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Emerging Function and Clinical Values of Exosomal MicroRNAs in Cancer

2019; Cell Press; Volume: 16; Linguagem: Inglês

10.1016/j.omtn.2019.04.027

2162-2531

Man Wang, Fei Yu, Han Ding, Yu Wang, Peifeng Li, Kun Wang,

Circular RNAs in diseases

Exosomes are a subset of membrane-bound extracellular vesicles with diameters ranging from 30 to 100 nm. Exosomes enclose a variety of molecules, such as lipids, proteins, and non-coding RNAs. In the past decades, microRNAs (miRNAs) have attracted great attention in cancer research, as they play an important role in the occurrence and development of cancer. Increasing evidence indicates that tumor cells communicate with not only other tumor cells but also cells present in the tumor microenvironment via secretion and transfer of exosomal miRNAs. More importantly, exosomal miRNAs are found to serve as signaling molecules to regulate tumor growth, angiogenesis, metastasis, sensitivity to chemotherapy, and immune evasion. Deregulated expression of exosomal miRNAs is an early event in carcinogenesis and may reflect the malignant characteristics of cancer. Owing to the wide existence and high stability of exosomal miRNAs in body fluids, they may represent a novel class of non-invasive biomarkers for cancer. In this review, we highlight the recent advances on the functional role of exosomal miRNAs in cancer pathogenesis. We also discuss the potential clinical utility of exosome-shuttled miRNAs as biomarkers for the diagnosis and treatment of cancer. Exosomes are a subset of membrane-bound extracellular vesicles with diameters ranging from 30 to 100 nm. Exosomes enclose a variety of molecules, such as lipids, proteins, and non-coding RNAs. In the past decades, microRNAs (miRNAs) have attracted great attention in cancer research, as they play an important role in the occurrence and development of cancer. Increasing evidence indicates that tumor cells communicate with not only other tumor cells but also cells present in the tumor microenvironment via secretion and transfer of exosomal miRNAs. More importantly, exosomal miRNAs are found to serve as signaling molecules to regulate tumor growth, angiogenesis, metastasis, sensitivity to chemotherapy, and immune evasion. Deregulated expression of exosomal miRNAs is an early event in carcinogenesis and may reflect the malignant characteristics of cancer. Owing to the wide existence and high stability of exosomal miRNAs in body fluids, they may represent a novel class of non-invasive biomarkers for cancer. In this review, we highlight the recent advances on the functional role of exosomal miRNAs in cancer pathogenesis. We also discuss the potential clinical utility of exosome-shuttled miRNAs as biomarkers for the diagnosis and treatment of cancer. Exosomes are 30- to 100-nm extracellular vesicles of endosomal origin, comprising a lipid bilayer and a great variety of bioactive molecules, such as nucleic acids, lipids, and proteins.1Abak A. Abhari A. Rahimzadeh S. 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Moreover, accessory proteins, such as ALG-2-interacting protein X (ALIX) and tumor susceptibility gene 101 (TSG101), play a crucial role in cargo packaging and exosome biogenesis. ALIX not only encloses cargoes to enter internalized vesicles but also induces vesicle formation.35Baietti M.F. Zhang Z. Mortier E. Melchior A. Degeest G. Geeraerts A. Ivarsson Y. Depoortere F. Coomans C. Vermeiren E. et al.Syndecan-syntenin-ALIX regulates the biogenesis of exosomes.Nat. Cell Biol. 2012; 14: 677-685Crossref PubMed Scopus (1022) Google Scholar ALIX recruits the ESCRT-III complex, resulting in the formation of ILVs.36Hurley J.H. Odorizzi G. Get on the exosome bus with ALIX.Nat. Cell Biol. 2012; 14: 654-655Crossref PubMed Scopus (145) Google Scholar TSG101, a component of the ESCRT machinery, is required for epidermal growth factor (EGF)-stimulated MVB formation.37Razi M. Futter C.E. Distinct roles for Tsg101 and Hrs in multivesicular body formation and inward vesiculation.Mol. Biol. 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A great variety of molecules can be incorporated into exosomes, including miRNAs, DNAs, RNAs, and proteins. Among these bioactive compositions, miRNAs have attracted substantial attention owing to their regulatory function in gene expression. miRNAs are short ncRNAs of approximately 19–24 nt in length.42Chen X. Liang H. Zhang J. Zen K. Zhang C.Y. Secreted microRNAs: a new form of intercellular communication.Trends Cell Biol. 2012; 22: 125-132Abstract Full Text Full Text PDF PubMed Scopus (573) Google Scholar miRNAs function to suppress the expression of protein-coding genes at the post-transcriptional level.43Bartel D.P. MicroRNAs: genomics, biogenesis, mechanism, and function.Cell. 2004; 116: 281-297Abstract Full Text Full Text PDF PubMed Scopus (28659) Google Scholar, 44Ambros V. The functions of animal microRNAs.Nature. 