Circ008913, via miR-889 regulation of DAB2IP/ZEB1, is involved in the arsenite-induced acquisition of CSC-like properties by human keratinocytes in carcinogenesis

Abstract

Arsenic is a known human carcinogen and the mechanisms underlying arsenic-induced tumorigenesis remain elusive. Circular RNAs (circRNAs) are involved in the development of cancers, generally acting as sponges for microRNAs (miRNAs). Here, we screened the circRNA expression profiles of HaCaT cells, which are immortalized human keratinocytes, and arsenite-transformed HaCaT cells (T-HaCaT). The presence of has_circRNA-008913 (circ008913) was confirmed in HaCaT cells. Among the circRNAs down-regulated in T-HaCaT cells, circ008913 showed the greatest decrease and was chosen for further research. In HaCaT cells, arsenite induced increases of mRNA levels of the genes for cell-surface markers (k5 and CD34) of skin stem cells, decreases of DAB2IP, and increases of ZEB1. MicroRNA (miR)-889 suppressed the expression of DAB2IP and was involved in regulation of cancer stem cells (CSCs). Moreover, overexpression of circ008913 with pLCDH-circ008913 or transfection with an miR-889 inhibitor reduced the capacity of T-HaCaT cells for colony formation, invasion, migration, and the sizes of tumors in nude mice, effects that were reversed by co-transfection with an miR-889 mimic. These results suggest that, in HaCaT cells, arsenite decreases circ008913 levels, which act as a sponge for miR-889 and down-regulate the miR-889 target, DAB2IP, which, in turn, up-regulates ZEB1, increases mRNA levels of the cell-surface markers of skin stem cells, and is involved in arsenite-induced acquisition of CSC-like properties that lead to malignant transformation. The results also indicate that circ008913 functions as a competing endogenous RNA (ceRNA) for miR-889, which is involved in the arsenite-induced acquisition of CSC-like properties by regulation of DAB2IP and elucidate a previously unknown mechanism between arsenite-induced acquisition of CSC-like properties and carcinogenesis.