Suppressed miR-424 expression via upregulation of target gene Chk1 contributes to the progression of cervical cancer

被引:201
作者
Xu, J. [1 ]
Li, Y. [1 ]
Wang, F. [1 ]
Wang, X. [2 ]
Cheng, B. [2 ]
Ye, F. [1 ]
Xie, X. [2 ]
Zhou, C. [3 ]
Lu, W. [2 ]
机构
[1] Zhejiang Univ, Sch Med, Womens Hosp, Womens Reprod Hlth Lab Zhejiang Prov, Hangzhou 310006, Zhejiang, Peoples R China
[2] Zhejiang Univ, Sch Med, Womens Hosp, Dept Gynecol Oncol, Hangzhou 310006, Zhejiang, Peoples R China
[3] Zhejiang Univ, Sch Med, Womens Hosp, Dept Pathol, Hangzhou 310006, Zhejiang, Peoples R China
基金
中国国家自然科学基金;
关键词
miR-424; cervical cancer; progression; Chk1; p-Chk1; SQUAMOUS-CELL CARCINOMAS; MICRORNA MIR-21; BREAST-CANCER; CHECKPOINT; IDENTIFICATION; PROFILES; TONGUE; MMP9;
D O I
10.1038/onc.2012.121
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
MicroRNAs (miRNAs) act as important gene regulators in human genomes and their aberrant expression links to many malignancies. We previously identified a different characteristic miRNA expression profile in cervical cancer from that in cervical normal tissues, including the downregulated miR-424. However, the role and mechanism of miR-424 in cervical cancer still remain unknown. Here, we focused on identifying the tumor-suppressive function and clinical significance of miR-424 and exploring the mechanistic relevance by characterizing its target. We showed a significantly decreased expression of miR-424 in 147 cervical cancer tissues versus 74 cervical normal tissues by performing quantitative RT-PCR. In 147 cervical cancer tissue samples, low-level expression of miR-424 was positively correlated with poor tumor differentiation, advanced clinical stage, lymph node metastasis and other poor prognostic clinicopathological parameters. Further in vitro observations showed that enforced expression of miR-424 inhibited cell growth by both enhancing apoptosis and blocking G1/S transition, and suppressed cell migration and invasion in two human cervical cancer cell lines, SiHa and CaSki, implying that miR-424 functions as a tumor suppressor in the progression of cervical cancer. Interestingly, overexpression of miR-424 inhibited the expression of protein checkpoint kinase 1 (Chk1) and phosphorylated Chk1 (p-Chk1) at residues Ser345 and decreased the activity of luciferase-reporter containing the 3'-untranslated region (UTR) of Chk1 with predicted miR-424-binding site. Moreover, miR-424 expression levels were inversely correlated with Chk1 and p-Chk1 protein levels in both cervical cancer and normal tissues. Furthermore, RNAi-mediated knockdown of Chk1 decreased matrix metalloproteinase 9 expression and phenocopied the tumor suppressive effects of miR-424 in cell models. Taken together, our results identify a crucial tumor suppressive role of miR-424 in the progression of cervical cancer at least partly via upreglating the expression of Chk1 and p-Chk1, and suggest that miR-424 might be a candidate of prognostic predictor or an anticancer therapeutic target for cervical cancer patients. Oncogene (2013) 32, 976-987; doi:10.1038/onc.2012.121; published online 2 April 2012
引用
收藏
页码:976 / 987
页数:12
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