The microRNAs, MiR-31 and MiR-375, as candidate markers in Barrett's esophageal carcinogenesis
Rom S. Leidner
Division of Hematology and Oncology, Case Western Reserve University School of Medicine, Cleveland, OH
Department of Veterans Affairs Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorLakshmeswari Ravi
Division of Hematology and Oncology, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorPatrick Leahy
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
Division of General Medical Sciences–Oncology, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorYanwen Chen
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorBeth Bednarchik
Division of Gastroenterology, Case Western Reserve University School of Medicine, Cleveland, OH
University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorMirte Streppel
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
Search for more papers by this authorMarcia Canto
Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorJean S.Wang
Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO
Search for more papers by this authorAnirban Maitra
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorJoseph Willis
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorSanford D. Markowitz
Division of Hematology and Oncology, Case Western Reserve University School of Medicine, Cleveland, OH
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorJill Barnholtz-Sloan
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorMark D. Adams
Department of Genetics and Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorAmitabh Chak
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
Division of Gastroenterology, Case Western Reserve University School of Medicine, Cleveland, OH
University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorCorresponding Author
Kishore Guda
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
Division of General Medical Sciences–Oncology, Case Western Reserve University School of Medicine, Cleveland, OH
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, USASearch for more papers by this authorRom S. Leidner
Division of Hematology and Oncology, Case Western Reserve University School of Medicine, Cleveland, OH
Department of Veterans Affairs Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorLakshmeswari Ravi
Division of Hematology and Oncology, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorPatrick Leahy
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
Division of General Medical Sciences–Oncology, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorYanwen Chen
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorBeth Bednarchik
Division of Gastroenterology, Case Western Reserve University School of Medicine, Cleveland, OH
University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorMirte Streppel
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
Search for more papers by this authorMarcia Canto
Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorJean S.Wang
Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO
Search for more papers by this authorAnirban Maitra
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorJoseph Willis
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorSanford D. Markowitz
Division of Hematology and Oncology, Case Western Reserve University School of Medicine, Cleveland, OH
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorJill Barnholtz-Sloan
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorMark D. Adams
Department of Genetics and Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorAmitabh Chak
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
Division of Gastroenterology, Case Western Reserve University School of Medicine, Cleveland, OH
University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH
Search for more papers by this authorCorresponding Author
Kishore Guda
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
Division of General Medical Sciences–Oncology, Case Western Reserve University School of Medicine, Cleveland, OH
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, USASearch for more papers by this authorAbstract
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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