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

Zaidi, AH and Saldin, LT and Kelly, LA and Bergal, L and Londono, R and Kosovec, JE and Komatsu, Y and Kasi, PM and Shetty, AA and Keane, TJ and Thakkar, SJ and Huleihel, L and Landreneau, RJ and Badylak, SF and Jobe, BA (2015) MicroRNA signature characterizes primary tumors that metastasize in an esophageal adenocarcinoma rat model. PLoS ONE, 10 (3).

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Abstract

Objective: To establish a miRNA signature for metastasis in an animal model of esophageal adenocarcinoma (EAC). Background: 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. Methods: 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. miRNAlinked gene expression analysis was performed on a secondary cohort of metastasis positive (n=5) and metastasis negative (n=28) primary tumors. Results: 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-PLOS 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.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Zaidi, AH
Saldin, LTlsaldin@pitt.eduLSALDIN
Kelly, LA
Bergal, L
Londono, R
Kosovec, JE
Komatsu, Y
Kasi, PM
Shetty, AA
Keane, TJtik6@pitt.eduTIK6
Thakkar, SJ
Huleihel, Lluh20@pitt.eduLUH20
Landreneau, RJ
Badylak, SF
Jobe, BA
Centers: Other Centers, Institutes, Offices, or Units > McGowan Institute for Regenerative Medicine
Date: 31 March 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 10
Number: 3
DOI or Unique Handle: 10.1371/journal.pone.0122375
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Medicine
Refereed: Yes
Date Deposited: 23 Aug 2016 14:01
Last Modified: 03 Apr 2021 21:55
URI: http://d-scholarship.pitt.edu/id/eprint/28488

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