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

GASTROENTEROLOGY

dc.creatorChen, Zheng
dc.creatorLi, Zheng
dc.creatorSoutto, Mohammed
dc.creatorWang, Weizhi
dc.creatorPiazuelo, M Blanca
dc.creatorZhu, Shoumin
dc.creatorGuo, Yan
dc.creatorMaturana, María José
dc.creatorCorvalán-Rodriguez, Alejandro Hernán
dc.creatorChen, Xi
dc.creatorXu, Zekuan
dc.creatorEl-Rifai, Wael M
dc.date2021-08-23T22:57:01Z
dc.date2022-07-07T02:38:50Z
dc.date2021-08-23T22:57:01Z
dc.date2022-07-07T02:38:50Z
dc.date2019
dc.date.accessioned2023-08-22T05:47:20Z
dc.date.available2023-08-22T05:47:20Z
dc.identifier1151411
dc.identifier1151411
dc.identifierhttps://hdl.handle.net/10533/251968
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8325444
dc.descriptionBACKGROUND & 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.descriptionRegular 2015
dc.descriptionFONDECYT
dc.descriptionFONDECYT
dc.languageeng
dc.relationhandle/10533/111557
dc.relationhandle/10533/111541
dc.relationhandle/10533/108045
dc.relationhttps://doi.org/10.1053/j.gastro.2018.11.052
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 Chile
dc.rightshttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/
dc.rightsinfo:eu-repo/semantics/article
dc.rightsinfo:eu-repo/semantics/openAccess
dc.titleIntegrated Analysis of Mouse and Human Gastric Neoplasms Identifies Conserved microRNA Networks in Gastric Carcinogenesis
dc.titleGASTROENTEROLOGY
dc.typeArticulo
dc.typeinfo:eu-repo/semantics/publishedVersion


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