Targeting Circulating SINEs and LINEs with DNase I Provides Metastases Inhibition in Experimental Tumor Models

Abstract

Tumor-associated cell-free DNAs (cfDNAs) are found to play some important roles at different stages of tumor progression; they are involved in the transformation of normal cells and contribute to tumor migration and invasion. DNase I is considered a promising cancer cure, due to its ability to degrade cfDNAs. Previous studies using murine tumor models have proved the high anti-metastatic potential of DNase I. Later circulating cfDNAs, especially tandem repeats associated with short-interspersed nuclear elements (SINEs) and long-interspersed nuclear elements (LINEs), have been found to be the enzyme's main molecular targets. Here, using Lewis lung carcinoma, melanoma B16, and lymphosarcoma RLS₄₀ murine tumor models, we reveal that tumor progression is accompanied by an increase in the level of SINE and LINEs in the pool of circulating cfDNAs. Treatment with DNase I decreased in the number and area of metastases by factor 3-10, and the size of the primary tumor node by factor 1.5-2, which correlated with 5- to 10-fold decreasing SINEs and LINEs. We demonstrated that SINEs and LINEs from cfDNA of tumor-bearing mice are able to penetrate human cells. The results show that SINEs and LINEs could be important players in metastasis, and this allows them to be considered as attractive new targets for anticancer therapy.

Keywords: LINEs; SINEs; circulating cell-free DNA; horizontal transfer; metastasis; tumor.