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,Tingting Xu,Feng Chen,Ying Zhang

doi:10.1007/s12253-018-0552-z

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.

Highlights

Non-small-cell lung cancer (NSCLC) is considered as the major subtype of lung cancer with accounting for 85%–90% of all cases [1]
Using the Chi-square analysis, we found decreased miR-195-5p expression was significantly correlated with tumor size (p = 0.031), TNM stage (p = 0.012) and lymph node metastasis (p = 0.006) (Table 1)
The present study provided evidence that miR-195-5p is significantly downregulated in NSCLC tissues and cell lines and that miR-195-5p acts as tumor suppressor in NSCLC in vitro

Summary

Introduction

Non-small-cell lung cancer (NSCLC) is considered as the major subtype of lung cancer with accounting for 85%–90% of all cases [1]. Despite great advances in surgery, adjuvant therapy, stereotactic radiotherapy, the 5-year overall survival (OS) rate of NSCLC patients remains very poor [3]. Recent key miRNAs including miR-21 [6], miR-451 [7], miR-126 [8], and miR-30a [9] have been shown to be deregulated in NSCLC and play a key role in cancer progression and metastasis. Down-regulation of miR-375 was found to be associated with advanced NSCLC stage and lymphatic metastasis [10]. It has been shown that miR-195-5p is increased in gemicitabine-resistant NSCLC cells provides the first suggestion of miR-195-5p may be associated with cellular response to drug treatment [11]. Novel diagnostic value of serum miR-195-5p and its role as a prognostic factor was revealed in NSCLC cancer [12]. The measurement and clinical significance of miR-195-5p in NSCLC remains undefined

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