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MicroRNA 223 is upregulated in the multistep progression of Barrett's esophagus and modulates sensitivity to chemotherapy by targeting PARP1.

ABSTRACT: Recent microarray and RNA-sequencing studies have uncovered aberrantly expressed microRNAs (miRNA) in Barrett's esophagus-associated esophageal adenocarcinoma. The functional significance of these miRNAs in esophageal adenocarcinoma initiation and progression is largely unknown.Expression levels of miR-199a/b-3p, -199a-5p, -199b-5p, -200b, -200c, -223, and -375 were determined in microdissected tissues from cardiac mucosa, Barrett's esophagus, dysplastic Barrett's esophagus, and esophageal adenocarcinoma using quantitative real-time PCR. miR-223 expression was validated in precursors and esophageal adenocarcinomas from 95 patients with esophageal adenocarcinoma by in situ hybridization (ISH). miR-223 was transfected into two esophageal adenocarcinoma cell lines, and in vitro assays were conducted. Target genes were identified using Illumina microarray, and results were validated in cell lines and human specimens.miR-199 family members and miR-223 were significantly overexpressed in esophageal adenocarcinoma, however, only miR-223 showed a stepwise increase during esophageal adenocarcinoma carcinogenesis. A similar trend was observed by ISH, which additionally showed that miR-223 is exclusively expressed by the epithelial compartment. miR-223-overexpressing cells had statistically significantly more migratory and invasive potential than scramble sequence-transfected cells. PARP1 was identified as a direct target gene of miR-223 in esophageal adenocarcinoma cells. Increased sensitivity to chemotherapy was observed in cells with enforced miR-223 expression and reduced PARP1.miR-223 is significantly upregulated during the Barrett's esophagus-dysplasia-esophageal adenocarcinoma sequence. Although high miR-223 levels might contribute to an aggressive phenotype, our results also suggest that patients with esophageal adenocarcinoma with high miR-223 levels might benefit from treatment with DNA-damaging agents.

SUBMITTER: Streppel MM

PROVIDER: S-EPMC3745277 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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MicroRNA 223 is upregulated in the multistep progression of Barrett's esophagus and modulates sensitivity to chemotherapy by targeting PARP1.

Streppel Mirte Mayke MM Pai Shweta S Campbell Nathaniel R NR Hu Chaoxin C Yabuuchi Shinichi S Canto Marcia Irene MI Wang Jean S JS Montgomery Elizabeth A EA Maitra Anirban A

Clinical cancer research : an official journal of the American Association for Cancer Research 20130611 15

<h4>Purpose</h4>Recent microarray and RNA-sequencing studies have uncovered aberrantly expressed microRNAs (miRNA) in Barrett's esophagus-associated esophageal adenocarcinoma. The functional significance of these miRNAs in esophageal adenocarcinoma initiation and progression is largely unknown.<h4>Experimental design</h4>Expression levels of miR-199a/b-3p, -199a-5p, -199b-5p, -200b, -200c, -223, and -375 were determined in microdissected tissues from cardiac mucosa, Barrett's esophagus, dysplast ...[more]

PMID: 23757351

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Project description:AimTo investigate the microRNA expression profile in esophageal neosquamous epithelium from patients who had undergone ablation of Barrett's esophagus.MethodsHigh throughput screening using TaqMan® Array Human MicroRNA quantitative PCR was used to determine expression levels of 754 microRNAs in distal esophageal mucosa (1 cm above the gastro-esophageal junction) from 16 patients who had undergone ablation of non-dysplastic Barrett's esophagus using argon plasma coagulation vs pretreatment mucosa, post-treatment proximal normal non-treated esophageal mucosa, and esophageal mucosal biopsies from 10 controls without Barrett's esophagus. Biopsies of squamous mucosa were also taken from 5 cm above the pre-ablation squamo-columnar junction. Predicted mRNA target pathway analysis was used to investigate the functional involvement of differentially expressed microRNAs.ResultsForty-four microRNAs were differentially expressed between control squamous mucosa vs post-ablation neosquamous mucosa. Nineteen microRNAs were differentially expressed between post-ablation neosquamous and post-ablation squamous mucosa obtained from the more proximal non-treated esophageal segment. Twelve microRNAs were differentially expressed in both neosquamous vs matched proximal squamous mucosa and neosquamous vs squamous mucosa from healthy patients. Nine microRNAs (miR-424-5p, miR-127-3p, miR-98-5p, miR-187-3p, miR-495-3p, miR-34c-5p, miR-223-5p, miR-539-5p, miR-376a-3p, miR-409-3p) were expressed at higher levels in post-ablation neosquamous mucosa than in matched proximal squamous and healthy squamous mucosa. These microRNAs were also more highly expressed in Barrett's esophagus mucosa than matched proximal squamous and squamous mucosa from controls. Target prediction and pathway analysis suggests that these microRNAs may be involved in the regulation of cell survival signalling pathways. Three microRNAs (miR-187-3p, miR-135b-5p and miR-31-5p) were expressed at higher levels in post-ablation neosquamous mucosa than in matched proximal squamous and healthy squamous mucosa. These miRNAs were expressed at similar levels in pre-ablation Barrett's esophagus mucosa, matched proximal squamous and squamous mucosa from controls. Target prediction and pathway analysis suggests that these microRNAs may be involved in regulating the expression of proteins that contribute to barrier function.ConclusionNeosquamous mucosa arising after ablation of Barrett's esophagus expresses microRNAs that may contribute to decreased barrier function and microRNAs that may be involved in the regulation of survival signaling pathways.

Dataset Information

MicroRNA 223 is upregulated in the multistep progression of Barrett's esophagus and modulates sensitivity to chemotherapy by targeting PARP1.

Publications

MicroRNA 223 is upregulated in the multistep progression of Barrett's esophagus and modulates sensitivity to chemotherapy by targeting PARP1.

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