2004; 431: 350-355Crossref PubMed Scopus (8837) Google Scholar, 45Kim V.N. Han J. Siomi M.C. Biogenesis of small RNAs in animals.Nat. Rev. Mol. 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Exosome and exosomal microRNA: trafficking, sorting, and function.Genomics Proteomics Bioinformatics. 2015; 13: 17-24Crossref PubMed Scopus (1050) Google Scholar Overexpression of nSMase2 caused an increase in the abundance of exosomal miRNAs.56Kosaka N. Iguchi H. Hagiwara K. Yoshioka Y. Takeshita F. Ochiya T. Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis.J. Biol. Chem. 2013; 288: 10849-10859Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar In contrast, inhibition of nSMase2 expression decreased the levels of exosomal miRNAs. The second sorting mechanism involves the sumoylated heterogeneous nuclear ribonucleoprotein (hnRNP)-dependent pathway. Three hnRNP family proteins (hnRNPA2B1, hnRNPA1, and hnRNPC) bound to exosomal miRNAs and induced the loading of miRNAs into exosomes.57Villarroya-Beltri C. Gutiérrez-Vázquez C. Sánchez-Cabo F. Pérez-Hernández D. Vázquez J. Martin-Cofreces N. Martinez-Herrera D.J. Pascual-Montano A. Mittelbrunn M. Sánchez-Madrid F. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs.Nat. Commun. 2013; 4: 2980Crossref PubMed Scopus (1124) Google Scholar Specially, the sumoylated hnRNPA2B1 controlled the exosomal assortment of miRNAs by recognizing the GGAG motif in the 3′ part of miRNA sequences. The third pathway depends on the 3′ end of the miRNA. The 3′ end of the miRNA sequence might contain an important sorting signal that contributed to guiding its incorporation into exosomes.58Koppers-Lalic D. Hackenberg M. Bijnsdorp I.V. van Eijndhoven M.A.J. Sadek P. Sie D. Zini N. Middeldorp J.M. Ylstra B. de Menezes R.X. et al.Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes.Cell Rep. 2014; 8: 1649-1658Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar The last sorting pathway is mediated by the miRNA-induced silencing complex (miRISC). The primary components of miRISC were found to co-localize with MVBs.59Gibbings D.J. Ciaudo C. Erhardt M. Voinnet O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity.Nat. Cell Biol. 2009; 11: 1143-1149Crossref PubMed Scopus (787) Google Scholar Moreover, blockade of the turnover of MVBs into lysosomes resulted in excessive accumulation of miRISCs, while suppression of MVB formation caused the loss of miRISC and relieved miRNA-mediated gene silencing.60Lee Y.S. Pressman S. Andress A.P. Kim K. White J.L. Cassidy J.J. Li X. Lubell K. Lim D.H. Cho I.S. et al.Silencing by small RNAs is linked to endosomal trafficking.Nat. Cell Biol. 2009; 11: 1150-1156Crossref PubMed Scopus (270) Google Scholar It was reported that exosomal miRNA sorting was controlled by cell activation-dependent changes of miRNA target abundance.61Squadrito M.L. Baer C. Burdet F. Maderna C. Gilfillan G.D. Lyle R. Ibberson M. De Palma M. Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells.Cell Rep. 2014; 8: 1432-1446Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar Artificially elevating the cellular levels of miRNAs or their target mRNAs benefited miRNA enrichment in MVBs. Additionally, Argonaute 2 (Ago2), a component of the RISC, was also implicated in the exosomal assortment of miRNAs. Knockout of Ago2 could reduce the abundance of some exosomal miRNAs, including miR-142-3p, miR-150, and miR-451.51Guduric-Fuchs J. O'Connor A. Camp B. O'Neill C.L. Medina R.J. Simpson D.A. Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types.BMC Genomics. 2012; 13: 357Crossref PubMed Scopus (363) Google Scholar Collectively, certain sequences present in miRNAs may favor their uptake into exosomes, and specific protein complexes may be involved in the loading of miRNAs into exosomes. Nevertheless, the sorting mechanisms of exosomal miRNAs remain unclear and deserve further investigation. Exosomal miRNAs have been shown to exert multifaceted effects on cancer progression, including the regulation of cancer growth, angiogenesis and metastasis, domination of host immune responses, manipulation of cancer chemoresistance, and remodeling of the tumor microenvironment (Figure 3). Proliferation is a crucial aspect of cancer progression that is commonly manifested by the deregulation of cell cycle-related proteins. Tumor growth is a contributing factor to the development of tumor angiogenesis and metastasis. Emerging evidence demonstrates that cancer-secreted exosomal miRNAs regulate cancer cell proliferation by targeting cell cycle-associated proteins or signaling pathways. Exosomal miR-200b could be transmitted between colorectal cancer (CRC) cells, and it promoted the proliferation of recipient cells by lowering p27 expression.62Zhang Z. Xing T. Chen Y. Xiao J. Exosome-mediated miR-200b promotes colorectal cancer proliferation upon TGF-β1 exposure.Biomed. Pharmacother. 