Abstract
Cervical cancer (CC) is the 4th 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-1α 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-1α expression. Consequently, targeting the hsa_circ_0004543/hsa-miR-217/HIF-1α axis might be a potential treatment approach for CC.
Highlights
Cancer is commonly acknowledged as a worldwide hazard to international development [1]. e latest United Nations high-level meeting on noncommunicable diseases (NCDs) confirmed this statement and further emphasized the slow development in meeting the 2011 Political Declaration on NCD prevention and control [1]. e lack of sufficient molecular mechanisms to detect new biomarkers for early diagnosis, antidrug development, and clinical outcome prognosis has been recognized as the main problems in reaching these goals
Cells cotransfected with hsa-miR-217 mimics or negative control, psiCHECK-2/hsa_circ_0004543 3′-UTR (WT), or psiCHECK2/hsa_circ_0004543 3′-UTR mutated (MT) plasmid were used for hsa_circ_0004543 activity analysis, while cotransfected with psiCHECK-2/HIF-1A 3′-UTR (WT) or psiCHECK-2/HIF-1A 3′-UTR mutated (MT) plasmid were used for HIF-1A activity analysis using Lipofectamine 3000
Discussion circRNAs are noncoding ribonucleic acid (RNA) that are highly stable in eukaryotic cells
Summary
Cancer is commonly acknowledged as a worldwide hazard to international development [1]. e latest United Nations high-level meeting on noncommunicable diseases (NCDs) confirmed this statement and further emphasized the slow development in meeting the 2011 Political Declaration on NCD prevention and control [1]. e lack of sufficient molecular mechanisms to detect new biomarkers for early diagnosis, antidrug development, and clinical outcome prognosis has been recognized as the main problems in reaching these goals. E lack of sufficient molecular mechanisms to detect new biomarkers for early diagnosis, antidrug development, and clinical outcome prognosis has been recognized as the main problems in reaching these goals. To explore the molecular mechanisms involved in the development and progression of CC [7]. It is essential to find out the abnormal circRNAs and the involved new molecular mechanisms to develop the therapeutic targets for CC management. The specific role and related molecular mechanism of hsa_circ_0004543 in CC oncogenesis and metastasis need to be explored further. MiR-217/HIF-1α/AXL signaling has been reported to be involved in lncRNA-HOTAIR-promoted renal cell carcinoma carcinogenesis, which provides a new target for the diagnosis and treatment of renal cell carcinoma [25]. We intend to explore the function and molecular mechanisms of hsa_circ_0004543 in CC oncogenesis and development, providing a potential biomarker for better management of CC. After analyzing the expressions of hsa_circ_0004543, hsa-miR-217, and HIF-1α in 40 paired CC and paracancerous tissues with qRT-PCR, which revealed that hsa_circ_0004543 and HIF-1α were increased, while hsa-miR-217 was decreased in tissues of CC patients; hsa_circ_0004543 was further found to increase HIF-1α expression via sponging hsa-miR-217. us, this promoted CC oncogenesis and development. ese findings may enable the progress of clinical management strategies against CC
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