Journal
GASTROENTEROLOGY
Volume 156, Issue 4, Pages 1127-+Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2018.11.052
Keywords
Stomach; Transcription Factor; Tumor Suppressor; Progression
Categories
Funding
- National Institutes of Health [R01CA93999, R01CA177372]
- Research Career Scientist Award from the U.S. Department of Veterans Affairs [1IK6BX003787]
- National Natural Science Foundation Project of International Cooperation [81361120398]
- National Natural Science Foundation of China [81572362]
- Jiangsu Key Medical Discipline [ZDXKA2016005]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) [JX10231801]
- 333 Project of Jiangsu Province [BRA2015474]
- CONICYT-FONDAP from the Government of Chile [15130011]
- Fondecyt from the Government of Chile [1151411]
- Bioinformatics and Biostatistics and Oncogenomics Shared Resources at Sylvester Comprehensive Cancer Center, University of Miami
- merit award from the U.S. Department of Veterans Affairs [I01BX001179]
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BACKGROUND & AIMS: microRNAs (miRNAs) are small noncoding RNAs that bind to the 3 0 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 MIR135B5p, MIR196B-5p, and MIR92A-5p to be increased in tumor tissues, whereas levels of MIR143-3p, MIR204-5p, and MIR1333p 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 MIR1433p or inhibit BRD2 might be developed for treatment of gastric cancer.
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