DCTPP1 attenuates the sensitivity of human gastric cancer cells to 5-fluorouracil by up-regulating MDR1 expression epigenetically
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Li-liang Xia1,4,*, Ya-bin Tang2,*, Fei-fei Song2, Ling Xu2, Ping Ji2, Shu-jun Wang2, Ji-min Zhu3, Yong Zhang2, Guo-ping Zhao1,4,5, Ying Wang2, Tao-tao Liu3
1State Key Laboratory of Genetic Engineering, Department of Microbiology, School of Life Sciences and Institute of Biomedical Sciences, Fudan University, Shanghai, China
2Shanghai Institute of Immunology, Department of Immunology and Microbiology, Department of Pharmacology and Chemical Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China
3Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
4Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China
5Department of Microbiology and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
*These authors have contributed equally to this work
Tao-tao Liu, email: [email protected]
Li-liang Xia, email: [email protected]
Keywords: dCTP pyrophosphatase 1, chemoresistance to 5-fluorouracil, 5-methyl-dCTP, methylation, multidrug resistance 1
Received: March 31, 2016 Accepted: August 24, 2016 Published: September 06, 2016
Gastric cancer (GC) is among the most malignant cancers with high incidence and poor prognoses worldwide as well as in China. dCTP pyrophosphatase 1 (DCTPP1) is overexpressed in GC with a poor prognosis. Given chemotherapeutic drugs share similar structures with pyrimidine nucleotides, the role of DCTPP1 in affecting the drug sensitivity in GC remains unclear and is worthy of investigation. In the present study, we reported that DCTPP1-knockdown GC cell line BGC-823 exhibited more sensitivity to 5-fluorouracil (5-FU), demonstrated by the retardation of cell proliferation, the increase in cell apoptosis, cell cycle arrest at S phase and more DNA damages. Multidrug resistance 1 (MDR1) expression was unexpectedly down-regulated in DCTPP1-knockdown BGC-823 cells together with more intracellular 5-FU accumulation. This was in large achieved by the elevated methylation in promoter region of MDR1 gene. The intracellular 5-methyl-dCTP level increased in DCTPP1-knockdown BGC-823 cells as well. More significantly, the strong correlation of DCTPP1 and MDR1 expression was detectable in clinical GC samples. Our results thus imply a novel mechanism of chemoresistance mediated by the overexpression of DCTPP1 in GC. It is achieved partially through decreasing the concentration of intracellular 5-methyl-dCTP, which in turn results in promoter hypomethylation and hyper-expression of drug resistant gene MDR1. Our study suggests DCTPP1 as a potential indicative biomarker for the predication of chemoresistance in GC.
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