Abstract
Exosomes mediate cell-to-cell communication by releasing miRNAs, mRNA, etc. However, there is little research about the effects on the donor cells after miRNAs are excreted out of cells through exosomes. Here, we found that miR-378a-3p was specifically enriched in exosomes and inhibited cell proliferation, migration, invasion, and colony formation in ESCC. In addition, miR-378a-3p was sorted into exosomes through TOM1L1 and extracted mainly out of ESCC cells. Overexpression of TOM1L1 led to tumor suppressor miR-378a-3p accumulation in exosomes rather than in donor cells, promoting ESCC progression. Moreover, miR-378a-3p targets DYRK1A that directly binds to NPM1 and the phosphorylation state of NPM1 at Ser125 to suppress tumor growth. Taken together, our findings demonstrate that TOM1L1-mediated the tumor suppressor miR-378a-3p into exosomes and excreted out of cells to promote tumor progression.
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Fig. 1: miR-378a-3p is secreted outside of tumor cells.
Fig. 2: miR-378a-3p suppressed ESCC cell migration and invasion in vitro.
Fig. 3: miR-378a-3p was sorted into exosomes.
Fig. 4: TOM1L1 regulates miR-378a-3p sorting into exosomes.
Fig. 5: TOM1L1-mediated exosome sorting of miR-378a-3p promotes tumor progression.
Fig. 6: DYRK1A is a critical downstream target of miR-378a-3p in ESCC cells.
Fig. 7: DYRK1A physically interacts with NPM1 and phosphorylates it at Ser125.
Fig. 8: The mechanism of miR-378a-3p sorted into exosomes by TOM1L1 in ESCC.
Data availability
The data generated in this study are available upon request from the corresponding author.
References
Lin Y, Totsuka Y, He Y, Kikuchi S, Qiao Y, Ueda J, et al. Epidemiology of esophageal cancer in Japan and China. J Epidemiol. 2013;23:233–42.
PubMedGoogle Scholar
Wang T, Liu NS, Seet LF, Hong W. The emerging role of VHS domain-containing Tom1, Tom1L1 and Tom1L2 in membrane trafficking. Traffic. 2010;11:1119–28.
CASPubMedGoogle Scholar
Zhang L, Zhou Y, Cheng C, Cui H, Cheng L, Kong P, et al. Genomic analyses reveal mutational signatures and frequently altered genes in esophageal squamous cell carcinoma. Am J Hum Genet. 2015;96:597–611.
CASPubMedPubMed CentralGoogle Scholar
Tran GD, Sun XD, Abnet CC, Fan JH, Dawsey SM, Dong ZW, et al. Prospective study of risk factors for esophageal and gastric cancers in the Linxian general population trial cohort in China. Int J Cancer. 2005;113:456–63.
CASPubMedGoogle Scholar
Kalra H, Drummen GP, Mathivanan S. Focus on extracellular vesicles: introducing the next small big thing. Int J Mol Sci. 2016;17:170.
PubMedPubMed CentralGoogle Scholar
Qazi REM, Sajid Z, Zhao C, Hussain I, Iftikhar F, Jameel M, et al. Lyophilization based isolation of exosomes. Int J Mol Sci. 2023;24:10477.
Gross JC, Chaudhary V, Bartscherer K, Boutros M. Active Wnt proteins are secreted on exosomes. Nat Cell Biol. 2012;14:1036–45.
CASPubMedGoogle Scholar
Chagraoui J, Girard S, Spinella JF, Simon L, Bonneil E, Mayotte N, et al. UM171 preserves epigenetic marks that are reduced in ex vivo culture of human HSCs via potentiation of the CLR3-KBTBD4 complex. Cell Stem Cell. 2021;28:48–62.e6.
CASPubMedGoogle Scholar
Wang L, Liu H, Wu Q, Liu Y, Yan Z, Chen G, et al. miR-451a was selectively sorted into exosomes and promoted the progression of esophageal squamous cell carcinoma through CAB39. Cancer Gene Ther. 2024;31:1060–9.
