Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, Liaoning Province, People's Republic of China.
Department of Pathology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, China.
J Exp Clin Cancer Res. 2021 Jan 30;40(1):48. doi: 10.1186/s13046-021-01849-2.
As a novel type of non-coding RNA, circular RNAs (circRNAs) play a critical role in the initiation and development of various diseases, including cancer. However, the exact function of circRNAs in human cervical cancer remains largely unknown.
We identified the circRNA signature of upregulated circRNAs between cervical cancer and paired adjacent normal tissues. Using two different cohorts and GEO database, a total of six upregulated circRNAs were identified with a fold change > 2, and P < 0.05. Among these six circRNAs, hsa_circ_0072088 (circZFR) was the only exonic circRNA significantly overexpressed in cervical cancer. Functional experiments were performed to investigate the biological function of circZFR. CircRNA pull-down, circRNA immunoprecipitation (circRIP) and Co-immunoprecipitation (Co-IP) assays were executed to investigate the molecular mechanism underlying the function of circZFR.
Functionally, circZFR knockdown represses the proliferation, invasion, and tumor growth. Furthermore, circRNA pull-down experiments combined with mass spectrometry unveil the interactions of circZFR with Single-Stranded DNA Binding Protein 1 (SSBP1). Mechanistically, circZFR bound with SSBP1, thereby promoting the assembly of CDK2/cyclin E1 complexes. The activation of CDK2/cyclin E1 complexes induced p-Rb phosphorylation, thus releasing activated E2F1 leading to cell cycle progression and cell proliferation.
Our findings provide the first evidence that circZFR is a novel onco-circRNA and might be a potential biomarker and therapeutic target for cervical cancer patients.
作为一种新型的非编码 RNA，circRNAs 在包括癌症在内的各种疾病的发生和发展中起着关键作用。然而，circRNAs 在人宫颈癌中的确切功能仍知之甚少。
我们鉴定了宫颈癌与配对的相邻正常组织之间上调的 circRNA 的 circRNA 特征。使用两个不同的队列和 GEO 数据库，总共鉴定出 6 个上调的 circRNA，其 fold change > 2，且 P < 0.05。在这 6 个 circRNA 中，hsa_circ_0072088（circZFR）是唯一在宫颈癌中显著过表达的外显 circRNA。进行了功能实验以研究 circZFR 的生物学功能。进行了 circRNA 下拉、circRNA 免疫沉淀（circRIP）和 Co-免疫沉淀（Co-IP）实验，以研究 circZFR 功能的分子机制。
功能上，circZFR 敲低抑制了增殖、侵袭和肿瘤生长。此外，circRNA 下拉实验结合质谱揭示了 circZFR 与单链 DNA 结合蛋白 1（SSBP1）的相互作用。机制上，circZFR 与 SSBP1 结合，从而促进 CDK2/细胞周期蛋白 E1 复合物的组装。CDK2/细胞周期蛋白 E1 复合物的激活诱导 p-Rb 磷酸化，从而释放激活的 E2F1 导致细胞周期进程和细胞增殖。
我们的研究结果首次提供了证据表明 circZFR 是一种新型的癌相关 circRNA，可能是宫颈癌患者的潜在生物标志物和治疗靶点。
