MicroRNA-125b promotes tumor metastasis through targeting tumor protein 53-induced nuclear protein 1 in patients with non-small-cell lung cancer

Cancer Cell International, Sep 2015

Background Lung cancer, predominantly non-small-cell lung cancer (NSCLC), is the leading cause of cancer deaths worldwide. There is a great need to identify critical effectors involved in metastasis of NSCLC that will facilitate the development of new therapeutic strategies. Here we evaluated the potential role of miR-125b in the metastasis of NSCLC cells. Methods Human NSCLC cells were isolated from surgical tissues with Cancer Cell Isolation Kit. Expressions of miR-125b and TP53INP1 were detected with real-time PCR and western blot. Human miR-125b mimics, miR-125b inhibitor, TP53INP1 expression plasmid and TP53INP1 siRNA were transfected into NSCLC cells with nucleofector transfection kit. NSCLC metastasis was determined with adhesion assay, invasive assay and lung tumor metastasis model. Results The expression of miR-125b was significantly higher in poorly differentiated NSCLC cells that are endowed with high metastatic potentials. Up-regulation of miR-125b could enhance the metastatic potential of NSCLC cells in vitro and in vivo, while down-regulation of miR-125b resulted in decreased metastatic potentials in vitro and in vivo. Further, tumor protein 53-induced nuclear protein 1 (TP53INP1) was an important target of miR-125b involved in metastasis of NSCLC cells. TP53INP1 served as a negative regulator of NSCLC metastasis. Decreased expression of TP53INP1 in tumor tissues was inversely associated with their expression of miR-125b, significantly lower in poorly differentiated tumors and inversely correlated with the clinical stages in patients with NSCLC. Conclusions These findings demonstrated that miR-125b promoted tumor metastasis via targeting TP53INP1 in human NSCLC cells, which uncovered a real clinical relevance of microRNAs in tumor biology, and provided novel potential candidates for NSCLC clinical practice.

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MicroRNA-125b promotes tumor metastasis through targeting tumor protein 53-induced nuclear protein 1 in patients with non-small-cell lung cancer

Li et al. Cancer Cell Int MicroRNA-125b promotes tumor metastasis through targeting tumor protein 53-induced nuclear protein 1 in patients with non-small-cell lung cancer Qinchuan Li 1 3 Yang Han 1 2 Chunhong Wang 0 1 Shan Shan 0 Yuanyuan Wang 0 Jingang Zhang 4 Tao Ren 0 0 Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine , 150 Jimo Road, Pudong New Area, 200120 Shanghai , China 1 Qinchuan Li, Yang Han and Chunhong Wang contribute equally to this work 2 Department of Pathology, East Hospital, Tongji University School of Medicine , Shanghai , China 3 Department of Cardiothoracic Surgery, East Hospital, Tongji University School of Medicine , Shanghai , China 4 Service Center for Family plan- ning, Maternal and Child Health Care , Lanshan, Linyi, Shandong , China Background: Lung cancer, predominantly non-small-cell lung cancer (NSCLC), is the leading cause of cancer deaths worldwide. There is a great need to identify critical effectors involved in metastasis of NSCLC that will facilitate the development of new therapeutic strategies. Here we evaluated the potential role of miR-125b in the metastasis of NSCLC cells. Methods: Human NSCLC cells were isolated from surgical tissues with Cancer Cell Isolation Kit. Expressions of miR125b and TP53INP1 were detected with real-time PCR and western blot. Human miR-125b mimics, miR-125b inhibitor, TP53INP1 expression plasmid and TP53INP1 siRNA were transfected into NSCLC cells with nucleofector transfection kit. NSCLC metastasis was determined with adhesion assay, invasive assay and lung tumor metastasis model. Results: The expression of miR-125b was significantly higher in poorly differentiated NSCLC cells that are endowed with high metastatic potentials. Up-regulation of miR-125b could enhance the metastatic potential of NSCLC cells in vitro and in vivo, while down-regulation of miR-125b resulted in decreased metastatic potentials in vitro and in vivo. Further, tumor protein 53-induced nuclear protein 1 (TP53INP1) was an important target of miR-125b involved in metastasis of NSCLC cells. TP53INP1 served as a negative regulator of NSCLC metastasis. Decreased expression of TP53INP1 in tumor tissues was inversely associated with their expression of miR-125b, significantly lower in poorly differentiated tumors and inversely correlated with the clinical stages in patients with NSCLC. Conclusions: These findings demonstrated that miR-125b promoted tumor metastasis via targeting TP53INP1 in human NSCLC cells, which uncovered a real clinical relevance of microRNAs in tumor biology, and provided novel potential candidates for NSCLC clinical practice. NSCLC; Metastasis; miR-125b; TP53INP1 - Lung cancer, especially non-small-cell lung cancer (NSCLC), is the most common cause of human cancer related mortality [1–4]. Although combined treatments including surgery, chemotherapy, radiotherapy and targeted therapy were applied in clinical management, the current outcome of NSCLC patients is still far from satisfied, which is mostly because of NSCLC metastasis [4–7]. Therefore, exploration of critical effectors involved in NSCLC metastasis is urgently needed. MicroRNAs (miRNAs) are non-coding RNAs and regulate target genes at post-transcriptional level [8, 9]. It is well acknowledged that deregulation of miRNAs was involved in tumor initiation and progression [10]. MiR-125b, a human homologue of lin-4, was reported © 2015 Li et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/ zero/1.0/) applies to the data made available in this article, unless otherwise stated. to be involved in tumor progression [11–15]. MiR-125b could regulate tumor cellular apoptosis and proliferation [16–21]. In NSCLC, serum miR-125b was significantly increased and was positively associated with NSCLC stages and poor patient survival [9, 10]. Of note, miR125b expression in poorly differentiated NSCLC was significantly higher than those in well and moderately differentiated NSCLC [9, 10]. These findings indicated an involvement of miR-125b in NSCLC metastasis, which is largely undefined. In this study, we evaluated the effect of miR-125b on metastasis of lung cancer cells from NSCLC patients. We observed a significant higher expression level of miR125b in poorly differentiated NSCLC cells. Of important, management of miR-125b expression could modulate the NSCLC metastasis in  vitro and in  vivo. Further, tumor protein 53-induced nuclear protein 1 (TP53INP1) was identified as a critical target of miR-125b involved in NSCLC metastas (...truncated)


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Qinchuan Li, Yang Han, Chunhong Wang, Shan Shan, Yuanyuan Wang, Jingang Zhang, Tao Ren. MicroRNA-125b promotes tumor metastasis through targeting tumor protein 53-induced nuclear protein 1 in patients with non-small-cell lung cancer, Cancer Cell International, 2015, pp. 84, 15, DOI: 10.1186/s12935-015-0233-x