CASPubMedGoogle Scholar
Guduric-Fuchs J, O’Connor A, Camp B, O’Neill CL, Medina RJ, Simpson DA. Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types. BMC Genomics. 2012;13:357.
CASPubMedPubMed CentralGoogle Scholar
Yu X, Odenthal M, Fries JW. Exosomes as miRNA carriers: formation-function-future. Int J Mol Sci. 2016;17:2028.
PubMedPubMed CentralGoogle Scholar
Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.
CASPubMedGoogle Scholar
Hinds PW, Weinberg RA. Tumor suppressor genes. Curr Opin Genet Dev. 1994;4:135–41.
CASPubMedGoogle Scholar
Yao Y, Bellon M, Shelton SN, Nicot C. Tumor suppressors p53, p63taα, p63tay, p73α, and p73β use distinct pathways to repress telomerase expression. J Biol Chem. 2012;287:20737–47.
CASPubMedPubMed CentralGoogle Scholar
Hoppe-Seyler K, Bossler F, Braun JA, Herrmann AL, Hoppe-Seyler F. The HPV E6/E7 oncogenes: key factors for viral carcinogenesis and therapeutic targets. Trends Microbiol. 2018;26:158–68.
CASPubMedGoogle Scholar
Chang Y, Jin H, Cui Y, Yang F, Chen K, Kuang W, et al. PUS7-dependent pseudouridylation of ALKBH3 mRNA inhibits gastric cancer progression. Clin Transl Med. 2024;14:e1811.
CASPubMedPubMed CentralGoogle Scholar
Kim JW, Moon SW, Mo HY, Son HJ, Choi EJ, Yoo NJ, et al. Concurrent inactivating mutations and expression losses of RGS2, HNF1a, and CAPN12 candidate tumor suppressor genes in colon cancers. Pathol Res Pract. 2023;241:154288.
CASPubMedGoogle Scholar
Cojocaru E, Lozneanu L, Giuşcă SE, Căruntu ID, Danciu M. Renal carcinogenesis—insights into signaling pathways. Rom J Morphol Embryol. 2015;56:15–9.
PubMedGoogle Scholar
Kobayashi H. [The cell cycle and the tumor suppressor genes]. Rinsho Byori. 1996;44:3–11.
CASPubMedGoogle Scholar
Llinàs-Arias P, Esteller M. Epigenetic inactivation of tumour suppressor coding and non-coding genes in human cancer: an update. Open Biol. 2017;7:170152.
PubMedPubMed CentralGoogle Scholar
Li M, Xu H, Qi Y, Pan Z, Li B, Gao Z, et al. Tumor-derived exosomes deliver the tumor suppressor miR-3591-3p to induce M2 macrophage polarization and promote glioma progression. Oncogene. 2022;41:4618–32.
CASPubMedPubMed CentralGoogle Scholar
Au Yeung CL, Co NN, Tsuruga T, Yeung TL, Kwan SY, Leung CS, et al. Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nat Commun. 2016;7:11150.
PubMedPubMed CentralGoogle Scholar
Ponath V, Hoffmann N, Bergmann L, Mäder C, Alashkar Alhamwe B, Preußer C, et al. Secreted ligands of the NK cell receptor NKp30: B7-H6 is in contrast to BAG6 only marginally released via extracellular vesicles. Int J Mol Sci. 2021;22:2189.
Audic S, Claverie JM. The significance of digital gene expression profiles. Genome Res. 1997;7:986–95.
CASPubMedGoogle Scholar
Briand J, Garnier D, Nadaradjane A, Clément-Colmou K, Potiron V, Supiot S, et al. Radiotherapy-induced overexpression of exosomal miRNA-378a-3p in cancer cells limits natural killer cells cytotoxicity. Epigenomics. 2020;12:397–408.
