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

Abstract

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.

Chk1-induced CCNB1 overexpression promotes cell proliferation and tumor growth in human colorectal cancer

“…[22][23][24][25][26] In contrast to the well-known utility of Chk1 inhibitors in sensitizing tumors to chemotherapy agents, 23,27,28 Chk1 overexpression or downexpression also occurs in some types of tumors, including breast cancer, ovarian cancer, cervical cancer, and neuroblastoma. 22,[29][30][31][32][33] In our study, we found Chk1 mRNA and protein levels were upregulated in colorectal cancer tissues compared with paired normal tissues, and positively correlated with CCNB1 expression. We hypothesized that CCNB1 might serve as a Chk1-induced oncogene in colorectal cancer.…”

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

“…Of the four most effective miRNAs identified, let-7c and miR200b belong to the let-7 and miRNA-200s families, respectively, of which the tumour-suppressor roles in TICs have been well appreciated 8,23,46 , while miR-222 and miR-424 were first identified as TIC-suppressing miRNAs despite a tumoursuppressor role of both miRNAs has been identified in a number of cancers other than HCC [47][48][49][50] . Paradoxically, miR-222 was previously regarded as oncogene in some reports because it could enhance some tumour cell growth by targeting CDK inhibitor p27 in vitro, and was found to be upregulated in HCC and some other types of cancers 42,51,52 ; however, its tumourpromoting role was rarely validated in vivo.…”

ATM and ATR signaling at a glance

“…Although the current view in the field is that ATM and ATR signaling inhibits tumor progression rather than promoting cancer (Bartkova et al, 2006;Gorgoulis et al, 2005;Halazonetis et al, 2008), there has been a number of recent reports of overexpression of ATM or ATR, or of activation of the downstream pathways in different cancers (Albiges et al, 2014;Bhatia et al, 2013;Hoglund et al, 2011;Mahajan et al, 2012;Sarmento et al, 2015;Tho et al, 2012;Vadnais et al, 2012;Verlinden et al, 2007;Xu et al, 2013) (see poster). Of note, the addition of an extra allele of Chk1 has even been found to promote Ras-or E1A-mediated transformation more efficiently in comparison to such transformation of wild-type littermates (Lopez-Contreras et al, 2012), suggesting that the ATR-Chk1 axis has a pro-malignant transformation role.…”