Methylation and transcriptome analyses construct a prognostic model and reveal the suppressor role of VMO1 in lung...

DNA methylation is an important epigenetic mechanism of gene regulation. The aberrant DNA methylation has been found to play an important role in the initiation and progression of tumors.

Transcriptome and DNA methylation data of lung adenocarcinoma (LUAD) patients were co-analyzed and 95 methylation-driven genes (MDGs) was found in relation to LUAD. A prognostic model based on 3 MDGs (GMNN, SPINK2 and VMO1) was constructed by Univariate and Multivariate cox regression analyses. The risk score generated from the prognostic model could be used to classify LUAD patients into high and low risk groups. Furthermore, it was found that the risk score was associated with tumor microenvironment (TME) and clinical characteristics (survival status and T stage) of patients. Interestingly, we identified and validated that the patients in the low-risk group responded better to immunotherapy treatment. Then, a nomogram model based on the risk score and clinical characteristics was established which showed significant prediction value. The down-regulation and hypermethylation levels of vitelline membrane outer layer protein 1 homolog (VMO1) were verified in paired LUAD tumor and non-tumor tissues by pyrosequencing assay and RT-qPCR. Furthermore, MTT, migration and wound healing assays were performed with lentivector-mediated ectopic over-expression and 5-Aza-dC demethylation followed by siRNA rescue experiments to investigate the role of VMO1 in LUAD cells. Our results indicated that VMO1 could inhibit proliferation and migration of A549 and NCI-H1299 cells.

In summary, our experiments constructed a prognostic model with high capacity for risk prediction in LUAD patients. VMO1 had a malignant suppressor role in LUAD cells. The correlation between risk score and TME might elucidate a potential mechanism of oncogenesis and provide an avenue for further therapeutic targets.