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

作者：Li, Meifen; Zhai, Guanghua; Gu, Xiuyu; Sun, Kangyun^*

来源：Gene, 2018, 672: 93-105.

DOI：10.1016/j.gene.2018.06.017

• ATF3
• PRAP1
• CDDP-specific
• Microvascular endothelial
• Biomarkers

Background: 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.
Methods: 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 gamma H2AX level was evaluated to monitor the DNA damages caused by cisplatin.
Result: For the 'acute-exposure' settings that HMEC-1 were treated with 12.9 mu M 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 mu M cisplatin twice a week, SULF2, ACTA2 and PRAP1 were identified. In addition, further in vitro validation showed that knockdown of ATF3 attenuated the gamma H2AX level in cells exposed to cisplatin for 6 or 24 h and knockdown of PRAP1 increased the gamma H2AX level in cells exposed to cisplatin for 2 days. Notably, ATF3 has the ability to regulate the expression of HIST1H1D, FBX06, APP, MDM2, STAT1 and TRAF1, while PRAP1 regulates YWHAB, MDM2, ISG15, LYN and CUL1 during cisplatin-induced DNA damage repair process.
Conclusion: 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.

• 出版日期2018-9-25
• 单位南京医科大学