MicroRNA signatures associated with lymph node metastasis in intramucosal gastric cancer

• Published in: Modern pathology Vol. 34; no. 3; pp. 672 - 683
• Main Authors: Kim, Seokhwi, Bae, Won Jung, Ahn, Ji Mi, Heo, Jin-Hyung, Kim, Kyoung-Mee, Choi, Kyeong Woon, Sung, Chang Ohk, Lee, Dakeun
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.03.2021; Nature Publishing Group US; Elsevier Limited
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/51; 38/39; 45/61; 45/90; 631/67/1504/1829; 692/308/53/2421; AKT protein; Apoptosis; Biomarkers; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Carcinoma; E2F protein; Gastric cancer; Gastric mucosa; Gastric Mucosa - enzymology; Gastric Mucosa - pathology; Gene Expression Profiling; Gene Regulatory Networks; Humans; Hypoxia; Immunohistochemistry; Laboratory Medicine; Learning algorithms; Lymph nodes; Lymphatic Metastasis; Lymphatic system; Machine Learning; MAP kinase; Medicine; Medicine & Public Health; Metastases; Metastasis; MicroRNAs; MicroRNAs - genetics; miRNA; Pathology; Predictive Value of Tests; Reproducibility of Results; Republic of Korea; Signal transduction; Signal Transduction - genetics; Smad7 protein; Stomach Neoplasms - enzymology; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; TOR protein; Transcriptome; Republic of Korea
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/s41379-020-00681-x

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.