Format

Send to

Choose Destination
Gastroenterology. 2019 Mar;156(4):1127-1139.e8. doi: 10.1053/j.gastro.2018.11.052. Epub 2018 Nov 28.

Integrated Analysis of Mouse and Human Gastric Neoplasms Identifies Conserved microRNA Networks in Gastric Carcinogenesis.

Author information

1
Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
2
Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
3
Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida; Department of Veterans Affairs, Miami Healthcare System, Miami, Florida.
4
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
5
Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
6
Bioinformatics Shared Resources, University of New Mexico Comprehensive Cancer Center, New Mexico.
7
Advanced Center for Chronic Diseases, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile.
8
Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, Florida.
9
Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. Electronic address: xuzekuan@njmu.edu.cn.
10
Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida; Department of Veterans Affairs, Miami Healthcare System, Miami, Florida; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida. Electronic address: welrifai@med.miami.edu.

Abstract

BACKGROUND & AIMS:

microRNAs (miRNAs) are small noncoding RNAs that bind to the 3' untranslated regions of mRNAs to promote their degradation or block their translation. Mice with disruption of the trefoil factor 1 gene (Tff1) develop gastric neoplasms. We studied these mice to identify conserved miRNA networks involved in gastric carcinogenesis.

METHODS:

We performed next-generation miRNA sequencing analysis of normal gastric tissues (based on histology) from patients without evidence of gastric neoplasm (n = 64) and from TFF1-knockout mice (n = 22). We validated our findings using 270 normal gastric tissues (including 61 samples from patients without evidence of neoplastic lesions) and 234 gastric tumor tissues from 3 separate cohorts of patients and from mice. We performed molecular and functional assays using cell lines (MKN28, MKN45, STKM2, and AGS cells), gastric organoids, and mice with xenograft tumors.

RESULTS:

We identified 117 miRNAs that were significantly deregulated in mouse and human gastric tumor tissues compared with nontumor tissues. We validated changes in levels of 6 miRNAs by quantitative real-time polymerase chain reaction analyses of neoplastic gastric tissues from mice (n = 39) and 3 independent patient cohorts (n = 332 patients total). We found levels of MIR135B-5p, MIR196B-5p, and MIR92A-5p to be increased in tumor tissues, whereas levels of MIR143-3p, MIR204-5p, and MIR133-3p were decreased in tumor tissues. Levels of MIR143-3p were reduced not only in gastric cancer tissues but also in normal tissues adjacent to tumors in humans and low-grade dysplasia in mice. Transgenic expression of MIR143-3p in gastric cancer cell lines reduced their proliferation and restored their sensitivity to cisplatin. AGS cells with stable transgenic expression of MIR143-3p grew more slowly as xenograft tumors in mice than control AGS cells; tumor growth from AGS cells that expressed MIR143-3p, but not control cells, was sensitive to cisplatin. We identified and validated bromodomain containing 2 (BRD2) as a direct target of MIR143-3p; increased levels of BRD2 in gastric tumors was associated with shorter survival times for patients.

CONCLUSIONS:

In an analysis of miRNA profiles of gastric tumors from mice and human patients, we identified a conserved signature associated with the early stages of gastric tumorigenesis. Strategies to restore MIR143-3p or inhibit BRD2 might be developed for treatment of gastric cancer.

KEYWORDS:

Progression; Stomach; Transcription Factor; Tumor Suppressor

PMID:
30502323
PMCID:
PMC6409191
[Available on 2020-03-01]
DOI:
10.1053/j.gastro.2018.11.052
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center