<p>Circular RNA HIPK3 Promotes EMT of Cervical Cancer Through Sponging miR-338-3p to Up-Regulate HIF-1α</p>

Abstract

Background: Cervical cancer (CC) is the 4th most common malignancy and cancer-related fatality in women worldwide. Circular RNA is a newly recognized noncoding RNA form. More reports have confirmed their important regulatory functions in diverse physiological and cancer processes. However, the function and mechanisms of circ-HIPK3 in CC remain unknown. Methods: circ-HIPK3 expression status was verified between 45 paired CC and normal adjacent tissues from 45 CC patients, also the 6 CC cell lines and a normal human cervical epithelial End1/E6E7 cell line by qRT-PCR. Effects of circ-HIPK3 silence on CC cell phenotypes were estimated. Circular RNA interactome was applied to forecast binding site between circ-HIPK3 and miRNAs. Pearson correlation analysis was used to confirm the relationship between genes. Point mutation, RNA pull-down, luciferase assay and rescue experiments were applied for molecular mechanism exploration. Results: circ-HIPK3 expression was significantly elevated in CC cells and tissues. circ-HIPK3 silence repressed growth and metastasis, while induced apoptosis in CC cells. circ-HIPK3 sponged miRNA-338-3p (miR-338-3p); miR-338-3p to up-regulate hypoxia-inducible factor-1α (HIF-1α) and CC progress. MiR-338-3p silence or HIF-1α over-expression rescued circ-HIPK3 knockdown caused inhibition of CC malignant characteristics. Conclusion: circ-HIPK3 acts as a competing endogenous RNA of miR-338-3p to promote cell growth and metastasis in CC, via regulating HIF-1α mediated EMT. Therefore, targeting circ-HIPK3/miR-338-3p/HIF-1α axis may be a novel therapeutic strategy for CC.

The Expression, Functions and Mechanisms of Circular RNAs in Gynecological Cancers

“…CircCLK3 induces the levels of FOXM1 via sponging miR-320a, and overexpression of FOXM1 could trigger EMT-like changes, including the acquisition of Vimentin and N-cadherin expression and reduction of E-cadherin expression [99]. Also, the upregulation of circ0067934, circ0000745, ciRS-7 and circHIPK3 in CC cells was shown to increase the expression of mesenchymal markers and decrease the expression of epithelial markers [80,89,100,104]. Inactivation of p53 in human tumors occurs through missense mutations in the DNA-binding domain of the p53 protein, and can also result from the amplification/overexpression of its specific inhibitors (such as MDM2 and MDM4) [112].…”

“…Epithelial-mesenchymal transition (EMT) is a biological process in which epithelial cells acquire mesenchymal phenotypes, thus conferring the malignant properties to cancer cells including invasive behaviors, cancer stem cell properties, and greater resistance to cancer treatment [110]. Experimental studies have revealed that circRNAs affect the EMT program in human cancers (including CC) through different mechanisms [77,80,89,99,100,104,111]. For instance, circ000284 indirectly increases Snail-2 expression to promote EMT and invasion of CC cells through sponging miR-506 [77].…”

“…High-risk subtypes (16 and 18) of human papillomavirus (HPV) are well established as the causative agents responsible for CC [ 69 ]. Massive studies have shown that a large number of circRNAs were differentially expressed in CC tissues compared with adjacent normal cervical tissues, and play oncogenic or tumor-suppressive roles in the initiation and progression of CC [ 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 ]. All of the circRNAs that are abnormally expressed in CC are summarized in Table 1 , and their functions in CC are shown in Figure 3 .…”

CircAMOTL1 Promotes Tumorigenesis Through miR-526b/SIK2 Axis in Cervical Cancer

“…circRNAs act as important roles in the development and progression of cancers and are involved in various biological processes, such as cell proliferation, apoptosis, and migration by regulating gene expression ( Liu et al, 2019 ; Di Agostino et al, 2020 ; Ji et al, 2020 ; Tang and Chen, 2020 ; Wang et al, 2020c ). Mangy circRNAs have been reported to play important functions in cervical cancers, such as hsa_circ_0000515 ( Tang and Chen, 2020 ), has_ circ_0000388 ( Meng et al, 2020 ), circ-HIPK3 ( Qian and Huang, 2020 ), circ-ITCH ( Li et al, 2020 ; Wu et al, 2020b ), circCLK3 ( Jin et al, 2020 ), etc. However, the role and mechanism of circAMOTL1 in the cervical cancer are thoroughly unclear.…”

Emerging Roles and Potential Biological Value of CircRNA in Osteosarcoma

“…CircRNAs have been studied in a variety of human tumor types, including those affecting the reproductive and urinary systems, digestive system, nervous system, respiratory system, etc. (17)(18)(19)(20)(21). Currently, the enormous potential for circRNA use in targeted therapy and as a noninvasive biomarker has garnered much attention from the broader scientific community (22).…”