

  8. 8

    Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands

  9. 9

    Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands

  10. 10

    Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD

  11. 11

    Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO

  12. 12

    Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD

  13. 13

    Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH

  14. 14

    Department of Genetics and Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH

  1. †

    Tel.: +216-368-5665. Fax: +216-368-8928

*2103, Cornell Rd, Wolstein Research Building, Rm 3-143, Case Western Reserve University Comprehensive Cancer Center, Cleveland, OH 44106, USA

Publication History

  1. Issue published online: 6 MAR 2012
  2. Article first published online: 3 FEB 2012
  3. Manuscript Accepted: 3 JAN 2012
  4. Manuscript Revised: 8 DEC 2011
  5. Manuscript Received: 26 OCT 2011

Funded by

  • NCRR-CTSA. Grant Number: UL1 RR024989
  • NCI. Grant Number: CA135692
  • NCI. Grant Number: CA152756
  • NCI. Grant Number: CA163060
  • NIDDK. Grant Number: K23 DK068149
  • Case Comprehensive Cancer Center Core Grant. Grant Number: NCI-P30 CA043703
  • American Society of Clinical Oncology Young Investigator Award
  • NCI K12 Clinical Oncology Research Career Development Award through the Case Comprehensive Cancer Center. Grant Number: CA076917
  • K24 grant from the NIDDK. Grant Number: DK002800
  • NCI K08 Mentored Clinical Scientist Research Career Development Award. Grant Number: CA148980
  • Case Comprehensive Cancer Center Specialized Program of Research Excellence (SPORE) Career Development Program Scholar Award. Grant Number: NCI-CA150964

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Abstract

There is a critical need to identify molecular markers that can reliably aid in stratifying esophageal adenocarcinoma (EAC) risk in patients with Barrett's esophagus. MicroRNAs (miRNA/miR) are one such class of biomolecules. In the present cross-sectional study, we characterized miRNA alterations in progressive stages of neoplastic development, i.e., metaplasia–dysplasia–adenocarcinoma, with an aim to identify candidate miRNAs potentially associated with progression. Using next generation sequencing (NGS) as an agnostic discovery platform, followed by quantitative real-time PCR (qPCR) validation in a total of 20 EACs, we identified 26 miRNAs that are highly and frequently deregulated in EACs (≥4-fold in >50% of cases) when compared to paired normal esophageal squamous (nSQ) tissue. We then assessed the 26 EAC-derived miRNAs in laser microdissected biopsy pairs of Barrett's metaplasia (BM)/nSQ (n = 15), and high-grade dysplasia (HGD)/nSQ (n = 14) by qPCR, to map the timing of deregulation during progression from BM to HGD and to EAC. We found that 23 of the 26 candidate miRNAs were deregulated at the earliest step, BM, and therefore noninformative as molecular markers of progression. Two miRNAs, miR-31 and −31*, however, showed frequent downregulation only in HGD and EAC cases suggesting association with transition from BM to HGD. A third miRNA, miR-375, showed marked downregulation exclusively in EACs and in none of the BM or HGD lesions, suggesting its association with progression to invasive carcinoma. Taken together, we propose miR-31 and −375 as novel candidate microRNAs specifically associated with early- and late-stage malignant progression, respectively, in Barrett's esophagus. © 2012 Wiley Periodicals, Inc.

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