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MicroRNA signatures associated with lymph node metastasis in intramucosal gastric cancer

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Abstract
Although a certain proportion of intramucosal carcinomas (IMCs) of the stomach does metastasize, the majority of patients are currently treated with endoscopic resection without lymph node dissection, and this potentially veils any existing metastasis and may put some patients in danger. In this regard, biological markers from the resected IMC that can predict metastasis are warranted. Here, we discovered unique miRNA expression profiles that consist of 21 distinct miRNAs that are specifically upregulated (miR-628-5p, miR-1587, miR-3175, miR-3620-5p, miR-4459, miR-4505, miR-4507, miR-4720-5p, miR-4742-5p, and miR-6779-5p) or downregulated (miR-106b-3p, miR-125a-5p, miR-151b, miR-181d-5p, miR-486-5p, miR-500a-3p, miR-502-3p, miR-1231, miR-3609, and miR-6831-5p) in metastatic (M)-IMC compared to nonmetastatic (N)-IMC, or nonneoplastic gastric mucosa. Intriguingly, most of these selected miRNAs showed stepwise increased or decreased expression from nonneoplastic tissue to N-IMC to M-IMC. This suggests that common oncogenic mechanisms are gradually intensified during the metastatic process. Using a machine-learning algorithm, we demonstrated that such miRNA signatures could distinguish M-IMC from N-IMC. Gene ontology and pathway analysis revealed that TGF-β signaling was enriched from upregulated miRNAs, whereas E2F targets, apoptosis-related, hypoxia-related, and PI3K/AKT/mTOR signaling pathways, were enriched from downregulated miRNAs. Immunohistochemical staining of samples from multiple institutions indicated that PI3K/AKT/mTOR pathway components, MAPK1, phospho-p44/42 MAPK, and pS6 were highly expressed and the expression of SMAD7, a TGF-β pathway component, was decreased in M-IMC, which could aid in distinguishing M-IMC from N-IMC. The miRNA signature discovered in this study is a valuable biological marker for identifying metastatic potential of IMCs, and provides novel insights regarding the metastatic progression of IMC.
Author(s)
김경미김석휘배원정성창옥안지미이다근최경운허진형
Issued Date
2021
Type
Article
Keyword
Tumor / analysisTumor / genetics*Gastric Mucosa / enzymologyGastric Mucosa / pathologyGene ExpressionProfilingGene Regulatory NetworksHumansImmunohistochemistryLymphatic MetastasisMachine LearningMicroRNAs / genetics*Predictive Value of TestsReproducibility of ResultsRepublic of KoreaSignal Transduction / geneticsStomach Neoplasms / enzymologyStomach Neoplasms / genetics*Stomach Neoplasms / pathologymTranscriptome*
DOI
10.1038/s41379-020-00681-x
URI
https://oak.ulsan.ac.kr/handle/2021.oak/7453
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_proquest_miscellaneous_2446666706&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,MicroRNA%20signatures%20associated%20with%20lymph%20node%20metastasis%20in%20intramucosal%20gastric%20cancer&offset=0&pcAvailability=true
Publisher
MODERN PATHOLOGY
Location
미국
Language
영어
ISSN
0893-3952
Citation Volume
34
Citation Number
3
Citation Start Page
672
Citation End Page
683
Appears in Collections:
Medicine > Medicine
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