Abstract
Adenocarcinoma of the esophagus is increasing in frequency and is the 6th most common cause of cancer death in North America. In adenocarcinoma cell lines, we have previously demonstrated that expression of miR-145, leads to enhanced invasion, resistance to anoikis and better attachment to fibronectin in esophageal adenocarcinoma. In contrast, expression of miR-145 acts as a tumor suppressor in squamous cell carcinoma. The molecular mechanisms responsible for the oncogenic effects of miR-145 were investigated. In this report, we demonstrate that we can partially recreate the miR-145 effects in EAC by knock down of the expression of c-Myc, which is one of the targets of miR-145. Knocking down of c-Myc expression resulted in upregulation of integrin subunits α5 and β3. Finally, we demonstrated that integrin α5 expression correlates to fibronectin attachment potential whereas integrin β3 expression correlates with resistance to anoikis and invasion potential. Finally, we demonstrate that expression of miR-145 in esophageal adenocarcinoma cell line (SK-GT-4) enhances tumor growth and metastasis in a NOD/SCID xenograft model. Overall, the oncogenic potential of miR-145 in EAC appears to be mediated by downregulation of c-Myc leading to the expression of integrins subunits α5 and β3.
Highlights
Carcinoma of the esophagus has a high case fatality ratio
We previously demonstrated that miR-145 expression in esophageal adenocarcinoma (EAC) cell lines promotes cell invasion, resistance to anoikis and increased their ability to bind fibronectin
We discovered that SK-GT-4 miR-145 cells expressed higher level of integrins α5 and β3 compared to the SK-GT-4 pcmv cells
Summary
Carcinoma of the esophagus has a high case fatality ratio. Over the past 20 years, the incidence of the esophageal adenocarcinoma (EAC) subtype has been increasing in North America and Europe [1]. Esophageal cancer has become the eighth most common cancer and the sixth most common cause of cancer death in men [2]. This dramatic increase has been associated with gastroesophageal reflux disease (GERD), obesity and Barrett’s esophagus, which increases the risk of esophageal adenocarcinoma by 30-fold [3]. MiRNAs have been shown to play an important role in the regulation of cell differentiation, proliferation and apoptosis [4,5,6,7]. Previous www.oncotarget.com studies have reported that the expression of miRNAs is altered in cancers, linking miRNA expression to either initiation or progression of cancers such as breast, lung, pancreas, prostate and CLL [8]
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