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

Ali H. Zaidi, Lindsey T. Saldin, Lori A. Kelly, Linda Bergal, Ricardo Londono, Juliann E. Kosovec, Yoshihiro Komatsu, Pashtoon M. Kasi, Amit A. Shetty, Timothy J. Keane, Shyam J. Thakkar, Luai Huleihel, Rodney J. Landreneau, Stephen F. Badylak, Blair A. Jobe

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere0122375
JournalPLoS One
Volume10
Issue number3
DOIs
StatePublished - Mar 31 2015
Externally publishedYes

Fingerprint

esophageal neoplasms
adenocarcinoma
MicroRNAs
microRNA
metastasis
Rats
Tumors
Adenocarcinoma
animal models
Neoplasm Metastasis
neoplasms
Neoplasms
Mucin 5AC
Histology
Gene expression
Esophagectomy
Surgery
mucins
Esophageal Neoplasms
Animals

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Zaidi, A. H., Saldin, L. T., Kelly, L. A., Bergal, L., Londono, R., Kosovec, J. E., ... Jobe, B. A. (2015). MicroRNA signature characterizes primary tumors that metastasize in an esophageal adenocarcinoma rat model. PLoS One, 10(3), [e0122375]. https://doi.org/10.1371/journal.pone.0122375

MicroRNA signature characterizes primary tumors that metastasize in an esophageal adenocarcinoma rat model. / Zaidi, Ali H.; Saldin, Lindsey T.; Kelly, Lori A.; Bergal, Linda; Londono, Ricardo; Kosovec, Juliann E.; Komatsu, Yoshihiro; Kasi, Pashtoon M.; Shetty, Amit A.; Keane, Timothy J.; Thakkar, Shyam J.; Huleihel, Luai; Landreneau, Rodney J.; Badylak, Stephen F.; Jobe, Blair A.

In: PLoS One, Vol. 10, No. 3, e0122375, 31.03.2015.

Research output: Contribution to journalArticle

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 2015, 'MicroRNA signature characterizes primary tumors that metastasize in an esophageal adenocarcinoma rat model', PLoS One, vol. 10, no. 3, e0122375. https://doi.org/10.1371/journal.pone.0122375
Zaidi, Ali H. ; Saldin, Lindsey T. ; Kelly, Lori A. ; Bergal, Linda ; Londono, Ricardo ; Kosovec, Juliann E. ; Komatsu, Yoshihiro ; Kasi, Pashtoon M. ; Shetty, Amit A. ; Keane, Timothy J. ; Thakkar, Shyam J. ; Huleihel, Luai ; Landreneau, Rodney J. ; Badylak, Stephen F. ; Jobe, Blair A. / MicroRNA signature characterizes primary tumors that metastasize in an esophageal adenocarcinoma rat model. In: PLoS One. 2015 ; Vol. 10, No. 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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T1 - MicroRNA signature characterizes primary tumors that metastasize in an esophageal adenocarcinoma rat model

AU - Zaidi, Ali H.

AU - Saldin, Lindsey T.

AU - Kelly, Lori A.

AU - Bergal, Linda

AU - Londono, Ricardo

AU - Kosovec, Juliann E.

AU - Komatsu, Yoshihiro

AU - Kasi, Pashtoon M.

AU - Shetty, Amit A.

AU - Keane, Timothy J.

AU - Thakkar, Shyam J.

AU - Huleihel, Luai

AU - Landreneau, Rodney J.

AU - Badylak, Stephen F.

AU - Jobe, Blair A.

PY - 2015/3/31

Y1 - 2015/3/31

N2 - 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.

AB - 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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