ATF3 and PRAP1 play important roles in cisplatin-induced damages in microvascular endothelial cells

• Published in: Gene 2018-09, Vol.672, p.93-105
• Main Authors: Li, Meifen, Zhai, Guanghua, Gu, Xiuyu, Sun, Kangyun
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 3 - genetics; Antineoplastic Agents - toxicity; ATF3; Biomarkers; CDDP-specific; Cells, Cultured; Cisplatin - toxicity; DNA Breaks, Double-Stranded; DNA Repair; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium, Vascular - drug effects; Endothelium, Vascular - pathology; Gene Ontology; Humans; Microvascular endothelial; Microvessels - drug effects; Microvessels - pathology; PRAP1; Pregnancy Proteins - genetics; Protein Interaction Maps
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2018.06.017

The early intervention is a rational approach to reduce the cardiovascular disease mortality in cancer patients. Here, we tried to identify potential biomarkers for the endothelial damage caused by cisplatin, a typical chemotherapy compound, and explore its underlying mechanisms. Microarray dataset GSE62523 were utilized to assess the gene differential expression from human micro-vascular endothelial cells (HMEC-1) treated with cisplatin. Then, the potential key genes were further validated by qRT-PCR and the γH2AX level was evaluated to monitor the DNA damages caused by cisplatin. For the ‘acute-exposure’ settings that HMEC-1 were treated with 12.9 μM cisplatin for 6, 24 and 48 h, ATF3, LRRTM2, VCAM1 and PAPPA were identified as potential key genes in endothelial damage, while for the ‘chronic-exposure’ settings that cells were exposed to 0.52 μM cisplatin twice a week, SULF2, ACTA2 and PRAP1 were identified. In addition, further in vitro validation showed that knockdown of ATF3 attenuated the γH2AX level in cells exposed to cisplatin for 6 or 24 h and knockdown of PRAP1 increased the γH2AX level in cells exposed to cisplatin for 2 days. Notably, ATF3 has the ability to regulate the expression of HIST1H1D, FBXO6, APP, MDM2, STAT1 and TRAF1, while PRAP1 regulates YWHAB, MDM2, ISG15, LYN and CUL1 during cisplatin-induced DNA damage repair process. ATF3 and PRAP1 play important roles in cisplatin-induced DNA damage repair process. They may serve as potential early surrogate biomarkers of microvascular endothelial damage for cancer patients receiving chemotherapies. •ATF3 and PRAP1 play important roles in cisplatin-induced DNA damage repair process.•ATF3 regulates the expression of HIST1H1D, FBXO6, APP, MDM2, STAT1 and TRAF1.•PRAP1 regulates YWHAB, MDM2, ISG15, LYN and CUL1.