METTL16 Inhibits the Malignant Progression of Epithelial Ovarian Cancer through the lncRNA MALAT1/ β -Catenin Axis.
Changshu LiJi LiuYuanyuan LyuShizhang LingYonghong LuoPublished in: Analytical cellular pathology (Amsterdam) (2023)
Epithelial ovarian cancer (EOC) ranks third in the incidence of gynecological malignancies. m6A methylation as RNA modification plays a crucial role in the evolution, migration, and invasion of various tumors. However, the role of m6A methylation in ovarian cancer (OC) only recently has begun to be appreciated. Therefore, we used various bioinformatic methods to screen the public GEO datasets of epithelial ovarian cancer (EOC) for m6A methylation-related regulators. We identified methyltransferase 16 (METTL16) that was dramatically downregulated in EOC as such a regulator. We also identified metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a known target lncRNA of METTL16, in these five GEO datasets. RT-qPCR and immunohistochemical staining confirmed that compared with the normal ovarian tissues and cells, METTL16 was significantly downregulated, while lncRNA MALAT1 was significantly upregulated, in 30 EOC tissues of our own validation cohorts and EOC cell lines, revealing a negative correlation between METTL16 and lncRNA MALAT1. Moreover, our analysis unveiled a correlation between downregulated METTL16 and the known adverse prognostic factors of EOC patients in our own cohorts. The CCK-8, EdU, scratch wound healing, and transwell invasion assays revealed that METTL16 significantly suppressed the proliferating, migrating, and invading abilities of OC cells. The inhibitory effects of METTL16 on the in vivo tumor growth of EOC cells were measured by subcutaneous tumor formation assay in mice. Furthermore, the RIP, RNA stability assay, western blotting, and cytoimmunofluorescence staining showed that METTL16 hindered the growth of EOC cells through promoting the degradation of MALAT1 by binding that, in turn, upregulates β -catenin protein and promotes nuclear transport of β -catenin protein in EOC cells. This study suggests that METTL16 acts as a tumor suppressor gene of EOC by achieving its inhibitory function on the malignant progression of EOC through the METTL16/MALAT1/ β -catenin axis that are new targets for EOC diagnosis and therapy.
Keyphrases
- induced apoptosis
- cell cycle arrest
- prognostic factors
- epithelial mesenchymal transition
- cell proliferation
- genome wide
- dna methylation
- gene expression
- signaling pathway
- stem cells
- high throughput
- healthcare
- endoplasmic reticulum stress
- long non coding rna
- cell death
- type diabetes
- mental health
- pi k akt
- end stage renal disease
- long noncoding rna
- single cell
- rna seq
- living cells
- cell therapy
- south africa
- ejection fraction
- insulin resistance
- sensitive detection
- adverse drug
- bone marrow
- single molecule
- dna binding
- patient reported
- chemotherapy induced