Meifen Li1, Guanghua Zhai1, Xiuyu Gu1, Kangyun Sun2. 1. Department of Laboratory Medicine, The North District of Affiliated Suzhou Hospital, Nanjing Medical University, Suzhou 215008, China. 2. Department of Cardiology, The North District of Affiliated Suzhou Hospital, Nanjing Medical University, Suzhou 215008, China. Electronic address: sunkangyun_js@126.com.
Abstract
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 γH2AX 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 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. 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.
BACKGROUND: The early intervention is a rational approach to reduce the cardiovascular disease mortality in cancerpatients. 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 γH2AX 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 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. 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 cancerpatients receiving chemotherapies.