N⁶-Methyladenosine (m⁶A) is the most common posttranscriptional modification of RNA and plays critical roles in cancer pathogenesis. However, the biological function of long noncoding RNA (lncRNA) methylation remains unclear. As a demethylase, ALKBH5 (alkylation repair homolog protein 5) is involved in mediating methylation reversal. The purpose of this study was to investigate lncRNA m⁶A modification and its role in gastric cancer (GC). Bioinformatics predicted interactions of ALKBH5 with lncRNAs. Five methods were employed to assess the function of nuclear paraspeckle assembly transcript 1 (NEAT1), including gene silencing, RT-PCR, separation of nuclear and cytoplasmic fractions, scrape motility assays, and transwell migration assays. Then, m⁶A RNA immunoprecipitation and immunofluorescence were used to detect methylated NEAT1 in GC cells. Rescue assays were performed to define the relationship between NEAT1 and ALKBH5. NEAT1 is a potential binding lncRNA of ALKBH5. NEAT1 was overexpressed in GC cells and tissue. Additional experiments confirmed that knockdown of NEAT1 significantly repressed invasion and metastasis of GC cells. ALKBH5 affected the m⁶A level of NEAT1. The binding of ALKBH5 and NEAT1 influences the expression of EZH2 (a subunit of the polycomb repressive complex) and thus affects GC invasion and metastasis. Our findings indicate a novel mechanism by which ALKBH5 promotes GC invasion and metastasis by demethylating the lncRNA NEAT1. They may be potential therapeutic targets for GC.

In the last 2 decades, nanomedicine has gained enormous attention due to its promising potential in various biomedical applications such as targeted drug delivery, molecular imaging, biomarker mapping, and diagnosis. Owing to their low toxicity, and longer half-life, several nano-delivery systems such as nanoparticles, lipid carriers, dendrimers, liposomes, and micelles have been developed with unique functions and properties. With benefits such as size variability, good drug loading capacity, stable interactions, and binding with both hydrophobic and hydrophilic substances, nano-delivery systems are designed to overcome problems that are associated with conventional therapies. In the context of gastrointestinal disorders, nano-drug delivery systems are effective in improving drug efficacy, bioavailability, and sustained drug release with minimal side effects. Despite all these technological advancements, nano-delivery systems encounter potential biological barriers in the form of enzymatic degradation, pH variability, and other barriers that hinder the smooth operations of the delivery process. Targeted delivery to specific receptors, passive accumulation of nanoparticles, and pH-sensitive drug release systems are the counter strategies that researchers have been using. This overview explores the role of nano-delivery systems in the treatment of gastrointestinal disorders, focusing on their therapeutic applications and the biological barriers that may limit their efficacy. Additionally, it summarizes the current research landscape and discusses the future prospects for advancing nano-delivery technologies in the management of gastrointestinal diseases.

(Cancer Sci 2010; 101: 639–645)Gastric cancers show high frequency of DNA aneuploidy, a phenotype of chromosomal instability. It is suggested that the abnormal spindle assembly checkpoint is involved in DNA aneuploidy, but the underlying mechanism is still unclear. We studied the mechanism by assessing the expression of BUBR1 in gastric cancer. The DNA ploidy patterns of 116 gastric cancer samples obtained from the Department of Surgery and Science at Kyushu University Hospital were analyzed. Of those, DNA aneuploidy was seen in 70 (60.3%) cases of gastric cancer. The expression of BUBR1 was studied by immunohistochemistry in 181 gastric cancer samples and by real‐time RT‐PCR in several gastric cancer cell lines. Ninety‐one (50.3%) cases had high expression of BUBR1 and those cases correlated significantly with DNA aneuploidy (P < 0.05). Also high expression of BUBR1 cases had significant correlation with deep invasion, lymph node metastasis, liver metastasis, and poor prognosis. In gastric cancer cell lines, high expression of BUBR1 had a significant relationship with DNA aneuploidy (P < 0.05). Then, gastric cancer cell lines MKN‐28 and SNU‐1 were transfected with full‐length BUBR1 to observe the significance of the change in BUBR1 expression. Enforced expression of BUBR1 resulted in changes to the ploidy pattern and high Ki‐67 expression. Collectively, our clinical and in vitro data indicate that high expression of BUBR1 may be one of causative factors for the induction of DNA aneuploidy and progression of gastric cancer.

To investigate the relationship between hypoxia-inducible factor-1α (HIF-1α), prolyl 4-hydroxylase beta (P4HB) expression, and clinicopathologic parameters, as well as the prognostic value of these genes for patients with gastric cancer (GC). Hypoxia is a critical factor that shapes the GC microenvironment. In previous reports, we have demonstrated that P4HB is a potential target of HIF-1α. In the present study, gene expression profiling interactive analysis (GEPIA) was used to analyze the relationship between P4HB and hypoxia-associated genes. To this end, 428 GC tissue samples were used to analyze the expression of HIF-1α and P4HB via immunohistochemical staining. Patient samples were classified as having weak-expression or over-expression both in terms of HIF-1α and P4HB. Correlations between biomarkers and clinicopathological factors were analyzed to predict survival. P4HB demonstrated a positive correlation with hypoxia-associated genes (P < 0.05). HIF-1α and P4HB overexpression have a significant correlation with TNM staging (χ2 = 23.32, P = 0.00; χ2 = 65.64, P = 0.00) and peritoneum cavity metastasis (χ2 = 12.67, P = 0.00; χ2 = 39.29, P = 0.00). In univariate analysis, patients with a high HIF-1α expression trend had a shorter disease-free survival (DFS: 44.80 mo vs 22.06 mo) and overall survival (OS: 49.58 mo vs 39.92 mo). P4HB overexpression reflected similar results: patients with over-expression of P4HB had a shorter survival time than those with weak-expression (DFS: 48.03 mo vs 29.64 mo, OS: 52.48 mo vs 36.87 mo). Furthermore, HIF-1α is also a clinicopathological predictor of dismal prognosis according to multivariate analysis (DFS, 95%CI: 0.52-0.88, P < 0.00; OS, 95%CI: 0.50-0.85, P < 0.00). However, P4HB was meaningful in DFS (95%CI: 0.58-1.00, P < 0.05) but not in OS (95%CI: 0.72-1.23, P > 0.05). Overexpression of HIF-1α and P4HB is associated with poor prognosis in patients with GC. Thus, these genes may be potential prognostic biomarker candidates in GC.