Abstract
Taking into account recently obtained data indicating the participation of circulating extracellular DNA (exDNA) in tumorigenesis, enzymes with deoxyribonucleic activity have again been considered as potential antitumour and antimetastatic drugs. Previously, using murine Lewis lung carcinoma and hepatocellular carcinoma A1 tumour models, we have shown the antimetastatic activity of bovine DNase I, which correlates with an increase of DNase activity and a decrease of exDNA concentration in the blood serum of tumour-bearing mice. In this work, using next-generation sequencing on the ABS SOLiD™ 5.500 platform, we performed a search for molecular targets of DNase I by comparing the exDNA profiles of healthy animals, untreated animals with Lewis lung carcinoma (LLC) and those with LLC treated with DNase I. We found that upon DNase I treatment of LLC-bearing mice, together with inhibition of metastasis, a number of strong alterations in the patterns of exDNA were observed. The major differences in exDNA profiles between groups were: i) the level of GC-poor sequences increased during tumour development was reduced to that of healthy mice; ii) levels of sequences corresponding to tumour-associated genes Hmga2, Myc and Jun were reduced in the DNase I-treated group in comparison with non-treated mice; iii) 224 types of tandem repeat over-presented in untreated LLC-bearing mice were significantly reduced after DNase I treatment. The most important result obtained in the work is that DNase I decreased the level of B-subfamily repeats having homology to human ALU repeats, known as markers of carcinogenesis, to the level of healthy animals. Thus, the obtained data lead us to suppose that circulating exDNA plays a role in tumour dissemination, and alteration of multiple molecular targets in the bloodstream by DNase I reduces the invasive potential of tumours.
Highlights
Extracellular DNA is a recently discovered component of blood plasma and its elevated level is a characteristic feature of patients with oncological diseases often associated with heavy tumor progression and poor prognosis [1,2,3]
We demonstrated the antimetastatic activity of bovine pancreatic DNase I using two tumour models, Lewis lung carcinoma (LLC) and hepatocellular carcinoma A1 (HA-1) [34]
It was shown that DNase I in the dose range 0.02–2.3 mg/kg inhibited the development of metastasis by 60–90% and caused an increase of the deoxyribonucleic activity of blood plasma and a reduction of the concentration of circulating Extracellular DNA (exDNA)
Summary
Extracellular DNA (exDNA) is a recently discovered component of blood plasma and its elevated level is a characteristic feature of patients with oncological diseases often associated with heavy tumor progression and poor prognosis [1,2,3]. It has been firmly established that circulating exDNA contains oncogenes including hypermethylated tumour suppressor genes, aberrant microsatellites, aberrant DNA methylation genes and rearranged chromosomes [4,5,6,7]. In this regard, diagnostic and prognostic tools are being developed based on determination of the total concentration of exDNA [8], the ratio of the levels of normal and mutant exDNA [9] and the incidence of certain types of aberrant exDNA[10], tandem repeats, etc. Cancer has the propensity to settle down metastatically in specific tissues since there are DNA-binding proteins or receptors on the surface of these cells [16,17,18,19,20,21,22,23]
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