MicroRNA signature characterizes primary tumors that metastasize in an esophageal adenocarcinoma rat model.

Published

Journal Article

To establish a miRNA signature for metastasis in an animal model of esophageal adenocarcinoma (EAC).The 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.The 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.The 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.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.

Full Text

Duke Authors

Cited Authors

  • Zaidi, AH; Saldin, LT; Kelly, LA; Bergal, L; Londono, R; Kosovec, JE; Komatsu, Y; Kasi, PM; Shetty, AA; Keane, TJ; Thakkar, SJ; Huleihel, L; Landreneau, RJ; Badylak, SF; Jobe, BA

Published Date

  • January 2015

Published In

Volume / Issue

  • 10 / 3

Start / End Page

  • e0122375 -

PubMed ID

  • 25826212

Pubmed Central ID

  • 25826212

Electronic International Standard Serial Number (EISSN)

  • 1932-6203

International Standard Serial Number (ISSN)

  • 1932-6203

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0122375

Language

  • eng