Research progress and prospects of exosomal microRNAs in bone malignancies_West China Medical Journal

Authors：

LI Linyang ¹ , ZHANG Yongbo ¹ , ZHANG Yujie ¹ , HUO Lukuan ¹ ,  LIU Yanbin ²

1. School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong 261000, P. R. China;
2. Department of Spine Surgery, Liaocheng People’s Hospital, Beijing Jishuitan Hospital Liaocheng Branch, Liaocheng, Shandong 252000, P. R. China;

Corresponding author：

LIU Yanbin, Email: 15315388294@163.com

Keywords：

Exosomes; microRNA; bone malignancies; drug resistance; therapeutic targets

DOI：

10.7507/1002-0179.202410007

Video：

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Bone malignancies exhibit the characteristics of high incidence, poor prognosis, and strong chemoresistance. Exosomal microRNAs can regulate the proliferation of bone malignant cells, improve chemoresistance, influence cell communication and the microenvironment, and have significant potential in the diagnosis and treatment of bone malignancies. Due to their stability, exosomal microRNAs can serve as non-invasive biomarkers for diagnosis and prognosis. However, their widespread application in clinical settings requires standardized research. This review summarizes the progress of exosomal microRNA research in various bone malignancies including osteosarcoma, chondrosarcoma, Ewing sarcoma, and fibrosarcoma, to provide new theoretical foundations and perspectives for the field.

Citation： LI Linyang, ZHANG Yongbo, ZHANG Yujie, HUO Lukuan, LIU Yanbin. Research progress and prospects of exosomal microRNAs in bone malignancies. West China Medical Journal, 2024, 39(12): 1978-1982. doi: 10.7507/1002-0179.202410007 Copy