2018; 106: 1135-1143Crossref PubMed Scopus (2) Google Scholar Exosomal miR-6869-5p could depress CRC cell proliferation and inhibit the production of inflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor alpha [TNF-α]) in CRC cells by blocking the Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB)-signaling pathway.63Yan S. Liu G. Jin C. Wang Z. Duan Q. Xu J. Xu D. MicroRNA-6869-5p acts as a tumor suppressor via targeting TLR4/NF-κB signaling pathway in colorectal cancer.J. Cell. Physiol. 2018; 233: 6660-6668Crossref PubMed Scopus (0) Google Scholar Inhibition of oncogenic miR-21 sorting into exosomes suppressed the growth and migration of hepatocellular carcinoma (HCC) cells.64Liang J. Zhang X. He S. Miao Y. Wu N. Li J. Gan Y. Sphk2 RNAi nanoparticles suppress tumor growth via downregulating cancer cell derived exosomal microRNA.J. Control. Release. 2018; 286: 348-357Crossref PubMed Scopus (1) Google Scholar Exosomal miR-9-3p restrained HCC cell proliferation by directly targeting fibroblast growth factor 5 (HBGF-5).65Tang J. Li Y. Liu K. Zhu Q. Yang W.H. Xiong L.K. Guo D.L. Exosomal miR-9-3p suppresses HBGF-5 expression and is a functional biomarker in hepatocellular carcinoma.Minerva Med. 2018; 109: 15-23PubMed Google Scholar Exosomal miR-1246, enriched in metastatic breast cancer cells, could be transferred into non-malignant breast cells.66Li X.J. Ren Z.J. Tang J.H. Yu Q. Exosomal MicroRNA MiR-1246 Promotes Cell Proliferation, Invasion and Drug Resistance by Targeting CCNG2 in Breast Cancer.Cell. Physiol. Biochem. 2017; 44: 1741-1748Crossref PubMed Scopus (167) Google Scholar miR-1246 promoted the proliferation, migration, and drug resistance of breast cancer cells by downregulating cyclin-G2 (CCNG2). Exosomal miR-193a impeded the cell cycle progression and exerted an inhibitory effect on colon cancer cell proliferation by directly targeting cell cycle-associated protein 1 (Caprin1).67Teng Y. Ren Y. Hu X. Mu J. Samykutty A. Zhuang X. Deng Z. Kumar A. Zhang L. Merchant M.L. et al.MVP-mediated exosomal sorting of miR-193a promotes colon cancer progression.Nat. Commun. 2017; 8: 14448Crossref PubMed Scopus (260) Google Scholar Moreover, exosomal miRNAs can orchestrate the apoptotic signaling pathway in cancer cells. For instance, exosomal miR-128 reduced the expression of Bcl-2-associated X protein (Bax) in recipient breast cancer cells.68Wei Y. Li M. Cui S. Wang D. Zhang C.Y. Zen K. Li L. Shikonin Inhibits the Proliferation of Human Breast Cancer Cells by Reducing Tumor-Derived Exosomes.Molecules. 2016; 21: 777Crossref Scopus (21) Google Scholar Exosomal miR-373 repressed the expression of estrogen receptor (ER) and inhibited the apoptosis of breast cancer cells.69Eichelser C. Stückrath I. Müller V. Milde-Langosch K. Wikman H. Pantel K. Schwarzenbach H. Increased serum levels of circulating exosomal microRNA-373 in receptor-negative breast cancer patients.Oncotarget. 2014; 5: 9650-9663Crossref PubMed Google Scholar Human adipose mesenchymal stem cell (hAMSC)-derived exosomal miRNAs could induce the apoptosis of human ovarian cancer (OC) cells by upregulating apoptotic proteins (Bax, caspase 3, and caspase 9) and downregulating anti-apoptotic Bcl-2.70Reza A.M.M.T. Choi Y.J. Yasuda H. Kim J.H. Human adipose mesenchymal stem cell-derived exosomal-miRNAs are critical factors for inducing anti-proliferation signalling to A2780 and SKOV-3 ovarian cancer cells.Sci. Rep. 2016; 6: 38498Crossref PubMed Scopus (31) Google Scholar Exosomal miR-101 promoted GC cell apoptosis by targeting anti-apoptotic myeloid cell leukemia-1 (Mcl-1).71Imamura T. Komatsu S. Ichikawa D. Miyamae M. Okajima W. Ohashi T. Kiuchi J. Nishibeppu K. Kosuga T. Konishi H. et al.Low plasma levels of miR-101 are associated with tumor progression in gastric cancer.Oncotarget. 2017; 8: 106538-106550Crossref PubMed Scopus (9) Google Scholar The epithelial-mesenchymal transition (EMT), a vital process in cancer cell invasion and metastasis, is characterized