Abstract
ObjectiveTo establish a miRNA signature for metastasis in an animal model of esophageal adenocarcinoma (EAC).BackgroundThe incidence of esophageal adenocarcinoma (EAC) has dramatically increased and esophageal cancer is now the sixth leading cause of cancer deaths worldwide. Mortality rates remain high among patients with advanced stage disease and esophagectomy is associated with high complication rates. Hence, early identification of potentially metastatic disease would better guide treatment strategies.MethodsThe modified Levrat’s surgery was performed to induce EAC in Sprague-Dawley rats. Primary EAC and distant metastatic sites were confirmed via histology and immunofluorescence. miRNA profiling was performed on primary tumors with or without metastasis. A unique subset of miRNAs expressed in primary tumors and metastases was identified with Ingenuity Pathway Analysis (IPA) along with upstream and downstream targets. miRNA-linked gene expression analysis was performed on a secondary cohort of metastasis positive (n=5) and metastasis negative (n=28) primary tumors.ResultsThe epithelial origin of distant metastasis was established by IF using villin (VIL1) and mucin 5AC (MUC5AC) antibodies. miRNome analysis identified four down-regulated miRNAs in metastasis positive primary tumors compared to metastasis negative tumors: miR-92a-3p (p=0.0001), miR-141-3p (p=0.0022), miR-451-1a (p=0.0181) and miR133a-3p (p=0.0304). Six target genes identified in the top scoring networks by IPA were validated as significantly, differentially expressed in metastasis positive primary tumors: Ago2, Akt1, Kras, Bcl2L11, CDKN1B and Zeb2.Conclusion In vivo metastasis was confirmed in the modified Levrat’s model. Analysis of the primary tumor identified a distinctive miRNA signature for primary tumors that metastasized.
Highlights
Surveillance Epidemiology and End Results Program (SEER) statistics show that approximately 34,000 people live with esophageal cancer in the United States[1,2,3]
Primary esophageal adenocarcinoma (EAC) and distant metastatic sites were confirmed via histology and immunofluorescence. miRNA profiling was performed on primary tumors with or without metastasis
A unique subset of miRNAs expressed in primary tumors and metastases was identified with Ingenuity Pathway Analysis (IPA) along with upstream and downstream targets. miRNAlinked gene expression analysis was performed on a secondary cohort of metastasis positive (n=5) and metastasis negative (n=28) primary tumors
Summary
Surveillance Epidemiology and End Results Program (SEER) statistics show that approximately 34,000 people live with esophageal cancer in the United States[1,2,3]. Previous studies have focused on identifying protein biomarkers of esophageal adenocarcinoma (EAC) to help predict tumor behavior and treatment response [6]. MiRNA expression patterns have been identified for different tumor types [7] and are known to play important roles in tumor development and associated pathways [8]. These expression patterns are thought to have potential roles as biomarkers, predictors of tumor response, and/or potential treatment targets [9,10,11]. Early identification of potentially metastatic disease would better guide treatment strategies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
