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Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
03, 2021;34 (3): 672-683.

MicroRNA signatures associated with lymph node metastasis in intramucosal gastric cancer.

Seokhwi Kim, Won Jung Bae, Ji Mi Ahn, Jin-Hyung Heo, Kyoung-Mee Kim, Kyeong Woon Choi, Chang Ohk Sung, Dakeun Lee
Author Information
  1. Seokhwi Kim: Department of Pathology, Ajou University School of Medicine, Suwon, Korea.
  2. Won Jung Bae: Department of Pathology, Ajou University School of Medicine, Suwon, Korea.
  3. Ji Mi Ahn: Department of Pathology, Ajou University School of Medicine, Suwon, Korea.
  4. Jin-Hyung Heo: Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam, Korea.
  5. Kyoung-Mee Kim: Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. ORCID
  6. Kyeong Woon Choi: Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  7. Chang Ohk Sung: Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. co.sung@amc.seoul.kr.
  8. Dakeun Lee: Department of Pathology, Ajou University School of Medicine, Suwon, Korea. dakeun@gmail.com. ORCID
PMID: 32973329 DOI: 10.1038/s41379-020-00681-x

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.

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MeSH Term

Biomarkers, Tumor
Gastric Mucosa
Gene Expression Profiling
Gene Regulatory Networks
Humans
Immunohistochemistry
Lymphatic Metastasis
Machine Learning
MicroRNAs
Predictive Value of Tests
Reproducibility of Results
Republic of Korea
Signal Transduction
Stomach Neoplasms
Transcriptome

Chemicals

Biomarkers, Tumor
MicroRNAs
Journal Article Multicenter Study Research Support, Non-U.S. Gov't Validation Study
Article has an altmetric score of 3

Word Cloud

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