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      Hypoxic BMSC-derived exosomal miRNAs promote metastasis of lung cancer cells via STAT3-induced EMT

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          Abstract

          Background

          Metastasis is the main cause of lung cancer mortality. Bone marrow-derived mesenchymal stem cells (BMSCs) are a component of the cancer microenvironment and contribute to cancer progression. Intratumoral hypoxia affects both cancer and stromal cells. Exosomes are recognized as mediators of intercellular communication. Here, we aim to further elucidate the communication between BMSC-derived exosomes and cancer cells in the hypoxic niche.

          Methods

          Exosomal miRNA profiling was performed using a microRNA array. Lung cancer cells and an in vivo mouse syngeneic tumor model were used to evaluate the effects of select exosomal microRNAs. Hypoxic BMSC-derived plasma exosomal miRNAs were assessed for their capacity to discriminate between cancer patients and non-cancerous controls and between cancer patients with or without metastasis.

          Results

          We demonstrate that exosomes derived from hypoxic BMSCs are taken by neighboring cancer cells and promote cancer cell invasion and EMT. Exosome-mediated transfer of select microRNAs, including miR-193a-3p, miR-210-3p and miR-5100, from BMSCs to epithelial cancer cells activates STAT3 signaling and increases the expression of mesenchymal related molecules. The diagnostic accuracy of individual microRNA showed that plasma exosomal miR-193a-3p can discriminate cancer patients from non-cancerous controls. A panel of these three plasma exosomal microRNAs showed a better diagnostic accuracy to discriminate lung cancer patients with or without metastasis than individual exosomal microRNA.

          Conclusions

          Exosome-mediated transfer of miR-193a-3p, miR-210-3p and miR-5100, could promote invasion of lung cancer cells by activating STAT3 signalling-induced EMT. These exosomal miRNAs may be promising noninvasive biomarkers for cancer progression.

          Electronic supplementary material

          The online version of this article (10.1186/s12943-019-0959-5) contains supplementary material, which is available to authorized users.

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          Hypoxia signalling in cancer and approaches to enforce tumour regression.

          Jacques Pouysségur, Frédéric Dayan, Nathalie M Mazure (2006)
          Tumour cells emerge as a result of genetic alteration of signal circuitries promoting cell growth and survival, whereas their expansion relies on nutrient supply. Oxygen limitation is central in controlling neovascularization, glucose metabolism, survival and tumour spread. This pleiotropic action is orchestrated by hypoxia-inducible factor (HIF), which is a master transcriptional factor in nutrient stress signalling. Understanding the role of HIF in intracellular pH (pH(i)) regulation, metabolism, cell invasion, autophagy and cell death is crucial for developing novel anticancer therapies. There are new approaches to enforce necrotic cell death and tumour regression by targeting tumour metabolism and pH(i)-control systems.
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            Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells.

            Mario Squadrito, Caroline Baer, Frédéric X. Burdet … (2014)
            MicroRNA (miRNA) transfer via exosomes may mediate cell-to-cell communication. Interestingly, specific miRNAs are enriched in exosomes in a cell-type-dependent fashion. However, the mechanisms whereby miRNAs are sorted to exosomes and the significance of miRNA transfer to acceptor cells are unclear. We used macrophages and endothelial cells (ECs) as a model of heterotypic cell communication in order to investigate both processes. RNA profiling of macrophages and their exosomes shows that miRNA sorting to exosomes is modulated by cell-activation-dependent changes of miRNA target levels in the producer cells. Genetically perturbing the expression of individual miRNAs or their targeted transcripts promotes bidirectional miRNA relocation from the cell cytoplasm/P bodies (sites of miRNA activity) to multivesicular bodies (sites of exosome biogenesis) and controls miRNA sorting to exosomes. Furthermore, the use of Dicer-deficient cells and reporter lentiviral vectors (LVs) for miRNA activity shows that exosomal miRNAs are transferred from macrophages to ECs to detectably repress targeted sequences. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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              Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types

