Integrated analysis of DNA methylation and mRNA expression profiling reveals candidate genes associated with cisplatin resistance in non-small cell lung cancer
EPIGENETICS
Authors: Zhang, You-Wei; Zheng, Yun; Wang, Jing-Zi; Lu, Xiao-Xia; Wang, Zhu; Chen, Long-Bang; Guan, Xiao-Xiang; Tong, Jian-Dong
Abstract
DNA methylation plays a critical role during the development of acquired chemoresistance. The aim of this study was to identify candidate DNA methylation drivers of cisplatin (DDP) resistance in non-small cell lung cancer (NSCLC). The A549/DDP cell line was established by continuous exposure of A549 cells to increasing concentrations of DDP. Gene expression and methylation profiling were determined by high-throughput microarrays. Relationship of methylation status and DDP response was validated in primary tumor cell culture and the Cancer Genome Atlas (TCGA) samples. Cell proliferation, apoptosis, cell cycle, and response to DDP were determined in vitro and in vivo. A total of 372 genes showed hypermethylation and downregulation in A549/DDP cells, and these genes were involved in most fundamental biological processes. Ten candidate genes (S100P, GDA, WISP2, LOXL1, TIMP4, ICAM1, CLMP, HSP8, GAS1, BMP2) were selected, and exhibited varying degrees of association with DDP resistance. Low dose combination of 5-aza-2'-deoxycytidine (5-Aza-dC) and trichostatin A (TSA) reversed drug resistance of A549/DDP cells in vitro and in vivo, along with demethylation and restoration of expression of candidate genes (GAS1, TIMP4, ICAM1 and WISP2). Forced expression of GAS 1 in A549/DDP cells by gene transfection contributed to increased sensitivity to DDP, proliferation inhibition, cell cycle arrest, apoptosis enhancement, and in vivo growth retardation. Together, our study demonstrated that a panel of candidate genes downregulated by DNA methylation induced DDP resistance in NSCLC, and showed that epigenetic therapy resensitized cells to DDP.
Multifarious diagnostic possibilities of the S100 protein family: predominantly in pediatrics and neonatology
WORLD JOURNAL OF PEDIATRICS
Authors: Medkova, Anna; Srovnal, Josef; Potomkova, Jarmila; Volejnikova, Jana; Mihal, Vladimir
Abstract
BackgroundNumerous articles related to S100 proteins have been recently published.This review aims to introduce this large protein family and its importance in the diagnostics of many pathological conditions in children and adults.Data sourcesBased on original publications found in database systems, we summarize the current knowledge about the S100 protein group and highlight the most important proteinswith focus on pediatric use.ResultsTheS100 family is composed of Ca(2+)and Zn(2+)binding proteins, which are present only in vertebrates. Some of these proteins can be used as diagnostic markers in cardiology (S100A1, S100A12), oncology (S100A2, S100A5, S100A6, S100A14, S100A16, S100P, S100B), neurology (S100B), rheumatology (S100A8/A9,S100A4, S100A6, and S100A12), nephrology and infections (S100A8, S100A9, S100A8/A9, S100A12). The most useful S100 proteins in pediatrics are S100A8, S100A9, heterodimers S100A8/A9, S100B and S100A12.ConclusionsThe S100 family members are promising biomarkers and provide numerous possibilities for implementation into clinical practice to optimize the differential diagnostic process.