Circular RNA circACAP2 Suppresses Ferroptosis of Cervical Cancer during Malignant Progression by miR-193a-5p/GPX4

Abstract

Cervical cancer is among the most cancer types, with an extremely high global incidence and mortality. Ferroptosis is a newly reported programmed cell death process that differs from apoptosis, autophagy, and necroptosis. Circular RNAs (circRNAs) are covalently closed loops generated from back-splicing pre-mRNAs, with high stability, and are abundant in the physical environment. Here, we explored the effect of circACAP2 on ferroptosis of cervical cancer. We observed that the depletion of circACAP2 by siRNAs was validated in cervical cancer cells. The cervical cancer cell viability was inhibited by circACAP2 knockdown as well. The levels of lipid ROS, iron, and Fe ²⁺ were reduced by circACAP2 depletion in cervical cancer cells. The circACAP2 served as a ceRNA of miR-193a-5p and directly interacted with miR-193a-5p in cervical cancer cells. miR-193a-5p was able to target GPX4 and circACAP2 promoted GPX4 expression by sponging miR-193a-5p in cervical cancer cells. The knockdown of circACAP2 inhibited the cervical cancer cell viability, but the miR-193a-5p inhibitor or GPX4 overexpression could reverse the effect in the cells. The inhibition of miR-193a-5p or GPX4 overexpression repressed the circACAP2 depletion-induced levels of lipid ROS, iron, and Fe ²⁺ in cervical cancer cells. Clinically, the expression of circACAP2 and GPX4 was upregulated, and miR-193a-5p expression was downregulated in clinical cervical cancer samples. The expression of miR-193a-5p was negatively correlated with circACAP2 and GPX4, while the circACAP2 expression was positively correlated with GPX4 in the samples. Therefore, we concluded that circular RNA circACAP2 repressed ferroptosis of cervical cancer during malignant progression by miR-193a-5p/GPX4.