              Jasenka Guduric-Fuchs, Anna O’Connor, Bailey Camp … (2012)
              Background MicroRNAs (miRNAs) are a class of small RNA molecules that regulate expression of specific mRNA targets. They can be released from cells, often encapsulated within extracellular vesicles (EVs), and therefore have the potential to mediate intercellular communication. It has been suggested that certain miRNAs may be selectively exported, although the mechanism has yet to be identified. Manipulation of the miRNA content of EVs will be important for future therapeutic applications. We therefore wished to assess which endogenous miRNAs are enriched in EVs and how effectively an overexpressed miRNA would be exported. Results Small RNA libraries from HEK293T cells and vesicles before or after transfection with a vector for miR-146a overexpression were analysed by deep sequencing. A subset of miRNAs was found to be enriched in EVs; pathway analysis of their predicted target genes suggests a potential role in regulation of endocytosis. RT-qPCR in additional cell types and analysis of publicly available data revealed that many of these miRNAs tend to be widely preferentially exported. Whilst overexpressed miR-146a was highly enriched both in transfected cells and their EVs, the cellular:EV ratios of endogenous miRNAs were not grossly altered. MiR-451 was consistently the most highly exported miRNA in many different cell types. Intriguingly, Argonaute2 (Ago2) is required for miR-451 maturation and knock out of Ago2 has been shown to decrease expression of other preferentially exported miRNAs (eg miR-150 and miR-142-3p). Conclusion The global expression data provided by deep sequencing confirms that specific miRNAs are enriched in EVs released by HEK293T cells. Observation of similar patterns in a range of cell types suggests that a common mechanism for selective miRNA export may exist.
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                Author and article information

                Contributors
                Xina Zhang: 166511029@csu.edu.cn
                Buqing Sai: saibuqing@csu.edu.cn
                Fan Wang: 1508119871@qq.com
                Lujuan Wang: wanglujuan001@csu.edu.cn
                Yuhui Wang: 598709112@qq.com
                Leliang Zheng: zhengleliang@csu.edu.cn
                Guiyuan Li: lgy@csu.edu.cn
                Jingqun Tang: tangjq@csu.edu.cn
                Juanjuan Xiang:
                ORCID: http://orcid.org/0000-0001-8712-8952
                xiangjj@csu.edu.cn
                Journal
                Journal ID (nlm-ta): Mol Cancer
                Journal ID (iso-abbrev): Mol. Cancer
                Title: Molecular Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1476-4598
                Publication date (Electronic): 13 March 2019
                Publication date PMC-release: 13 March 2019
                Publication date Collection: 2019
                Volume: 18
                Electronic Location Identifier: 40
                Affiliations
                [1 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, ; Changsha, Hunan China
                [2 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute, School of Basic Medical Science, , Central South University, ; Changsha, Hunan China
                [3 ]ISNI 0000 0004 1803 0208, GRID grid.452708.c, Department of Thoracic Surgery, , the Second Xiangya Hospital, Central South University, ; Changsha, 410013 Hunan China
                [4 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, , Central South University, ; Changsha, Hunan China
                [5 ]Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, 410013 Hunan China
                Author information
                http://orcid.org/0000-0001-8712-8952
                Article
                Publisher ID: 959
                DOI: 10.1186/s12943-019-0959-5
                PMC ID: 6417285
                PubMed ID: 30866952
                SO-VID: 89dff340-561c-44d3-971e-41c5d5bde9f0
                Copyright © © The Author(s). 2019
                License:

                Open Access 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.

                History
                Date received : 6 November 2018
                Date accepted : 20 February 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81472695, 81773147
                Award Recipient :
                Funded by: Strategic Priority Research Program of Central South University
                Award ID: ZLXD2017004
                Award Recipient :
                Funded by: National Training and Research Base for Talents of principles of carcinogenesis foundation
                Award ID: 111 project: 111-2-12
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2019

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: bmscs, exosomal mirna,metastasis,emt,stat3
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: bmscs, exosomal mirna, metastasis, emt, stat3

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