The Role of circRNA-SETD2/miR-519a/PTEN Axis in Fetal Birth Weight through Regulating Trophoblast Proliferation

Abnormal birth weight is the one of the major causes of adulthood diseases such as obesity, metabolic syndrome, cardiovascular disease, type 2 diabetes, and hypertension. Accumulating evidence has suggested that the placental trophoblast is one of the most important reasons that influence birth weight. Our previous study showed that miR-519a are correlated with low fetal birth weight through regulating trophoblast proliferation. To further clarify the detailed mechanisms on how it is regulated, we screened the placental-specific circular RNAs (circRNAs) via microarray assay. The result identified that circ-SETD2 was highly expressed in the placenta of the patients with fetal macrosomia compared with healthy donors. Furthermore, bioinformatic analyses and the luciferase reporter assay revealed that miR-519a possessing the binding sites for both circ-SETD2 and phosphate and tensin homolog was deleted on chromosome 10 (PTEN). Interestingly, upregulation of circ-SETD2 enhanced the proliferation and invasion of the human trophoblast-like cell line HTR8/SVneo cell. A parallel study performed by Western blotting showed that overexpression of circ-SETD2 reduced miR-519a levels and increased PTEN levels in HTR8/SVneo cells. Importantly, the enhancement of HTR8/SVneo cell activity by circ-SETD2 overexpression was nullified when the cells were cotransfected by circ-SETD2 and miR-519a, suggesting the involvement of the circ-SETD2/miR-519a/PTEN axis in trophoblast activity. Taken together, we illustrate the role of circ-SETD2, as an upstream signaling of miR-519a/PTEN, in placenta development via regulating trophoblast proliferation and invasion. These findings improve our understanding of the mechanisms of progression of fetal macrosomia and will guide future development of therapeutic strategies against the disease by targeting the circ-SETD2/miR-519a/PTEN axis.