MicroRNA-130b promotes lung cancer progression via PPARγ/VEGF-A/BCL-2-mediated suppression of apoptosis.

Jianwei Tian,Xiao Li,Xiaoyan Bai,Jian Geng,Liping Hu,Meng Dai

doi:10.1186/s13046-016-0382-3

Abstract

BackgroundThe prognosis of non-small-cell lung cancer (NSCLC) is poor yet mechanistic understanding and therapeutic options remain limited. We investigated the biological and clinical significance of microRNA-130b and its relationship with apoptosis in NSCLC.MethodsThe level of microRNA-130b in relationship with the expression of PPARγ, VEGF-A, BCL-2 and apoptosis were analyzed in 91 lung cancer patient samples using immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay on tissue microarrays. Gain and loss-of-function studies were performed to investigate the effects of microRNA-130b, peroxisome proliferator-activated receptor γ (PPARγ) or vascular endothelial growth factor-A (VEGF-A) on biological functions of lung cancer cells using in vitro and in vivo approaches.ResultsMicroRNA-130b up-regulation conferred unfavorable prognosis of lung cancer patients. Notably, microRNA-130b targeted PPARγ and inhibiting microRNA-130b markedly repressed proliferation, invasion and metastasis of lung cancer cells, leading to increased apoptosis. MicroRNA-130b-dependent biologic effects were due to suppression of PPARγ that in turn activated BCL-2, the key mediator of anti-apoptosis. Administration of microRNA-130b mimic to mouse xenografts promoted tumor growth. In vitro and in vivo, miR-130b enrichment associated with down-regulation of PPARγ, up-regulation of VEGF-A and BCL-2, and decreased apoptosis.ConclusionsThe present study demonstrates that microRNA-130b promotes lung cancer progression via PPARγ/VEGF-A/BCL-2-mediated suppression of apoptosis. Targeting microRNA-130b might have remarkable therapeutic potential for lung cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0382-3) contains supplementary material, which is available to authorized users.

Highlights

The prognosis of non-small-cell lung cancer (NSCLC) is poor yet mechanistic understanding and therapeutic options remain limited
High miR-130b level corresponded with low peroxisome proliferator-activated receptor γ (PPARγ), high vascular endothelial growth factor-A (VEGF-A) and BCL-2, and decreased apoptosis (Figs. 1b, c and d)
Immunofluorescence co-labeling and Pearson correlation analysis (Fig. 2) revealed that PPARγ expression negatively correlated with VEGF-A (r = −0.351, p = 0.001), and VEGF-A positively correlated with BCL-2 (r = 0.328, p = 0.002)

Summary

Introduction

The prognosis of non-small-cell lung cancer (NSCLC) is poor yet mechanistic understanding and therapeutic options remain limited. Several microRNAs (miRNAs), such as miR-21, miR-152, miR-148b and miR-208a, play critical roles in lung cancer progression through modulating growth, apoptosis, metastasis and invasion [1,2,3,4]. A recent study has identified microRNA-130 (miR-130) as a contributor in mesenchymal differentiation, hypoxic response modulation and tumorigenesis in colorectal cancer [5]. Peroxisome proliferator-activated receptor γ (PPARγ), acting as a tumor suppressor, exerts an essential role in modulating tumor proliferation, differentiation, apoptosis and invasion [9,10,11]. Combined treatment with the cyclo-oxygenase-2 (Cox-2) inhibitor niflumic acid and PPARγ ligand ciglitazone induces endoplasmic reticulum stress/caspase-8-mediated apoptosis in human lung cancer cells [12]. Treatment of human NSCLC lines with PPARγ ligands results in growth arrest, loss of capacity and induction of apoptosis [13]. PPARresponse element (PPRE) has been identified in the human vascular endothelial growth factor-A (VEGF-A) promoter region [14] and PPARγ ligands have been

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Conclusion