Abstract
miR-128 is expressed in various tumors, but its expression and function in gastric cancer have not been defined. Thus, the goal of this study was to characterize miR-128 in gastric cancer. We found first that miR-128 is down-regulated in gastric cancer cell lines and tissues, and this dysregulation is correlated with DNA methylation and the transcription factor SNAIL. Using prediction tools, western blotting, and luciferase reporter assays, we found that Bmi-1 was the direct target of miR-128. Additionally, overexpression of miR-128 inhibited gastric cancer cell migration, invasion, and proliferation by targeting Bmi-1 in vitro and in vivo. We also documented, with receiver operating characteristic curves and Kaplan-Meier survival analysis, that miR-128 and Bmi-1 may be useful markers for diagnosing and estimating the prognosis of gastric cancer patients. As the epithelial-to-mesenchymal transition is an important mechanism associated with cancer invasion and metastasis, we inferred that miR-128 could regulate this mechanism in gastric cancer. In fact, we found that miR-128 could reverse epithelial-to-mesenchymal transition induced by Bmi-1 via the PI3K/AKT pathway. Because SNAIL also acts as a mesenchymal marker, our findings identified a novel positive feedback loop in which the transcription factor SNAIL curbs the expression of miR-128, and then down-regulated miR-128 promotes the expression of Bmi-1; finally, overexpression of Bmi-1 drives the epithelial-to-mesenchymal transition process via the PI3K/AKT pathway, and the expression of SNAIL is up-regulated.
Highlights
Gastric cancer is one of the most common cancers in the world [1]
We found first that miR-128 is down-regulated in gastric cancer cell lines and tissues, and this dysregulation is correlated with DNA methylation and the transcription factor SNAIL
Because SNAIL acts as a mesenchymal marker, our findings identified a novel positive feedback loop in which the transcription factor SNAIL curbs the expression of miR-128, and down-regulated miR-128 promotes the expression of Bmi-1; overexpression of Bmi-1 drives the epithelial-to-mesenchymal transition process via the PI3K/akt murine thymoma viral oncogene homolog (AKT) pathway, and the expression of SNAIL is up-regulated
Summary
Gastric cancer is one of the most common cancers in the world [1]. In 2008, approximately 989,000 new cases (7.8% of global cancer totals) and 738,000 deaths (9.7% of global cancer totals) were recorded, making gastric cancer the fourth most common malignancy and the second leading cause of cancer death worldwide [2]. The genesis and progression of human gastric cancer are thought to be influenced by genetic and epigenetic alterations, including the activation of oncogenes and the inactivation of tumor suppressor genes. MiRNAs are non-coding RNA molecules, approximately 21-23 nucleotides in length, which regulate gene expression at the posttranscriptional level [7,8,9]. Published evidence [6] indicates that both oncogenes and tumor suppressor genes can be regulated by microRNAs (miRNAs). It has been reported [10, 11] that miRNAs can regulate many malignant phenotypes of cancer, such as cancer cell proliferation, apoptosis, migration, and invasion. MiRNAs can function as tumor suppressors or oncogenes, and deregulated miRNA expression might contribute to tumor cell metastasis
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