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MiRNA-3978 regulates peritoneal gastric cancer metastasis by targeting legumain.

ABSTRACT: Gastric cancer incidence and mortality are among the highest in China, with majority of the mortality related to peritoneal metastasis of gastric cancer. Treatment is limited to radical resection, which is impeded by incidence of metastasis at time of initial diagnosis, thus making it imperative to identify diagnostic and prognostic biomarkers. Legumain, a lysosomal cysteine endopeptidase of the asparaginyl endopeptidase family, has been shown to be overexpressed in patients with metastatic gastric cancer disease and its expression was positively correlated to both disease progression and outcome. However, the mechanism of legumain expression is currently unknown. Legumain overexpression was found to occur at the level of post transcriptional gene regulation. In situ prediction algorithms identified legumain as a putative target of miR-3978. MiR-3978 was significantly decreased in peritoneal metastatic tissue specimens and in MKN45 cells that mimic peritoneal metastasis features. Reporter assays using LGMN (encoding legumain) 3' untranslated region (UTR) showed that miR-3978 interacted with the wild-type but not miR-3978-seed mutant. Ectopic expression of miR-3978 mimic in the MKN45 cell line significantly decreased proliferation and suppressed in vitro migration and invasion. The miR-3978 mimic inhibited gastric carcinoma and metastatic progression in a mice model by regulating legumain protein expression. Inverse correlation of LGMN mRNA and miR-3978 levels in 20 gastric patients at different stages of metastatic disease confirmed the same. Cumulatively, our results indicate that loss of miR-3978 leads to increased expression of legumain, which indicates that miR-3978might be a biomarker for peritoneal metastasis in patients with gastric cancer.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5347764 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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MiRNA-3978 regulates peritoneal gastric cancer metastasis by targeting legumain.

Zhang Yi Y Wu Yuan-Yu YY Jiang Jun-Nan JN Liu Xue-Song XS Ji Fu-Jian FJ Fang Xue-Dong XD

Oncotarget 20161201 50

Gastric cancer incidence and mortality are among the highest in China, with majority of the mortality related to peritoneal metastasis of gastric cancer. Treatment is limited to radical resection, which is impeded by incidence of metastasis at time of initial diagnosis, thus making it imperative to identify diagnostic and prognostic biomarkers. Legumain, a lysosomal cysteine endopeptidase of the asparaginyl endopeptidase family, has been shown to be overexpressed in patients with metastatic gast ...[more]

PMID: 27793040

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Project description:Background: Accumulating evidence has demonstrated that legumain (LGMN) is abnormally expressed in several malignancies and functions as an oncogene. However, the association between LGMN and gastric cancer (GC) has not yet been fully elucidated. In this study, we performed a comprehensive analysis of the role of LGMN in clinicopathologic characteristics and survival of GC patients. Methods: The study had two patient cohorts, The Cancer Genome Atlas (TCGA) cohort and the Zhongshan Hospital cohort, both of which were used to analyze the role of LGMN in GC samples. The relationship between LGMN and clinicopathologic characteristics was determined by the Chi-square test and logistic regression analysis. The Kaplan-Meier method and Cox proportional hazards regression analysis were conducted to investigate the prognostic role of LGMN in GC patients. Moreover, a nomogram was constructed based on the factors that were independently associated with peritoneal metastasis. Finally, the gene set enrichment analysis (GSEA) was conducted to explore the underlying pathways through which LGMN was involved in GC progression. Results: The mRNA and protein levels of LGMN were significantly upregulated in GC tissues, especially for diffuse-type GC. High level of LGMN was independently associated with poor prognosis in both TCGA and Zhongshan cohorts. Further analysis showed that increased protein level of LGMN was related to peritoneal metastasis in GC patients. In a nomogram model, the LGMN expression could help predict the possibility of peritoneal metastasis in GC patients. LGMN was a strong determinant for prediction of peritoneal metastasis. GC patients with high LGMN expression tended to have worse survival together with more frequent diffuse-type tumors and increased risk of peritoneal metastasis. The GSEA results showed that focal adhesion, ecm receptor interaction, cell adhesion molecules cams, TGF-β signaling pathway, JAK-STAT signaling pathway, gap junction, etc. were differentially enriched in the phenotype with high LGMN expression. Conclusion: LGMN was an independent prognostic factor for OS in GC patients. Increased expression of LGMN was significantly associated with peritoneal metastasis. The nomogram based on LGMN might guide the clinical decisions for patients with GC.

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MiRNA-3978 regulates peritoneal gastric cancer metastasis by targeting legumain.

Publications

MiRNA-3978 regulates peritoneal gastric cancer metastasis by targeting legumain.

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