The novel circCLK3/miR-320a/FoxM1 axis promotes cervical cancer progression

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作者
Hanqing Hong
Hai Zhu
Shujun Zhao
Kaili Wang
Nan Zhang
Yun Tian
Yan Li
Yaping Wang
Xiaofeng Lv
Tianxiang Wei
Yan Liu
Suzhen Fan
Yang Liu
Yuan Li
Aojie Cai
Shuo Jin
Qiaohong Qin
Hongyu Li
机构
[1] The Third Affiliated Hospital of Zhengzhou University,Department of obstetrics and gynecology
[2] Zhengzhou Key Laboratory of Gynecological Oncology,Department of medical genetics and cell biology
[3] School of Basic Medical Sciences of Zhengzhou University,Department of Obstetrics and Gynecology
[4] The First Affiliated Hospital of Zhengzhou University,Genetics and prenatal diagnosis center
[5] The First Affiliated Hospital of Zhengzhou University,undefined
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As a new class of non-coding RNA, circular RNAs (circRNAs) play crucial roles in the development and progression of various cancers. However, the detailed functions of circRNAs in cervical cancer have seldom been reported. In this study, circRNA sequence was applied to detect the differentially expressed circRNAs between cervical cancer tissues and adjacent normal tissues. The relationships between circCLK3 level with clinicopathological characteristics and prognosis were analyzed. In vitro CCK-8, cell count, cell colony, cell wound healing, transwell migration and invasion, and in vivo tumorigenesis and lung metastasis models were performed to evaluate the functions of circCLK3. The pull-down, RNA immunoprecipitation (RIP), luciferase reporter and rescue assays were employed to clarify the interaction between circCLK3 and miR-320a and the regulation of miR-320a on FoxM1. We found that the level of circCLK3 was remarkably higher in cervical cancer tissues than in adjacent normal tissues, and closely associated with tumor differentiation, FIGO stage and depth of stromal invasion. Down-regulated circCLK3 evidently inhibited cell growth and metastasis of cervical cancer in vitro and in vivo, while up-regulated circCLK3 significantly promoted cell growth and metastasis in vitro and in vivo. The pull-down, luciferase reporter and RIP assays demonstrated that circCLK3 directly bound to and sponge miR-320a. MiR-320a suppressed the expression of FoxM1 through directly binding to 3′UTR of FoxM1 mRNA. In addition, FoxM1 promoted cell proliferation, migration, and invasion of cervical cancer, while miR-320a suppressed cell proliferation, migration, and invasion through suppressing FoxM1, and circCLK3 enhanced cell proliferation, migration and invasion through sponging miR-320a and promoting FoxM1 expression. In summary, circCLK3 may serve as a novel diagnostic biomarker for disease progression and a promising molecular target for early diagnoses and treatments of cervical cancer.
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