Laura A Kresty1, Jennifer Clarke1, Kristin Ezell1, Amy Exum1, Amy B Howell2, Toumy Guettouche3
1Department of Epidemiology and Public Health, University of Miami Miller School of Medicine and Sylvester Cancer Center, Miami, FL, USA.
2Marucci Center for Blueberry Cranberry Research, Rutgers University, Chatsworth, NJ, USA.
3Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
Background: Aberrant expression of small noncoding endogenous RNA molecules known as microRNAs (miRNAs) is documented to occur in multiple cancer types including esophageal adencarcinoma (EAC) and its only known precursor, Barrett’s esophagus (BE). Recent studies have linked dysregulation of specific miRNAs to histological grade, neoplastic progression and metastatic potential. Materials and Methods: Herein, we present a summary of previously reported dysregulated miRNAs in BE and EAC tissues as well as EAC cell lines and evaluate a cranberry proanthocyanidin rich extract’s (C-PAC) ability to modulate miRNA expression patterns of three human EAC cell lines (JHEso-Ad-1, OE33 and OE19). Results: A review of 13 published studies revealed dysregulation of 87 miRNAs in BE and EAC tissues, whereas 52 miRNAs have been reported to be altered in BE or EAC cell lines, with 48% overlap with miRNA changes reported in tissues. We report for the first time C-PAC-induced modulation of five miRNAs in three EAC cell lines resulting in 26 validated gene targets and identification of key signaling pathways including p53, angiogenesis, T-cell activation and apoptosis. Additionally, mutiple cancer related networks were ideintified as modulated by C-PAC utilizing Kyoto Encyclopedia of Genes and Genomes (KEGG), Protein Analysis Through Evolutionary Relationships (PANTHER), and MetaCore analysis tools. Conclusions: Study results support the cancer inhibitory potential of C-PAC is in part attributable to C-PAC’s ability to modify miRNA profiles within EAC cells. A number of C-PAC-modulated miRNAs have been been identified as dysregulated in BE and EAC. Further insights into miRNA dysregulation and modulation by select cancer preventive agents will support improved targeted interventions in high-risk cohorts.
Keywords: Barrett′s esophagus, chemoprevention, cranberry, JHAD1, microRNA, OE19, OE33, esophageal adenocarcinoma, polyphenols, proanthocyanidins