MicroRNA-196a is a potential marker of progression during Barrett's metaplasia-dysplasia-invasive adenocarcinoma sequence in esophagus

Dipen M. Maru, Rajesh R. Singh, Christina Hannah, Constance T. Albarracin, Yong X. Li, Ronald Abraham, Angela M. Romans, Hui Yao, Madan G. Luthra, Sharmila Anandasabapathy, Stephen G. Swisher, Wayne L. Hofstetter, Asif Rashid, Rajyalakshmi Luthra

Research output: Contribution to journalArticlepeer-review

141 Scopus citations

Abstract

Barrett's esophagus (BE)/Barrett's metaplasia (BM) is a recognized precursor of esophageal adenocarcinoma (EA) with an intermediary stage of dysplasia. The low yield and high cost of endoscopic screening of patients with BE underscores the need for novel biomarkers, such as microRNA (miRNA), which have emerged as important players in neoplastic progression for risk assessment of developing dysplasia/adenocarcinoma. Recently, we reported highly elevated levels of miRNA-196a (miR-196a) in EA and demonstrated its growth-promoting and anti-apoptotic functions. Here, we evaluated miR-196a as a marker of BE progression to low-grade dysplasia, high-grade dysplasia, and EA using microdissected paraffin-embedded tissues from 11 patients. Higher levels of miR-196a were observed in EA, BE, and dysplastic lesions compared with normal squamous mucosa, and in high-grade dysplasia compared with BE and lowgrade dysplasia. Using frozen tumor tissues from 10 additional patients who had advanced EA, we evaluated the correlation of miR-196a with its in silicopredicted targets, keratin 5 (KRT5), small prolinerich protein 2C (SPRR2C), and S100 calcium-binding protein A9 (S100A9), which are down-regulated during BE progression. MiR-196a levels inversely correlated with the predicted target mRNA levels in EA. We confirmed that miR-196a specifically targets KRT5, SPRR2C, and S100A9 3′ UTRs using miR-196a-mimic and luciferase reporter-based assays. In conclusion, this study identified miR-196a as a potential marker of progression of BE and KRT5, SPRR2C, and S100A9 as its targets.

Original languageEnglish
Pages (from-to)1940-1948
Number of pages9
JournalAmerican Journal of Pathology
Volume174
Issue number5
DOIs
StatePublished - May 2009
Externally publishedYes

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