CASPubMedGoogle Scholar
Yang Q, Zhao S, Shi Z, Cao L, Liu J, Pan T, et al. Chemotherapy-elicited exosomal miR-378a-3p and miR-378d promote breast cancer stemness and chemoresistance via the activation of EZH2/STAT3 signaling. J Exp Clin Cancer Res. 2021;40:120.
CASPubMedPubMed CentralGoogle Scholar
Liu Z, Zhao Y, Kong P, Liu Y, Huang J, Xu E, et al. Integrated multi-omics profiling yields a clinically relevant molecular classification for esophageal squamous cell carcinoma. Cancer Cell. 2023;41:181–195.e9.
CASPubMedGoogle Scholar
Qin Y, Liang R, Lu P, Lai L, Zhu X. Depicting the implication of miR-378a in cancers. Technol Cancer Res Treat. 2022;21:15330338221134385.
CASPubMedPubMed CentralGoogle Scholar
Hu M, Yang J, Xu Y, Liu J. MDH1 and MDH2 promote cell viability of primary AT2 cells by increasing glucose uptake. Comput Math Methods Med. 2022;2022:2023500.
PubMedPubMed CentralGoogle Scholar
Zhang Z, Miao L, Xin X, Zhang J, Yang S, Miao M, et al. Underexpressed CNDP2 participates in gastric cancer growth inhibition through activating the MAPK signaling pathway. Mol Med. 2014;20:17–28.
CASPubMedGoogle Scholar
Liu H, Ma Y, He HW, Wang JP, Jiang JD, Shao RG. SLC9A3R1 stimulates autophagy via BECN1 stabilization in breast cancer cells. Autophagy. 2015;11:2323–34.
PubMedPubMed CentralGoogle Scholar
Yuan Q, Yin L, He J, Zeng Q, Liang Y, Shen Y, et al. Metabolism of asparagine in the physiological state and cancer. Cell Commun Signal. 2024;22:163.
CASPubMedPubMed CentralGoogle Scholar
Yin X, He Z, Chen K, Ouyang K, Yang C, Li J, et al. Unveiling the impact of CDK8 on tumor progression: mechanisms and therapeutic strategies. Front Pharmacol. 2024;15:1386929.
CASPubMedPubMed CentralGoogle Scholar
Jabbour E, Cortes J, O’Brien S, Giles F, Kantarjian H. New targeted therapies for chronic myelogenous leukemia: opportunities to overcome imatinib resistance. Semin Hematol. 2007;44:S25–31.
CASPubMedGoogle Scholar
Chevalier C, Roche S, Bénistant C. Vesicular trafficking regulators are new players in breast cancer progression: role of TOM1L1 in ERBB2-dependent invasion. Mol Cell Oncol. 2016;3:e1182241.
PubMedPubMed CentralGoogle Scholar
Chevalier C, Collin G, Descamps S, Touaitahuata H, Simon V, Reymond N, et al. TOM1L1 drives membrane delivery of MT1-MMP to promote ERBB2-induced breast cancer cell invasion. Nat Commun. 2016;7:10765.
CASPubMedPubMed CentralGoogle Scholar
Yanagida-Ishizaki Y, Takei T, Ishizaki R, Imakagura H, Takahashi S, Shin HW, et al. Recruitment of Tom1L1/Srcasm to endosomes and the midbody by Tsg101. Cell Struct Funct. 2008;33:91–100.
CASPubMedGoogle Scholar
Jia S, Meng A. Tob genes in development and homeostasis. Dev Dyn. 2007;236:913–21.
CASPubMedGoogle Scholar
Hutagalung AH, Novick PJ. Role of Rab GTPases in membrane traffic and cell physiology. Physiol Rev. 2011;91:119–49.
CASPubMedGoogle Scholar
Wang QC, Zheng Q, Tan H, Zhang B, Li X, Yang Y, et al. TMCO1 is an ER Ca2+ load-activated Ca2+ channel. Cell. 2016;165:1454–66.
CASPubMedGoogle Scholar
Sun J, Sheng W, Ma Y, Dong M. Potential role of Musashi-2 RNA-binding protein in cancer EMT. Oncotargets Ther. 2021;14:1969–80.
