Abstract
BackgroundGastric cancer (GC) is one of the most common human cancers with the high rate of recurrence, metastasis and mortality. Aberrantly expressed microRNAs (miRNAs) are associated with invasion and metastasis in various human cancers. Recently, miR-188-5p has been indicated as an oncogene in GC since it promotes GC cell growth and metastasis. However, the underlying molecular mechanism remains to be fully defined.MethodsUsing Significance Analysis of Microarrays (SAM) screening, we identified that miR-188-5p is associated with overall survival and lymph node metastasis in patients with GC. The functional impact of miR-188-5p on GC metastasis was validated using in vitro and in vivo assays. The regulatory function of miR-188-5p on Wnt/β-catenin signaling activation through directly targeting PTEN was proven using quantitative real-time PCR, western blot analysis, a dual-luciferase assay, a Transwell assay, and immunofluorescence. Immunohistochemical analyses further confirmed the clinical significance of miR-188-5p in GC.ResultsMiR-188-5p diminishes tumor suppressor PTEN expression, and further increases phospho-Ser9 of GSK3β to activate Wnt/β-catenin signaling in GC. Consequently, miR-188-5p enhanced the migration and invasion of GC cells in vitro and tumor metastasis in vivo, whereas inhibition of miR-188-5p had the opposite effects. Moreover, miR-188-5p was negatively correlated with PTEN expression but positively correlated with nuclear β-catenin staining in GC samples.ConclusionsOur findings revealed a model of the miR-188-5p-PTEN-β-catenin axis in GC, which mediates the constitutive activation of Wnt/β-catenin signaling and promotes tumor metastasis, inferring that miR-188-5p is a potential therapeutic target to treat GC.
Highlights
Gastric cancer (GC) is one of the most common human cancers with the high rate of recurrence, metastasis and mortality
Results miR-188-5p correlates with GC patient survival and lymph node metastasis To examine whether miRNAs were associated with GC patient survival and lymph node metastasis status, we analyzed the miRNA expression profiles in patients with stomach adenocarcinoma (STAD) using the stomach cancer data set of The Cancer Genome Atlas (TCGA)
From censored survival analysis of the Significance Analysis of Microarrays (SAM) in MeV4.9, we identified 13 distinctly expressed miRNAs that were closely correlated with Overall survival (OS) or lymph node metastasis status, corresponding to a median expected false discovery rate (FDR) of 10% (Table 1)
Summary
Gastric cancer (GC) is one of the most common human cancers with the high rate of recurrence, metastasis and mortality. In the absence of Wnt ligand stimulation, cytosolic β-catenin is normally sequestrated in the “destruction complex” and Wnt/βcatenin signaling is inactivated [9, 10]. That PI3K/Akt suppression inhibits β-catenin activity is one of the major mechanisms by which PTEN exerts its suppressive effect on tumor progression [12, 13]. While signaling in Wnt/β-catenin pathway is deliberately controlled, its constitutive activation is frequently observed in many human cancer types. Revealing how these factors regulate the Wnt/β-catenin signaling pathway in cancers is of biological and clinical important for the future development of more efficacious therapeutic strategies
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