Comparative gene expression profiling of human metallothionein-3 up-regulation in neuroblastoma cells and its impact on susceptibility to cisplatin
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Miguel Angel Merlos Rodrigo1,2, Simona Dostalova1,2, Hana Buchtelova1,2, Vladislav Strmiska1,2, Petr Michalek1,2, Sona Krizkova1,2, Ales Vicha3, Pavla Jencova3, Tomas Eckschlager3, Marie Stiborova4, Zbynek Heger1,2 and Vojtech Adam1,2
1Department of Chemistry and Biochemistry, Mendel University in Brno, CZ-613 00 Brno, Czech Republic
2Central European Institute of Technology, Brno University of Technology, CZ-616 00 Brno, Czech Republic
3Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, CZ-150 06 Prague 5, Czech Republic
4Department of Biochemistry, Faculty of Science, Charles University, CZ-128 40 Prague 2, Czech Republic
Vojtech Adam, email: [email protected]
Keywords: apoptosis; cisplatin; chemoresistance; metallothionein; oncogene-induced senescence
Received: August 02, 2017 Accepted: December 08, 2017 Published: December 16, 2017
Human metallothionein-3 (hMT-3), also known as growth inhibitory factor, is predominantly expressed in the central nervous system. hMT-3 is presumed to participate in the processes of heavy metal detoxification, regulation of metabolism and protection against oxidative damage of free radicals in the central nervous system; thus, it could play important neuromodulatory and neuroprotective roles. However, the primary functions of hMT-3 and the mechanism underlying its multiple functions in neuroblastoma have not been elucidated so far. First, we confirmed relatively high expression of hMT-3 encoding mRNA in biopsies (n = 23) from high-risk neuroblastoma subjects. Therefore, we focused on investigation of the impact of hMT-3 up-regulation in N-Myc amplifying neuroblastoma cells. The differentially up-regulated genes involved in biological pathways related to cellular senescence and cell cycle were identified using electrochemical microarray with consequent bioinformatic processing. Further, as experimental verification of microarray data, the cytotoxicity of the cisplatin (CDDP) was examined in hMT-3 and mock cells by MTT and clonogenic assays. Overall, our data strongly suggest that up-regulation of hMT-3 positively correlates with the genes involved in oncogene-induced senescence (CDKN2B and ANAPC5) or apoptosis (CASP4). Moreover, we identified a significant increase in chemoresistance to cisplatin (CDDP) due to hMT-3 up-regulation (24IC50: 7.5 vs. 19.8 μg/ml), indicating its multipurpose biological significance.
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