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.
Highlights
The Republic of China has one of the highest incidences of gastric cancer globally, with 300,000 patients with gastric cancer projected to die annually [1]
Legumain was earlier shown to aid in metastatic progression of legumain by inducing epithelial to mesenchymal transition (EMT) (13), we assayed the samples for expression of epithelial cell marker, E-cadherin, and mesenchymal cell markers, fibronectin and vimentin
To understand if the difference in legumain expression was due to differential transcription of LGMN in patients with peritoneal metastasis, we performed qRT-PCR (Figure 1B)
Summary
The Republic of China has one of the highest incidences of gastric cancer globally, with 300,000 patients with gastric cancer projected to die annually [1]. It has been shown that the lysosomal cysteine endopeptidase of the asparaginyl endopeptidase family, legumain or asparaginyl endopeptidase (AEP) [9, 10], is overexpressed in patients with metastatic gastric cancer [11, 12]. It has been shown that legumain facilitates epithelial to mesenchymal transition (EMT) and metastatic progression in gastric cancer through activation of MAPK and Akt signaling pathways and overexpressed in different cancers [13,14,15,16,17,18,19]. The precise mechanism about what induces legumain expression during metastatic progression of gastric cancer is not known, which was the objective of the present study. During gastric cancer progression miR-3978 expression is suppressed resulting in concomitant increase in legumain expression
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