Liu Jun, Liu Yingqiao, Zhang Yang, Zheng Jing, Wang Shuzhen, Cao Guangming
Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
Department of Obstetrics and Gynecology, Lu-He Teaching Hospital, Capital Medical University, Beijing, China.
J Oncol. 2022 Mar 9;2022:4031403. doi: 10.1155/2022/4031403. eCollection 2022.
Cervical cancer (CC) is the 4 principal source of cancer death in females with 604,000 new patients and 342,000 deaths in 2020 worldwide. It has been extensively shown that circRNAs are involved in regulating CC development. Nevertheless, the function and mechanisms of hsa_circ_0004543 in regulating CC need to be clearly elucidated. Herein, hsa_circ_0004543 expressions were compared between 40 paired paracancerous and cancerous specimens from CC patients and between 6 CC cell lines and a normal human cervical epithelial cell line based on qRT-PCR. Potential complementary binding sites between hsa-miR-217 and hsa_circ_0004543 were predicted using the interactome, while binding sites for the hypoxia-inducible factor-1a (HIF-1a) were predicted by TargetScan. The function and mechanism of hsa_circ_0004543 in the development of CC were estimated by silencing hsa_circ_0004543 with/without hsa-miR-217 or HIF-1a overexpression. The association between gene expressions was evaluated with Pearson's correlation analysis. Molecular mechanisms were explored by ribonucleic acid (RNA) pulldown, dual-luciferase activity, and rescue experimental assays. Our results revealed that the hsa_circ_0004543 expression was considerably increased in CC tissues and cells. Its silencing repressed proliferation and metastasis, while it increased apoptosis of CC cells. The investigation of the mechanism showed that hsa-miR-217 silencing or HIF-1a overexpression rescued hsa_circ_0004543, and silencing inhibited malignant phenotypes of CC cells. hsa_circ_0004543 upregulated the HIF-1 expression by sponging hsa-miR-217 in CC development. Therefore, the hsa_circ_0004543 functioned as a competing endogenous RNA (ceRNA) of hsa-miR-217 to increase CC oncogenesis and metastasis by the upregulation of the HIF-1 expression. Consequently, targeting the hsa_circ_0004543/hsa-miR-217/HIF-1 axis might be a potential treatment approach for CC.
宫颈癌（CC）是女性癌症死亡的第四大主要原因，2020年全球有60.4万新发病例和34.2万例死亡。已有大量研究表明，环状RNA（circRNAs）参与调控宫颈癌的发展。然而，hsa_circ_0004543在调控宫颈癌中的功能和机制仍需进一步明确。在此，基于qRT-PCR技术，比较了40对宫颈癌患者癌旁组织与癌组织标本以及6种宫颈癌细胞系与1种正常人宫颈上皮细胞系中hsa_circ_0004543的表达情况。利用相互作用组预测hsa-miR-217与hsa_circ_0004543之间的潜在互补结合位点，同时通过TargetScan预测缺氧诱导因子-1α（HIF-1α）的结合位点。通过沉默hsa_circ_0004543并过表达或不表达hsa-miR-217或HIF-1α，评估hsa_circ_0004543在宫颈癌发生发展中的功能和机制。采用Pearson相关分析评估基因表达之间的关联。通过RNA下拉实验、双荧光素酶活性实验和拯救实验探究分子机制。我们的结果显示，hsa_circ_0004543在宫颈癌组织和细胞中的表达显著增加。沉默hsa_circ_0004543可抑制宫颈癌细胞的增殖和转移，同时增加其凋亡。机制研究表明，沉默hsa-miR-217或过表达HIF-1α可挽救hsa_circ_0004543沉默对宫颈癌细胞恶性表型的抑制作用。在宫颈癌发生发展过程中，hsa_circ_0004543通过吸附hsa-miR-217上调HIF-1的表达。因此，hsa_circ_0004543作为hsa-miR-217的竞争性内源RNA（ceRNA），通过上调HIF-1的表达促进宫颈癌的发生和转移。因此，靶向hsa_circ_0004543/hsa-miR-217/HIF-1轴可能是一种潜在的宫颈癌治疗方法。
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