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.