1.	Hernandez RK, Wade SW, Reich A, et al. Incidence of bone metastases in patients with solid tumors: analysis of oncology electronic medical records in the United States. BMC Cancer, 2018, 18(1): 44.
2.	Sato-Kuwabara Y, Melo SA, Soares FA, et al. The fusion of two worlds: non-coding RNAs and extracellular vesicles--diagnostic and therapeutic implications (Review). Int J Oncol, 2015, 46(1): 17-27.
3.	Zhang J, Li S, Li L, et al. Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics Proteomics Bioinformatics, 2015, 13(1): 17-24.
4.	Tay Y, Zhang J, Thomson AM, et al. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature, 2008, 455(7216): 1124-1128.
5.	Gallo A, Tandon M, Alevizos I, et al. The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS One, 2012, 7(3): e30679.
6.	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin, 2018, 68(1): 7-30.
7.	Wang JW, Wu XF, Gu XJ, et al. Exosomal miR-1228 from cancer-associated fibroblasts promotes cell migration and invasion of osteosarcoma by directly targeting SCAI. Oncol Res, 2019, 27(9): 979-986.
8.	Wu C, Li Z, Feng G, et al. Tumor suppressing role of serum-derived exosomal microRNA-15a in osteosarcoma cells through the GATA binding protein 2/murine double minute 2 axis and the p53 signaling pathway. Bioengineered, 2021, 12(1): 8378-8395.
9.	Jiang M, Jike Y, Liu K, et al. Exosome-mediated miR-144-3p promotes ferroptosis to inhibit osteosarcoma proliferation, migration, and invasion through regulating ZEB1. Mol Cancer, 2023, 22(1): 113.
10.	Liu W, Long Q, Zhang W, et al. miRNA-221-3p derived from M2-polarized tumor-associated macrophage exosomes aggravates the growth and metastasis of osteosarcoma through SOCS3/JAK2/STAT3 axis. Aging (Albany NY), 2021, 13(15): 19760-19775.
11.	Gaspar N, Occean BV, Pacquement H, et al. Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study. Eur J Cancer, 2018, 88: 57-66.
12.	Bai Y, Li Y, Bai J, et al. Hsa_circ_0004674 promotes osteosarcoma doxorubicin resistance by regulating the miR-342-3p/FBN1 axis. J Orthop Surg Res, 2021, 16(1): 510.
13.	Ma Y, Ren Y, Han EQ, et al. Inhibition of the Wnt-β-catenin and Notch signaling pathways sensitizes osteosarcoma cells to chemotherapy. Biochem Biophys Res Commun, 2013, 431(2): 274-279.
14.	Meng C, Yang Y, Feng W, et al. Exosomal miR-331-3p derived from chemoresistant osteosarcoma cells induces chemoresistance through autophagy. J Orthop Surg Res, 2023, 18(1): 892.
15.	Nicolle R, Ayadi M, Gomez-Brouchet A, et al. Integrated molecular characterization of chondrosarcoma reveals critical determinants of disease progression. Nat Commun, 2019, 10(1): 4622.
16.	Zając AE, Kopeć S, Szostakowski B, et al. Chondrosarcoma-from molecular pathology to novel therapies. Cancers (Basel), 2021, 13(10): 2390.
17.	Cheng C, Zhang Z, Cheng F, et al. Exosomal lncRNA RAMP2-AS1 derived from chondrosarcoma cells promotes angiogenesis through miR-2355-5p/VEGFR2 axis. Onco Targets Ther, 2020, 13: 3291-3301.
18.	Chicón-Bosch M, Tirado OM. Exosomes in bone sarcomas: key players in metastasis. Cells, 2020, 9(1): 241.
19.	Yu J, Ostowari A, Gonda A, et al. Exosomes as a source of biomarkers for gastrointestinal cancers. Cancers (Basel), 2023, 15(4): 1263.
20.	Zhang XH, Song YC, Qiu F, et al. Hypoxic glioma cell-secreted exosomal circ101491 promotes the progression of glioma by regulating miR-125b-5p/EDN1. Brain Res Bull, 2023, 195: 55-65.
21.	Xie L, Zhang K, You B, et al. Hypoxic nasopharyngeal carcinoma-derived exosomal miR-455 increases vascular permeability by targeting ZO-1 to promote metastasis. Mol Carcinog, 2023, 62(6): 803-819.
22.	Park JE, Dutta B, Tse SW, et al. Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift. Oncogene, 2019, 38(26): 5158-5173.
23.	Tzeng HE, Lin SL, Thadevoos LA, et al. Nerve growth factor promotes lysyl oxidase-dependent chondrosarcoma cell metastasis by suppressing miR-149-5p synthesis. Cell Death Dis, 2021, 12(12): 1101.