Google Scholar
Rudack T, Jenrich S, Brucker S, Vetter IR, Gerwert K, Kötting C. Catalysis of GTP hydrolysis by small GTPases at atomic detail by integration of x-ray crystallography, experimental, and theoretical IR spectroscopy. J Biol Chem. 2015;290:24079–90.
CASPubMedPubMed CentralGoogle Scholar
Deboever E, Fistrovich A, Hulme C, Dunckley T. The omnipresence of DYRK1A in human diseases. Int J Mol Sci. 2022;23:9355.
CASPubMedPubMed CentralGoogle Scholar
Sebastiani G, Almeida-Toledano L, Serra-Delgado M, Navarro-Tapia E, Sailer S, Valverde O, et al. Therapeutic effects of catechins in less common neurological and neurodegenerative disorders. Nutrients. 2021;13:2232.
CASPubMedPubMed CentralGoogle Scholar
Giraud F, Pereira E, Anizon F, Moreau P. Recent advances in pain management: relevant protein kinases and their inhibitors. Molecules. 2021;26:2696.
CASPubMedPubMed CentralGoogle Scholar
Guo X, Zhang D, Zhang X, Jiang J, Xue P, Wu C, et al. Dyrk1A promotes the proliferation, migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis via down-regulating Spry2 and activating the ERK MAPK pathway. Tissue Cell. 2018;55:63–70.
CASPubMedGoogle Scholar
Ionescu A, Dufrasne F, Gelbcke M, Jabin I, Kiss R, Lamoral-Theys D. DYRK1A kinase inhibitors with emphasis on cancer. Mini Rev Med Chem. 2012;12:1315–29.
CASPubMedGoogle Scholar
Yang Y, Fan X, Liu Y, Ye D, Liu C, Yang H, et al. Function and inhibition of DYRK1A: emerging roles of treating multiple human diseases. Biochem Pharmacol. 2023;212:115521.
CASPubMedGoogle Scholar
Becker W, Joost HG. Structural and functional characteristics of Dyrk, a novel subfamily of protein kinases with dual specificity. Prog Nucleic Acid Res Mol Biol. 1999;62:1–17.
CASPubMedGoogle Scholar
Soundararajan M, Roos AK, Savitsky P, Filippakopoulos P, Kettenbach AN, Olsen JV, et al. Structures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition. Structure. 2013;21:986–96.
CASPubMedPubMed CentralGoogle Scholar
Murano K, Okuwaki M, Hisaoka M, Nagata K. Transcription regulation of the rRNA gene by a multifunctional nucleolar protein, B23/nucleophosmin, through its histone chaperone activity. Mol Cell Biol. 2008;28:3114–26.
CASPubMedPubMed CentralGoogle Scholar
Okuwaki M. The structure and functions of NPM1/Nucleophsmin/B23, a multifunctional nucleolar acidic protein. J Biochem. 2008;143:441–8.
CASPubMedGoogle Scholar
Lim MJ, Wang XW. Nucleophosmin and human cancer. Cancer Detect Prev. 2006;30:481–90.
CASPubMedPubMed CentralGoogle Scholar
Enomoto T, Lindström MS, Jin A, Ke H, Zhang Y. Essential role of the B23/NPM core domain in regulating ARF binding and B23 stability. J Biol Chem. 2006;281:18463–72.
CASPubMedGoogle Scholar
Mashouri L, Yousefi H, Aref AR, Ahadi AM, Molaei F, Alahari SK. Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance. Mol Cancer. 2019;18:75.
PubMedPubMed CentralGoogle Scholar
de Visser KE, Joyce JA. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell. 2023;41:374–403.
PubMedGoogle Scholar
Wang L, Liu H, Liu Y, Guo S, Yan Z, Chen G, et al. Potential markers of cancer stem-like cells in ESCC: a review of the current knowledge. Front Oncol. 2023;13:1324819.
