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. 2019 Jul;25(3):1181-1190.
doi: 10.1007/s12253-018-0552-z. Epub 2019 Jan 12.

MiRNA-195-5p Functions as a Tumor Suppressor and a Predictive of Poor Prognosis in Non-small Cell Lung Cancer by Directly Targeting CIAPIN1

Jing Zheng  1 , Tingting Xu  2 , Feng Chen  1 , Ying Zhang  1
Affiliations

MiRNA-195-5p Functions as a Tumor Suppressor and a Predictive of Poor Prognosis in Non-small Cell Lung Cancer by Directly Targeting CIAPIN1

Jing Zheng et al. Pathol Oncol Res. 2019 Jul.

Erratum in

Abstract

Accumulating evidence suggests that microRNAs (miRNAs) has been proven to be a critical regulator in the tumor progression, of which miR-195-5p was reported to function as tumor suppressor in prostate cancer and oral squamous cell carcinoma. However, studies on the clinical significance and biological function of miR-195-5p in non-small cell lung cancer (NSCLC) were still unavailable. Here, we reported that the expression of miR-195-5p was decreased in NSCLC tissues and cell lines. Downregulation of miR-195-5p was significantly associated with TNM stage, tumor size and lymph node metastasis. The Kaplan-Meier survival analysis demonstrated that the survival time of NSCLC patients with high expression of miR-195-5p was longer than those with low expression during the 5-year follow up period (p = 0.0410). COX regression analysis indicated that miR-195-5p expression was an independent prognostic indicator for the survival of NSCLC patients (HR = 2.45, 95% CI: 1.53-4.63; p = 0.007). Results of functional analyses revealed that overexpression of miR-195-5p in A549 cells inhibited cell proliferation, induced cell cycle G0/G1 phase arrest and apoptosis using MTT and flow cytometry analysis. Furthermore, bioinformatics and luciferase reporter assays demonstrated that cytokine-induced apoptosis inhibitor 1 (CIAPIN1), an anti-apoptotic molecule was a direct target of miR-195-5p in NSCLC cells. Meta-analysis based on Oncomine database showed CIAPIN1 was significantly up-regulated in human lung cancer tissues. Consistently, knockdown of CIAPIN1 phenocopied the inhibitory effects of miR-195-5p overexpression in NSCLC cell function. These findings suggest that miR-195-5p could be used as a potential prognostic predictor and tumor suppressor in NSCLC.

Keywords: CIAPIN1; Non-small cell lung cancer; Overall survival; Prognosis; miR-195-5p.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1. Downregulation of miR-195-5p correlated with poor prognosis of NSCLC.
(a) Relative expression of miR-195-5p in NSCLC samples (n = 60) and adjacent non-cancerous tissues (n = 60) was measured by quantitative real-time PCR. (b) Kaplan-Meier method was evaluate the five-year survival rate of the patients with high (n = 22) and low (n = 38) expression of miR-195-5p
Fig. 2
Fig. 2. Effects of miR-195-5p overexpression on cell proliferation, cell cycle progression and apoptosis in NSCLC cells.
a Expression of miR-195-5p in four NSCLC cell lines and normal bronchial epithelial cell BEAS-2B was determined by qRT-PCR. A549 cells were transfected with miR-195-5p or miR-NC for 48 h, respectively. b The expression of miR-195-5p was measured by quantitative real-time PCR. c Cell proliferation, (d) cell cycle distribution and (e) apoptosis were determined using MTT assay, flow cytometry with PI staining and flow cytometry with Annexin V/PI double staining assay, respectively in A549 cells. All values are represented as mean ± SD of three replicates. *p < 0.05, **p < 0.01, ***p < 0.001 compared with BEAS-2B cells, or miR-NC group
Fig. 3
Fig. 3. CIAPIN1 was a direct target of miR-195-5p in NSCLC.
a Diagrams show the miR-195-5p putative binding sites and corresponding mutant sites of CIAPIN1. b miR-195-5p overexpression significantly suppressed the luciferase activity of CIAPIN1 containing a wild-type (WT) of 3′-UTR but not a mutant (MUT) 3′-UTR in A549 cells. All values are represented as mean ± SD of three replicates. ***p < 0.001 compared with miR-NC group; (c) miR-195-5p overexpression reduced the expression of CIAPIN1 protein in A549 cells
Fig. 4
Fig. 4. CIAPIN1 mRNA expression in lung cancer tissues vs. normal lung tissues was analyzed by using Oncomine microarray database.
a Total seven microarray datasets regarding CIAPIN1 mRNA expression in lung cancer tissues vs. normal were included in our meta-analysis. Data are shown as the median rank of CIAPIN1 through each dataset analysis. P value for CIAPIN1 was presented using the median ranked analysis. b Three datasets, including Selamat Lung, Landi Lung and Okayama Lung were extracted for analyzing CIAPIN1 mRNA expression in NSCLC tissues vs. normal and data were presented as Log2 median-centered intensity
Fig. 5
Fig. 5. Knockdown of CIAPIN1 phenocopied the inhibitory effects of miR-195-5p overexpression in NSCLC.
A549 cells were transfected with siCIAPIN1 or siNC for 48 h. a The expression of CIAPIN1 protein was determined by western blot analysis. b Cell proliferation was determined using MTT assay. c Flow cytomery was performed to detect cell cycle distribution and the percentage of cells at G0/G1, S and G2/M phase was calculated. d Flow cytometry was used to detect cell apoptosis. All values are represented as mean ± SD of three replicates. ***p < 0.01, ***p < 0.001 compared with siNC group
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