Ou Rongying, Lu Shun, Wang Luhui, Wang Yebo, Lv Mingfen, Li Tian, Xu Yunsheng, Lu Jieqiang, Ge Ren-Shan
Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China.
Department of Obstetrics and Gynecology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
Front Oncol. 2022 Mar 7;12:858598. doi: 10.3389/fonc.2022.858598. eCollection 2022.
A 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 () and first identified as a tumor suppressor in gastric cancer. We aimed to identify the role of circLMO1 in cervical cancer progression.
CircLMO1 was verified through qPCR and Sanger sequencing. The biological role of circLMO1 in regulating cervical cancer growth and metastasis was investigated both 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.
The 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 and , 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 . 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.
CircLMO1 acted as a tumor suppressor of cervical cancer by regulating miR-4291/-mediated ferroptosis, and could be a promising biomarker for the clinical management of cervical cancer.
多项研究表明，环状RNA（circRNA）在肿瘤发生和肿瘤进展中起关键作用。然而，大多数circRNA对宫颈癌的生物学效应仍不清楚。Hsa_circ_0021087（以下简称circLMO1）是一种由仅含LIM结构域1（LMO1）的第2外显子和第3外显子环化产生的circRNA，最初在胃癌中被鉴定为肿瘤抑制因子。我们旨在确定circLMO1在宫颈癌进展中的作用。
通过qPCR和Sanger测序验证circLMO1。在体外和裸鼠异种移植瘤模型中研究circLMO1在调节宫颈癌生长和转移中的生物学作用。进行双荧光素酶报告基因检测和挽救实验，以评估circLMO1、微小RNA（miR）-4291和酰基辅酶A合成酶长链家族成员4（ACSL4）之间的相互作用。通过分析脂质活性氧（ROS）、丙二醛（MDA）和谷胱甘肽（GSH）含量，评估circLMO1在调节铁死亡中的作用。
circLMO1在宫颈癌组织中的水平下调，且与国际妇产科联盟（FIGO）分期相关。在功能上，circLMO1过表达在体外和体内均抑制宫颈癌的生长和转移，而circLMO1缺失则促进宫颈癌细胞的增殖和侵袭。机制上，circLMO1通过海绵吸附miR-4291作为竞争性内源RNA（ceRNA）来抑制靶基因ACSL4。circLMO1通过上调ACSL4表达促进宫颈癌细胞铁死亡。miR-4291过表达或ACSL4敲低可逆转circLMO1对促进铁死亡和抑制宫颈癌细胞增殖及侵袭的作用。
circLMO1通过调节miR-4291/ACSL4介导的铁死亡发挥宫颈癌肿瘤抑制因子的作用，可能成为宫颈癌临床管理中有前景的生物标志物。
