Methyl-CpG binding protein 2 (MeCP2) has recently been characterized as an oncogene frequently amplified in several types of cancer. However, its precise role in gastric cancer (GC) and the molecular mechanism of MeCP2 regulation are still largely unknown. Here we report that MeCP2 is highly expressed in primary GC tissues and the expression level is correlated with the clinicopathologic features of GC. In our experiments, knockdown of MeCP2 inhibited tumor growth. Molecular mechanism of MeCP2 regulation was investigated using an integrated approach with combination of microarray analysis and chromatin immunoprecipitation sequencing (ChIP-Seq). The results suggest that MeCP2 binds to the methylated CpG islands of FOXF1 and MYOD1 promoters and inhibits their expression at the transcription level. Furthermore, we show that MeCP2 promotes GC cell proliferation via FOXF1-mediated Wnt5a/β-Catenin signaling pathway and suppresses apoptosis through MYOD1-mediated Caspase-3 signaling pathway. Due to its high expression level in GC and its critical function in driving GC progression, MeCP2 represents a promising therapeutic target for GC treatment.

Methyl-CpG binding protein 2 (MeCP2) is involved in the carcinogenesis and progression of multiple types of cancer. However, its precise role in gastric cancer (GC) and the relevant molecular mechanism remain unknown. In the present study, we found that miR-638 levels were lower in GC tissues and GC cell lines than in adjacent normal tissues and normal gastric epithelial cell lines, respectively. Low miR-638 levels were associated with poor tumor differentiation, tumor size and lymph node metastasis. MeCP2 expression levels were higher in GC tissues than in adjacent normal tissues. It was found that miR-638 inhibited GC cell proliferation, colony formation, G1–S transition and tumor growth, and induced cell apoptosis by directly targeting MeCP2. MeCP2 promoted GC cell proliferation, colony formation and G1–S cell-cycle transition, and suppressed apoptosis. Molecular mechanistic investigations were performed using an integrated approach with a combination of microarray analysis, chromatin immunoprecipitation sequencing and a reporter gene assay. The results showed that MeCP2 bound to the methylated CpG islands of G-protein-coupled receptor kinase-interacting protein 1 (GIT1) promoter and upregulated its expression, thereby activating the MEK1/2–ERK1/2 signaling pathway and promoting GC cell proliferation. Taken together, our study demonstrates that MeCP2, a target of miR-638, facilitates GC cell proliferation and induces cell-cycle progression through activation of the MEK1/2–ERK1/2 signaling pathway by upregulating GIT1. The findings suggest that MeCP2 plays a significant role in GC progression, and may serve as a potential target for GC therapy.

Accumulated evidence has suggested that microRNAs (miRNAs) have an important role in tumor development and progression by regulating diverse signaling pathways. However, the precise role of miRNAs in gastric cancer (GC) has not been elucidated. In this study, we describe the function and regulation network of miR-491-5p in GC. miR-491-5p is frequently downregulated in GC tissues compared with adjacent non-cancerous tissues. Forced expression of miR-491-5p significantly inhibits proliferation and colony formation, and promotes apoptosis in GC cells. Through bioinformatic analysis and luciferase assays, we confirm that miR-491-5p targets Wnt3a. Silencing Wnt3a inhibits cell proliferation and induces apoptosis. Similarly, restoration of Wnt3a counteracts the effects of miR-491-5p expression. Moreover, bioinformatic and luciferase assays indicate that the expression of miR-491-5p is regulated by Foxi1, which binds to its promoter and activates miR-491-5p expression. In conclusion, to the best of our knowledge, our findings are the first to demonstrate that Foxi1 is a key player in the transcriptional control of miR-491-5p and that miR-491-5p acts as an anti-oncogene by targeting Wnt3a/β-catenin signaling in GC. Our study reveals that Foxi1/miR-491-5p/Wnt3a/β-catenin signaling is critical in the progression of GC. Targeting the pathway described in this study may open up new prospects to restrict the progression of GC.

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MicroRNA-25 (miR-25) has been reported to be a major miRNA marker in neural cells and is strongly expressed in ischemic brain tissues. However, the precise mechanism and effect of miR-25 in cerebral ischemia/reperfusion (I/R) injury needs further investigations. In the present study, the oxygen-glucose deprivation (OGD) model was constructed in human SH-SY5Y and IMR-32 cells to mimic I/R injury and to evaluate the role of miR-25 in regulating OGD/reperfusion (OGDR)-induced cell apoptosis. We found that miR-25 was downregulated in the OGDR model. Overexpression of miR-25 via miRNA-mimics transfection remarkably inhibited OGDR-induced cell apoptosis. Moreover, Fas was predicted as a target gene of miR-25 through bioinformatic analysis. The interaction between miR-25 and 3'-untranslated region (UTR) of Fas mRNA was confirmed by dual-luciferase reporter assay. Fas protein expression was downregulated by miR-25 overexpression in OGDR model. Subsequently, the small interfering RNA (siRNA)-mediated knockdown of Fas expression also inhibited cell apoptosis induced by OGDR model; in contrast, Fas overexpression abrogated the protective effects of miR-25 on OGDR-induced cells. Taken together, our results indicate that the upregulation of miR-25 inhibits cerebral I/R injury-induced apoptosis through downregulating Fas/FasL, which will provide a promising therapeutic target.