CASPubMedGoogle Scholar
Mei J, Bachoo R, Zhang CL. MicroRNA-146a inhibits glioma development by targeting Notch1. Mol Cell Biol. 2011;31:3584–92.
CASPubMedPubMed CentralGoogle Scholar
Li Y, Vandenboom TG 2nd, Wang Z, Kong D, Ali S, Philip PA, et al. miR-146a suppresses invasion of pancreatic cancer cells. Cancer Res. 2010;70:1486–95.
CASPubMedPubMed CentralGoogle Scholar
Katakowski M, Buller B, Zheng X, Lu Y, Rogers T, Osobamiro O, et al. Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett. 2013;335:201–4.
CASPubMedPubMed CentralGoogle Scholar
Qiu S, Xie L, Lu C, Gu C, Xia Y, Lv J, et al. Gastric cancer-derived exosomal miR-519a-3p promotes liver metastasis by inducing intrahepatic M2-like macrophage-mediated angiogenesis. J Exp Clin Cancer Res. 2022;41:296.
CASPubMedPubMed CentralGoogle Scholar
Jiao Y, Zhang T, Zhang C, Ji H, Tong X, Xia R, et al. Exosomal miR-30d-5p of neutrophils induces M1 macrophage polarization and primes macrophage pyroptosis in sepsis-related acute lung injury. Crit Care. 2021;25:356.
PubMedPubMed CentralGoogle Scholar
Chendrimada TP, Gregory RI, Kumaraswamy E, Norman J, Cooch N, Nishikura K, et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature. 2005;436:740–4.
CASPubMedPubMed CentralGoogle Scholar
Villarroya-Beltri C, Gutiérrez-Vázquez C, Sánchez-Cabo F, Pérez-Hernández D, Vázquez J, Martin-Cofreces N, et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun. 2013;4:2980.
PubMedGoogle Scholar
Teng Y, Ren Y, Hu X, Mu J, Samykutty A, Zhuang X, et al. MVP-mediated exosomal sorting of miR-193a promotes colon cancer progression. Nat Commun. 2017;8:14448.
CASPubMedPubMed CentralGoogle Scholar
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Acknowledgements
We would like to thank the Shanxi Medical University Key Laboratory of the Ministry of Education for providing us with the Cell physiology equipment platform.
Funding
This work was supported by the Shanxi Province Higher Education “Billion Project” Science and Technology Guidance Project(BYJL027); the Fundamental Research Program of Shanxi Province (20210302123292); the Central Guidance on Local Science and Technology Development Fund of Shanxi Province (YDZJSX2021A018); the Shenzhen Project of Science and Technology (JCYJ20190813094203600).
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Key Laboratory of Cellular Physiology of the Ministry of Education & Department of Pathology, Shanxi Medical University, Taiyuan, People’s Republic of China
Lu Wang, Huijuan Liu, Guohui Chen, Qinglu Wu, Songrui Xu, Qichao Zhou, Yadong Zhao, Qiaorong Wang, Ting Yan & Xiaolong Cheng
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Lu Wang
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2. Huijuan Liu
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3. Guohui Chen
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4. Qinglu Wu
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9. Ting Yan
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Xiaolong Cheng and Ting Yan: Formal analysis, Funding acquisition, Project administration; Lu Wang: Data curation, Validation, Writing—original draft; Huijuan Liu, Guohui Chen and Qinglu Wu: Supervision, Visualization, revised and edited the manuscript; Songrui Xu, Qichao Zhou, Yadong Zhao, and Qiaorong Wang: Formal analysis, Investigation. All authors read and approved the final manuscript.
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Wang, L., Liu, H., Chen, G. et al. TOM1L1 mediated the sort of tumor suppressive miR-378a-3p into exosomes and the excretion out of cells to promote ESCC progression. Cancer Gene Ther (2025). https://doi.org/10.1038/s41417-025-00889-6
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Received:01 December 2024
Revised:20 February 2025
Accepted:06 March 2025
Published:23 March 2025
DOI:https://doi.org/10.1038/s41417-025-00889-6
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