Abstract
Background: So far, the platinum-based chemotherapy (e.g. cisplatin-etoposide doublet) is still the backbone for SCLC management due to its high respond rate both in LS-SCLC and ES-SCLC. However, cisplatin treatment often results in the development of chemo-resistance, leading to therapeutic failure and becoming the main obstacle to improve the therapeutic efficacy. Currently, little has been known about the genome-wide abnormal methylation of SCLC induced by cisplatin, which might provide prospective layouts to discover the potential genes and the signal pathways related with chemo-resistance of SCLC.
Results: A total of 58,401 sites was identified to be differentially methylated (|Δβ| ≧ 0.20) in H446/DDP cells compared with that of H446 cells, of which 25,991 genes were found to be hypomethylated and 32,410 genes were shown to be hypermethylated. KEGG enrichment displayed that the differentially hypomethylated genes were mainly gathered in MAPK signaling pathway, ECM-receptor interaction, and Focal adhesion, while the differentially hypermethylated genes were clustered in Neuroactive ligand-receptor interaction, Type I diabetes mellitus, Focal adhesion, Allograft rejection, ECM-receptor interaction, CAMs, Graft-versus-host disease, Intestinal immune network for IgA production, ARVC, and Viral myocarditis (KEGG enrichment, qvalue < 0.05). Among the 152 genes which were selected as the MDR-related candidate genes for qRT-PCR to testify whether the abnormal methylation regulated the expression of related genes at the mRNA level, 69 hypomethylated genes were revealed to be significantly increased and the other 54 hypermethylated genes evidently decreased in H446/DDP cells compared with that of H446 cells. Moreover, the upregulated genes with the hypomethylated sites were found to be mainly clustered in Pathways in cancer, MAPK signaling pathway, Cytokine-cytokine receptor interaction, and Cell adhesion molecules (CAMs), while the downregulated genes with the hypermethylated sites were mainly clustered in MAPK signaling pathway, Pathways in cancer, Melanoma, Osteoclast differentiation, and Prostate cancer.
Conclusions: Cisplatin could induce a large-scale abnormal methylation in the whole genome of SCLC. Pathways in cancer, MAPK signaling pathway, Cytokine-cytokine receptor interaction, and Cell adhesion molecules (CAMs) were most likely to be affected by cisplatin via. methylation to contribute to the development of chemo-resistance and other malignant biological behavior of SCLC cells.
High-frequency electroacupuncture improves endometrial receptivity via regulating cell adhesion molecules and Leukemia Inhibitory Factor / Signal Transducer and Activator of Transcription signaling pathway