24.	Sánchez-Molina S, Figuerola-Bou E, Sánchez-Margalet V, et al. Ewing sarcoma meets epigenetics, immunology and nanomedicine: moving forward into novel therapeutic strategies. Cancers (Basel), 2022, 14(21): 5473.
25.	Kling MJ, Chaturvedi NK, Kesherwani V, et al. Exosomes secreted under hypoxia enhance stemness in Ewing’s sarcoma through miR-210 delivery. Oncotarget, 2020, 11(40): 3633-3645.
26.	Ventura S, Aryee DN, Felicetti F, et al. CD99 regulates neural differentiation of Ewing sarcoma cells through miR-34a-Notch-mediated control of NF-κB signaling. Oncogene, 2016, 35(30): 3944-3954.
27.	Galardi A, Colletti M, Di Paolo V, et al. Exosomal miRNAs in pediatric cancers. Int J Mol Sci, 2019, 20(18): 4600.
28.	Kohama I, Asano N, Matsuzaki J, et al. Comprehensive serum and tissue microRNA profiling in dedifferentiated liposarcoma. Oncol Lett, 2021, 22(2): 623.
29.	Weaver DT, Pishas KI, Williamson D, et al. Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma. PLoS Comput Biol, 2021, 17(10): e1008755.
30.	Rodriguez-Galindo C, Billups CA, Kun LE, et al. Survival after recurrence of Ewing tumors: the St Jude Children’s Research Hospital experience, 1979-1999. Cancer, 2002, 94(2): 561-569.
31.	Robin TP, Smith A, McKinsey E, et al. EWS/FLI1 regulates EYA3 in Ewing sarcoma via modulation of miRNA-708, resulting in increased cell survival and chemoresistance. Mol Cancer Res, 2012, 10(8): 1098-1108.
32.	Liu Y, Peng C, Zhang H, et al. DNA aptamer S11e recognizes fibrosarcoma and acts as a tumor suppressor. Bioact Mater, 2021, 12: 278-291.
33.	Augsburger D, Nelson PJ, Kalinski T, et al. Current diagnostics and treatment of fibrosarcoma -perspectives for future therapeutic targets and strategies. Oncotarget, 2017, 8(61): 104638-104653.
34.	Lyu TS, Ahn Y, Im YJ, et al. The characterization of exosomes from fibrosarcoma cell and the useful usage of Dynamic Light Scattering (DLS) for their evaluation. PLoS One, 2021, 16(1): e0231994.
35.	Liu P, Wilson MJ. miR-520c and miR-373 upregulate MMP9 expression by targeting mTOR and SIRT1, and activate the Ras/Raf/MEK/Erk signaling pathway and NF-κB factor in human fibrosarcoma cells. J Cell Physiol, 2012, 227(2): 867-876.
36.	Weng C, Dong H, Chen G, et al. miR-409-3p inhibits HT1080 cell proliferation, vascularization and metastasis by targeting angiogenin. Cancer Lett, 2012, 323(2): 171-179.
37.	Samantarrai D, Mallick B. miR-429 inhibits metastasis by targeting KIAA0101 in soft tissue sarcoma. Exp Cell Res, 2017, 357(1): 33-39.
38.	Jain N, Das B, Mallick B. miR-197-5p increases doxorubicin-mediated anticancer cytotoxicity of HT1080 fibrosarcoma cells by decreasing drug efflux. DNA Repair (Amst), 2022, 109: 103259.
39.	Jain N, Das B, Mallick B. Restoration of microRNA-197 expression suppresses oncogenicity in fibrosarcoma through negative regulation of RAN. IUBMB Life, 2020, 72(5): 1034-1044.
40.	Long F, Tian L, Chai Z, et al. Identification of stage-associated exosome miRNAs in colorectal cancer by improved robust and corroborative approach embedded miRNA-target network. Front Med (Lausanne), 2022, 9: 881788.
41.	Torres-Bustamante MI, Vazquez-Urrutia JR, Solorzano-Ibarra F, et al. The role of miRNAs to detect progression, stratify, and predict relevant clinical outcomes in bladder cancer. Int J Mol Sci, 2024, 25(4): 2178.
42.	Murshed A, Alnoud MAH, Ahmad S, et al. Genetic alchemy unveiled: microRNA-mediated gene therapy as the Artisan craft in the battlefront against hepatocellular carcinoma-a comprehensive chronicle of strategies and innovations. Front Genet, 2024, 15: 1356972.
43.	Xie Y, Chen Y, Zhang L, et al. The roles of bone-derived exosomes and exosomal microRNAs in regulating bone remodelling. J Cell Mol Med, 2017, 21(5): 1033-1041.

