Integrated Analysis of Mouse and Human Gastric Neoplasms Identifies Conserved microRNA Networks in Gastric Carcinogenesis
GASTROENTEROLOGY
dc.creator | Chen, Zheng | |
dc.creator | Li, Zheng | |
dc.creator | Soutto, Mohammed | |
dc.creator | Wang, Weizhi | |
dc.creator | Piazuelo, M Blanca | |
dc.creator | Zhu, Shoumin | |
dc.creator | Guo, Yan | |
dc.creator | Maturana, María José | |
dc.creator | Corvalán-Rodriguez, Alejandro Hernán | |
dc.creator | Chen, Xi | |
dc.creator | Xu, Zekuan | |
dc.creator | El-Rifai, Wael M | |
dc.date | 2021-08-23T22:57:01Z | |
dc.date | 2022-07-07T02:38:50Z | |
dc.date | 2021-08-23T22:57:01Z | |
dc.date | 2022-07-07T02:38:50Z | |
dc.date | 2019 | |
dc.date.accessioned | 2023-08-22T05:47:20Z | |
dc.date.available | 2023-08-22T05:47:20Z | |
dc.identifier | 1151411 | |
dc.identifier | 1151411 | |
dc.identifier | https://hdl.handle.net/10533/251968 | |
dc.identifier.uri | https://repositorioslatinoamericanos.uchile.cl/handle/2250/8325444 | |
dc.description | 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. | |
dc.description | Regular 2015 | |
dc.description | FONDECYT | |
dc.description | FONDECYT | |
dc.language | eng | |
dc.relation | handle/10533/111557 | |
dc.relation | handle/10533/111541 | |
dc.relation | handle/10533/108045 | |
dc.relation | https://doi.org/10.1053/j.gastro.2018.11.052 | |
dc.rights | Atribución-NoComercial-SinDerivadas 3.0 Chile | |
dc.rights | http://creativecommons.org/licenses/by-nc-nd/3.0/cl/ | |
dc.rights | info:eu-repo/semantics/article | |
dc.rights | info:eu-repo/semantics/openAccess | |
dc.title | Integrated Analysis of Mouse and Human Gastric Neoplasms Identifies Conserved microRNA Networks in Gastric Carcinogenesis | |
dc.title | GASTROENTEROLOGY | |
dc.type | Articulo | |
dc.type | info:eu-repo/semantics/publishedVersion |