The SNAIL/miR-128 axis regulated growth, invasion, metastasis, and epithelial-to-mesenchymal transition of gastric cancer

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.

miR‐128‐3p contributes to mitochondrial dysfunction and induces apoptosis in glioma cells via targeting pyruvate dehydrogenase kinase 1

“…miR‐128, one of the most abundant miRNAs expressed in mouse and human brain, is expressed in diverse brain regions, and plays a critical role in the development and maintenance of the nervous system. In addition, miR‐128 also plays an important role in regulating the proliferation and apoptosis in various types of tumors . As it was demonstrated in most publications, miR‐128‐3p was found to be markedly decreased in various cancers, including glioma .…”

“…18,48 As it was demonstrated in most publications, miR-128-3p was found to be markedly decreased in various cancers, including glioma. 22,48 miR-128 acted as a tumor suppressor via targeting ARP5, BMI-1 and E2F-3a, consequently attenuating the progression of glioma. 18 This result was similar to our study, in which miR-128-3p suppressed glioma cell proliferation through modulating PDK1.…”

“…In addition, miR‐128 also plays an important role in regulating the proliferation and apoptosis in various types of tumors . As it was demonstrated in most publications, miR‐128‐3p was found to be markedly decreased in various cancers, including glioma . miR‐128 acted as a tumor suppressor via targeting ARP5, BMI‐1 and E2F‐3a, consequently attenuating the progression of glioma .…”

Interplay among SNAIL Transcription Factor, MicroRNAs, Long Non-Coding RNAs, and Circular RNAs in the Regulation of Tumor Growth and Metastasis

“…The SNAIL/miR-128 axis regulates the growth, invasion, metastasis, and EMT of gastric cancer. miR-128 targets directly Bmi11, and it can reverse EMT induced by Bmi-1 via the PI3K/AKT pathway, whereas SNAIL curbs the expression of miR-128, and then down-regulated miR-128 promotes the expression of Bmi-1 [156]. The loss of SNAIL was also shown to inhibit cellular growth and metabolism through the miR-128-mediated signaling pathway in prostate cancer cells [157].…”

MicroRNA‐128/homeobox B8 axis regulates ovarian cancer cell progression

“…Accumulating evidence has proven that miRNAs regulate thousands of cancer‐associated genes, thereby participating in cancer progression and suppression . miRNA‐128 (miR‐128) has been found to be involved in various cancers, such as gastric cancer, colorectal cancer, osteosarcoma, breast cancer and lung cancer . Recently, miR‐128 was found to be dysregulated in ovarian cancer .…”