1. Hernandez RK, Wade SW, Reich A, et al. Incidence of bone metastases in patients with solid tumors: analysis of oncology electronic medical records in the United States. BMC Cancer, 2018, 18(1): 44.
2. Sato-Kuwabara Y, Melo SA, Soares FA, et al. The fusion of two worlds: non-coding RNAs and extracellular vesicles--diagnostic and therapeutic implications (Review). Int J Oncol, 2015, 46(1): 17-27.
3. Zhang J, Li S, Li L, et al. Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics Proteomics Bioinformatics, 2015, 13(1): 17-24.
4. Tay Y, Zhang J, Thomson AM, et al. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature, 2008, 455(7216): 1124-1128.
5. Gallo A, Tandon M, Alevizos I, et al. The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS One, 2012, 7(3): e30679.
6. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin, 2018, 68(1): 7-30.
7. Wang JW, Wu XF, Gu XJ, et al. Exosomal miR-1228 from cancer-associated fibroblasts promotes cell migration and invasion of osteosarcoma by directly targeting SCAI. Oncol Res, 2019, 27(9): 979-986.
8. Wu C, Li Z, Feng G, et al. Tumor suppressing role of serum-derived exosomal microRNA-15a in osteosarcoma cells through the GATA binding protein 2/murine double minute 2 axis and the p53 signaling pathway. Bioengineered, 2021, 12(1): 8378-8395.
9. Jiang M, Jike Y, Liu K, et al. Exosome-mediated miR-144-3p promotes ferroptosis to inhibit osteosarcoma proliferation, migration, and invasion through regulating ZEB1. Mol Cancer, 2023, 22(1): 113.
10. Liu W, Long Q, Zhang W, et al. miRNA-221-3p derived from M2-polarized tumor-associated macrophage exosomes aggravates the growth and metastasis of osteosarcoma through SOCS3/JAK2/STAT3 axis. Aging (Albany NY), 2021, 13(15): 19760-19775.
11. Gaspar N, Occean BV, Pacquement H, et al. Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study. Eur J Cancer, 2018, 88: 57-66.
12. Bai Y, Li Y, Bai J, et al. Hsa_circ_0004674 promotes osteosarcoma doxorubicin resistance by regulating the miR-342-3p/FBN1 axis. J Orthop Surg Res, 2021, 16(1): 510.
13. Ma Y, Ren Y, Han EQ, et al. Inhibition of the Wnt-β-catenin and Notch signaling pathways sensitizes osteosarcoma cells to chemotherapy. Biochem Biophys Res Commun, 2013, 431(2): 274-279.
14. Meng C, Yang Y, Feng W, et al. Exosomal miR-331-3p derived from chemoresistant osteosarcoma cells induces chemoresistance through autophagy. J Orthop Surg Res, 2023, 18(1): 892.
15. Nicolle R, Ayadi M, Gomez-Brouchet A, et al. Integrated molecular characterization of chondrosarcoma reveals critical determinants of disease progression. Nat Commun, 2019, 10(1): 4622.
16. Zając AE, Kopeć S, Szostakowski B, et al. Chondrosarcoma-from molecular pathology to novel therapies. Cancers (Basel), 2021, 13(10): 2390.
17. Cheng C, Zhang Z, Cheng F, et al. Exosomal lncRNA RAMP2-AS1 derived from chondrosarcoma cells promotes angiogenesis through miR-2355-5p/VEGFR2 axis. Onco Targets Ther, 2020, 13: 3291-3301.
18. Chicón-Bosch M, Tirado OM. Exosomes in bone sarcomas: key players in metastasis. Cells, 2020, 9(1): 241.
19. Yu J, Ostowari A, Gonda A, et al. Exosomes as a source of biomarkers for gastrointestinal cancers. Cancers (Basel), 2023, 15(4): 1263.
20. Zhang XH, Song YC, Qiu F, et al. Hypoxic glioma cell-secreted exosomal circ101491 promotes the progression of glioma by regulating miR-125b-5p/EDN1. Brain Res Bull, 2023, 195: 55-65.
21. Xie L, Zhang K, You B, et al. Hypoxic nasopharyngeal carcinoma-derived exosomal miR-455 increases vascular permeability by targeting ZO-1 to promote metastasis. Mol Carcinog, 2023, 62(6): 803-819.
