Circular RNA hsa_circ_0004543 Aggravates Cervical Cancer Development by Sponging MicroRNA hsa-miR-217 to Upregulate Hypoxia-Inducible Factor

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.

Emerging Roles of CircRNAs in Tumor Microenvironment

“…51 However, Jun Liu et al confirmed the high expression of circ 0004543 in cervical cancer tissues and cell lines and its upstream regulation mechanism of HIF1α, i.e., circ 0004543 binds to hsa-miR-217 to increase the expression of HIF-1a, triggering tumorgenesis, providing us with a novel possible therapeutic target. 52 Xiwu Ouyang et al focused on the phenomenon of androgen receptor (AR) restraining HCC progression in hypoxia and demonstrated that AR/circ-LNPEP/miR-532-3p/RAB9A axis are involved; the following rescue assay also demonstrated the function and the core role in the regulation. 53 Metabolic reprogramming is a hallmark of malignancy with the deepening understanding of tumor biology and the complexity of tumor metabolism.…”

Prevalence and predictive value of sarcopenia in surgically treated cholangiocarcinoma: a comprehensive review and meta-analysis

“…In recent decades, the global incidence of cholangiocarcinoma has increased, particularly in Asian nations ( 6 ). Presently, the predominant approach for the treatment of most patients with cholangiocarcinoma is surgical resection in conjunction with chemotherapy or chemoradiation ( 7 ). Nevertheless, post-surgery, chemotherapy, and chemoradiation frequently give rise to a range of complications and adverse reactions, thereby contributing to an unfavorable prognosis for patients.…”