melitten and Urinary-Bladder-Neoplasms

Abnormal RNA methylation and dysregulation of miRNA are frequently occurred in bladder cancer. Melittin is a potential drug candidate for intravesical chemotherapy against bladder cancer. However, the underlying epigenetic mechanism by which melittin-induced anti-tumor effect remains unclear. Here, we showed that melittin selectively induced apoptosis of bladder cancer cells in a METTL3-dependent manner. Ectopic expression of METTL3 significantly blocked melittin-induced apoptosis in vitro and in vivo. MicroRNA-sequence analysis identified miR-146a-5p suppression contributed to the melittin-induced selective antitumor effect. Further investigation revealed that METTL3-guided m6A modification methylated pri-miR-146 at the flanking sequence, which was responsible for the pri-miR-146 maturation. Moreover, NUMB/NOTCH2 axis was identified as a downstream target signal that mediated the pro-survival role of miR-146a-5p in bladder cancer cells. Importantly, METTL3 and miR-146a-5p were positively correlated with recurrence and poor prognosis of patients with bladder cancer. Our study indicates that METTL3 acts as a fate determinant that controls the sensitivity of bladder cancer cells to melittin treatment. Moreover, METTL3/miR-146a-5p/NUMB/NOTCH2 axis plays an oncogenic role in bladder cancer pathogenesis and could be a potential therapeutic target for recurrent bladder cancer treatment.

Topics: Gene Expression Regulation, Neoplastic; Humans; Melitten; Methyltransferases; MicroRNAs; Neoplasm Recurrence, Local; Urinary Bladder Neoplasms

The antitumour effect of melittin (MEL) has recently attracted considerable attention. Nonetheless, information regarding the functional role of MEL in bladder cancer (BC) is currently limited. Herein, we investigated the effect of MEL on critical module genes identified in BC. In total, 2015 and 4679 differentially expressed genes (DEGs) associated with BC were identified from the GSE31189 set and The Cancer Genome Atlas database, respectively. GSE-identified DEGs were mapped and analysed using Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes analyses to determine BC-involved crucial genes and signal pathways. Coupled with protein-protein interaction network and Molecular Complex Detection analyses, Modules 2 and 4 were highlighted in the progression of BC. In in-vitro experiments, MEL inhibited the proliferation, migration, and invasion of UM-UC-3 and 5637 cells. The expression of NRAS, PAK2, EGFR and PAK1 in Module 4-enriched in the MAPK signalling pathway-was significantly reduced after treatment with MEL at concentrations of 4 or 6 μg/mL. Finally, quantitative reverse transcription-polymerase chain reaction and Western blotting analyses revealed MEL inhibited the expression of genes at the mRNA (ERK1/2, ERK5, JNK and MEK5), protein (ERK5, MEK5, JNK and ERK1/2) and phosphorylation (p-ERK1/2, p-JNK, and p-38) levels. This novel evidence indicates MEL exerts effects on the ERK5-MAK pathway-a branch of MAPK signalling pathway. Collectively, these findings provide a theoretical basis for MEL application in BC treatment.

Topics: Apoptosis; Biomarkers, Tumor; Cell Movement; Cell Proliferation; Computational Biology; Gene Expression Regulation, Neoplastic; Humans; Melitten; Neoplasm Invasiveness; Prognosis; Protein Interaction Maps; Tumor Cells, Cultured; Urinary Bladder Neoplasms

This work is aimed at investigating the effect of melittin on identified key genes in bladder cancer (BC) and further providing a theoretical basis for BC treatment. GSE35014 downloaded from the Gene Expression Omnibus (GEO) database was used to screen differentially expressed genes (DEGs) in BC cells and control. Results showed that a total of 389 upregulated and 169 downregulated genes were identified. Subsequently, GO analysis, KEGG pathway enrichment analysis, and PPI network analysis were employed to disclose the crucial genes and signaling pathways involved in BC. Fifteen module-related DEGs and their associated signaling pathways were obtained according to the PPI network and modular analyses. Based on the analysis of articles retrieved in the PubMed database, we found that melittin could induce apoptosis and constrain the progression of tumor cells as a result of regulating critical cancer-related signaling pathways, such as PI3K-Akt and TNF signaling pathways. Furthermore, PI3K-Akt and TNF signaling pathways were also found to be associated with module-related DEGs according to biological analyses. At last, qRT-PCR analysis demonstrated that melittin could constrain the expression of module-related DEGs (LPAR1, COL5A1, COL6A2, CXCL1, CXCL2, and CXCL3) associated with PI3K-Akt and TNF signaling pathways in BC cells. Functional assays revealed that melittin could constrain the proliferative and migrated abilities of BC cells. Conjointly, these findings provide a theoretical basis for these six genes as drug-sensitive markers of melittin in BC treatment.

Topics: Bee Venoms; Chemokine CXCL1; Chemokine CXCL2; Chemokines, CXC; Collagen Type V; Collagen Type VI; Databases, Nucleic Acid; Datasets as Topic; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Medicine, Chinese Traditional; Melitten; Phosphatidylinositol 3-Kinases; Protein Interaction Maps; Proto-Oncogene Proteins c-akt; Receptors, Lysophosphatidic Acid; Signal Transduction; Tumor Necrosis Factors; Urinary Bladder Neoplasms