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Abstract：
Background. Tripartite motif-containing 22 (TRIM22) is characterized by a canonical RING domain with ubiquitin E3 ligase activity and is closely associated with tumorigenesis. As a product of TRIM22 transcription, whether hsa_circ_TRIM22 has a function of regulating tumorigenesis is unclear. Thus, we aimed to explore the role and mechanism of hsa_circ_TRIM22 in human papillomavirus (HPV) 16 positive cervical cancer (CC). Methods. We collected HPV16-positive cervical tissues including chronic cervicitis, high-grade squamous intraepithelial lesions (HSIL), low-grade squamous intraepithelial lesions (LSIL), and CC, and along with CC cell lines to detect the hsa_circ_TRIM22 level using real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). Hsa_circ_TRIM22 was silenced using specific short hairpin ribonucleic acid (shRNA) in CC cell lines and functional assays were performed thereafter. Mechanistically, the targeting and regulatory relationship between hsa_circ_TRIM22 and miR-154-5p were confirmed using the luciferase report assay and rescue experiments. Results. We found hsa_circ_TRIM22 expression level was significantly higher in CC cells and tissues. Further, hsa_circ_TRIM22 knockdown inhibited migration, proliferation, invasiveness, enhanced apoptosis, and slowed the cell cycle. Mechanistically, hsa_circ_TRIM22 could bind miR-154-5p and prevent miR-154-5p from reducing the levels of Cullin2 (CUL2). Notably, the application of miR-154-5p inhibitor significantly rescued hsa_circ_TRIM22-mediated tumorigenesis. Conclusions. Our observations suggest hsa_circ_TRIM22 is upregulated in HPV16-positive CC and promotes CC progression by regulating the miR-154-5p/CUL2 axis, thereby serving as a promising candidate for diagnosis and treatments of CC.
摘要：
背景。含有三方基序的22（TRIM22）的特征在于具有泛素E3连接酶活性的规范RING结构域，并且与肿瘤发生密切相关。作为TRIM22转录的产物，hsa_circ_TRIM22是否具有调节肿瘤发生的功能尚不清楚。因此，我们旨在探讨hsa_circ_TRIM22在人乳头瘤病毒（HPV）16阳性宫颈癌（CC）中的作用和机制。方法。我们收集了HPV16阳性宫颈组织，包括慢性宫颈炎，高级别鳞状上皮内病变（HSIL），低度鳞状上皮内病变（LSIL），CC,并与CC细胞系一起使用实时荧光定量聚合酶链反应（RT-qPCR）检测hsa_circ_TRIM22水平。在CC细胞系中使用特异性短发夹核糖核酸(shRNA)沉默Hsa_circ_TRIM22,然后进行功能测定。机械上,hsa_circ_TRIM22和miR-154-5p之间的靶向和调控关系使用荧光素酶报告测定和拯救实验进行确认。结果。我们发现hsa_circ_TRIM22在CC细胞和组织中的表达水平显着升高。Further,hsa_circ_TRIM22敲低抑制迁移，扩散,侵入性,细胞凋亡增强，减缓了细胞周期。机械上,hsa_circ_TRIM22可以结合miR-154-5p并阻止miR-154-5p降低Cullin2(CUL2)的水平。值得注意的是,miR-154-5p抑制剂的应用显着挽救了hsa_circ_TRIM22介导的肿瘤发生。Conclusions.我们的观察表明hsa_circ_TRIM22在HPV16阳性CC中上调，并通过调节miR-154-5p/CUL2轴来促进CC进展。从而成为CC诊断和治疗的有希望的候选者。
