Circular RNA circLMO1 Suppresses Cervical Cancer Growth and Metastasis by Triggering miR-4291/ACSL4-Mediated Ferroptosis

Abstract

BackgroundA number of studies have demonstrated that circular RNA (circRNA) plays a critical role in tumorigenesis and tumor progression. However, the biological effects of most circRNAs on cervical cancer remain unclear. Hsa_circ_0021087 (thereafter named circLMO1) is a circRNA generated from the circularization of exon 2 and exon 3 of LIM Domain Only 1 (LMO1) and first identified as a tumor suppressor in gastric cancer. We aimed to identify the role of circLMO1 in cervical cancer progression.MethodsCircLMO1 was verified through qPCR and Sanger sequencing. The biological role of circLMO1 in regulating cervical cancer growth and metastasis was investigated both in vitro and in the nude mouse xenograft tumor model. The dual luciferase reporter assay and rescue experiment were conducted to evaluate the interactions among circLMO1, microRNA (miR)-4291, and acyl-CoA synthetase long chain family member 4 (ACSL4). The role of circLMO1 in regulating ferroptosis was assessed by analyzing lipid reactive oxygen species (ROS), and malonyl dialdehyde (MDA), and glutathione (GSH) content.ResultsThe level of circLMO1 was down-regulated in cervical cancer tissues and was associated with the International Federation of Gynecology and Obstetrics (FIGO) staging. Functionally, circLMO1 overexpression inhibited cervical cancer growth and metastasis both in vitro and in vivo, whereas circLMO1 depletion promoted cervical cancer cell proliferation and invasion. Mechanistically, circLMO1 acted as a competing endogenous RNA (ceRNA) by sponging miR-4192 to repress target gene ACSL4. CircLMO1 promoted cervical cancer cell ferroptosis through up-regulating ACSL4 expression. Overexpression of miR-4291 or knockdown of ACSL4 reversed the effect of circLMO1 on facilitating ferroptosis and repressing cervical cancer cell proliferation and invasion.ConclusionCircLMO1 acted as a tumor suppressor of cervical cancer by regulating miR-4291/ACSL4-mediated ferroptosis, and could be a promising biomarker for the clinical management of cervical cancer.

ACSL4 as a Potential Target and Biomarker for Anticancer: From Molecular Mechanisms to Clinical Therapeutics

“…Moreover, previous studies have clarified that circular RNA (circRNA) could participate in inhibiting tumorigenesis and tumor progression. Ou et al (2022) found circular RNA (CircLMO1) could inhibit cervical cancer proliferation by activating ACSL4-induced ferroptosis, and could be a promising anti-cancer biomarker for cervical cancer. As for chemotherapy treatment of cervical cancer, ACSL4-mediated ferroptosis could play an important role in propofol synergistic anticancer effects with paclitaxel ( Zhao et al, 2022 ).…”

Regulation of Ferroptosis by Non-Coding RNAs: Mechanistic Insights

“…Tumor suppressive roles: circLMO1 antagonized miR-4192-mediated targeting of ACSL4 in cervical cancer cells (Ou et al, 2022). circLMO1 potently hampered proliferation and invasion capacities of CaSki cells, whereas ACSL4 depletion or miR-4291 overexpression exerted inhibitory effects on circLMO1mediated tumor suppressive effects.…”

“…Levels of circP4HB and SLC7A11 were increased in the tumor xenografts in mice injected with circP4HBoverexpressing cells (Pan et al, 2022). circ-BGN, an oncogenic circular RNA is frequently overexpressed in trastuzumab resistant-breast cancer cells (Wang et al, 2022). OTUB1 is a deubiquitinating enzyme and it de-ubiquitinates SLC7A11.…”

“…Importantly, circ-BGN interacted with OTUB1 and rapidly enhanced OTUB1-driven de-ubiquitination of SLC7A11. Orthotopically implanted tumor model clearly revealed that erastin and circ-BGN inhibition considerably impaired tumor growth by trastuzumab-resistant breast cancer cells (Wang et al, 2022). circCDK14 sponged miR-3938 and upregulated PDGFRA in glioma cells (Chen et al, 2022).…”

Emerging Roles and Potential Applications of Non-Coding RNAs in Cervical Cancer

“…CircLMO1 overexpression inhibited the growth and metastasis of CC cells both in vitro and in vivo whereas its knockdown increased the proliferation and invasion of CC cells. Mechanistically, CircLMO1 functioned as a competitive endogenous RNA (ceRNA) by sponging miR-4192 to inhibit target gene ACSL4, suggesting that it might be a promising biomarker for the clinical management of CC [ 91 ]. In depth research suggests that several miRNAs play a prominent role in CC suppression, many of which are listed in Table 2 .…”