Prognostic significance of low DICER expression regulated by miR-130a in cervical cancer.

L He,W-H Jia,H-Y Wang,M-Y Zhang,L Zhang,J-D Li,L Huang,M Zheng,R-Z Luo,J-P Yun,Y Xiong

doi:10.1038/cddis.2014.127

Abstract

Dicer is crucial for the maturation of microRNAs (miRNAs) and its dysregulation may contribute to tumor initiation and progression. The study explored the clinical implications of Dicer and its post-transcriptional regulation by microRNAs in cervical cancer. qRT-PCR and immunohistochemistry investigated Dicer mRNA and protein levels in cervical cancer tissues. The relationship between Dicer expression and survival was analyzed. MiRNA target prediction identified miRNAs that might target Dicer. Luciferase reporter and gain- or loss-of-function assays were performed. The results showed that 36.7% of cervical cancer cases showed low expression of Dicer mRNA and 63.3% cases showed high expression. At the protein level, 51% cases showed negative expression and 49% cases showed positive expression. Dicer mRNA and protein expressions were significantly associated with distant metastasis and recurrence in cervical cancer (P=0.002 and P=0.012, respectively). Multivariate Cox analysis indicated that low Dicer expression (P=0.016) and tumor stage (P=0.047) were independent predictors. Among the miRNAs predicted to target Dicer, 10 were detected by RT-PCR; their expressions were significantly higher in cervical cancers with lower Dicer expression than in those with higher Dicer expression and were negatively correlated with Dicer expression level (P<0.05). In vitro experiments demonstrated that miR-130a directly targeted Dicer mRNA to enhance migration and invasion in SiHa cells. Finally, survival analysis indicated that higher expression of miR-130a was significantly associated with poor disease-free survival. Taken together, Dicer expression regulated by miR-130a is an important potential prognostic factor in cervical cancer.

Highlights

Low Dicer expression is associated with worse clinical outcomes in lung cancer,[5] breast cancer,[6] and endometrial adenocarcinoma.[7]
Low Dicer expression was observed in 36.7% of samples; high Dicer mRNA expression was observed in 63.3% of samples
To determine whether Dicer mRNA levels reflected protein expression, 102 cervical cancers specimens, including samples from the same 90 cases detected by qRT-PCR, were examined using immunohistochemistry (IHC) (Table 1)

Summary

Introduction

Low Dicer expression is associated with worse clinical outcomes in lung cancer,[5] breast cancer,[6] and endometrial adenocarcinoma.[7]. MiRNAs are small non-coding RNAs that modulate gene expression, mainly by base pairing to the 30-untranslated region (UTR) of the target mRNA post-transcriptionally.[9] They are predicted to control 460% of human genes.[10] They have important roles in development, cellular differentiation, proliferation, cell cycle control and cell death,[11] and have been implicated in a variety of human diseases, including cancer.[11,12] For example, miRNA-130a antagonizes the inhibitory effects of GAX on endothelial cell proliferation, migration, and the inhibitory effects of HoxA5 on tube formation in vitro.[13] MiRNA-130a overexpression was associated with lymph node metastasis and poor prognosis of non-small cell lung cancer (NSCLC).[14] Higher expression of. There is increasing evidence that the expression of miRNA genes is aberrant in cervical cancer, and a subset of miRNAs is identified that correlate with disease stage and recurrence.[17,18,19] Till there has been no study on Dicer expression in cervical carcinoma

Methods

Results

Conclusion