22. Park JE, Dutta B, Tse SW, et al. Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift. Oncogene, 2019, 38(26): 5158-5173.
23. Tzeng HE, Lin SL, Thadevoos LA, et al. Nerve growth factor promotes lysyl oxidase-dependent chondrosarcoma cell metastasis by suppressing miR-149-5p synthesis. Cell Death Dis, 2021, 12(12): 1101.
24. Sánchez-Molina S, Figuerola-Bou E, Sánchez-Margalet V, et al. Ewing sarcoma meets epigenetics, immunology and nanomedicine: moving forward into novel therapeutic strategies. Cancers (Basel), 2022, 14(21): 5473.
25. Kling MJ, Chaturvedi NK, Kesherwani V, et al. Exosomes secreted under hypoxia enhance stemness in Ewing’s sarcoma through miR-210 delivery. Oncotarget, 2020, 11(40): 3633-3645.
26. Ventura S, Aryee DN, Felicetti F, et al. CD99 regulates neural differentiation of Ewing sarcoma cells through miR-34a-Notch-mediated control of NF-κB signaling. Oncogene, 2016, 35(30): 3944-3954.
27. Galardi A, Colletti M, Di Paolo V, et al. Exosomal miRNAs in pediatric cancers. Int J Mol Sci, 2019, 20(18): 4600.
28. Kohama I, Asano N, Matsuzaki J, et al. Comprehensive serum and tissue microRNA profiling in dedifferentiated liposarcoma. Oncol Lett, 2021, 22(2): 623.
29. Weaver DT, Pishas KI, Williamson D, et al. Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma. PLoS Comput Biol, 2021, 17(10): e1008755.
30. Rodriguez-Galindo C, Billups CA, Kun LE, et al. Survival after recurrence of Ewing tumors: the St Jude Children’s Research Hospital experience, 1979-1999. Cancer, 2002, 94(2): 561-569.
31. Robin TP, Smith A, McKinsey E, et al. EWS/FLI1 regulates EYA3 in Ewing sarcoma via modulation of miRNA-708, resulting in increased cell survival and chemoresistance. Mol Cancer Res, 2012, 10(8): 1098-1108.
32. Liu Y, Peng C, Zhang H, et al. DNA aptamer S11e recognizes fibrosarcoma and acts as a tumor suppressor. Bioact Mater, 2021, 12: 278-291.
33. Augsburger D, Nelson PJ, Kalinski T, et al. Current diagnostics and treatment of fibrosarcoma -perspectives for future therapeutic targets and strategies. Oncotarget, 2017, 8(61): 104638-104653.
34. Lyu TS, Ahn Y, Im YJ, et al. The characterization of exosomes from fibrosarcoma cell and the useful usage of Dynamic Light Scattering (DLS) for their evaluation. PLoS One, 2021, 16(1): e0231994.
35. Liu P, Wilson MJ. miR-520c and miR-373 upregulate MMP9 expression by targeting mTOR and SIRT1, and activate the Ras/Raf/MEK/Erk signaling pathway and NF-κB factor in human fibrosarcoma cells. J Cell Physiol, 2012, 227(2): 867-876.
36. Weng C, Dong H, Chen G, et al. miR-409-3p inhibits HT1080 cell proliferation, vascularization and metastasis by targeting angiogenin. Cancer Lett, 2012, 323(2): 171-179.
37. Samantarrai D, Mallick B. miR-429 inhibits metastasis by targeting KIAA0101 in soft tissue sarcoma. Exp Cell Res, 2017, 357(1): 33-39.
38. Jain N, Das B, Mallick B. miR-197-5p increases doxorubicin-mediated anticancer cytotoxicity of HT1080 fibrosarcoma cells by decreasing drug efflux. DNA Repair (Amst), 2022, 109: 103259.
39. Jain N, Das B, Mallick B. Restoration of microRNA-197 expression suppresses oncogenicity in fibrosarcoma through negative regulation of RAN. IUBMB Life, 2020, 72(5): 1034-1044.
40. Long F, Tian L, Chai Z, et al. Identification of stage-associated exosome miRNAs in colorectal cancer by improved robust and corroborative approach embedded miRNA-target network. Front Med (Lausanne), 2022, 9: 881788.
41. Torres-Bustamante MI, Vazquez-Urrutia JR, Solorzano-Ibarra F, et al. The role of miRNAs to detect progression, stratify, and predict relevant clinical outcomes in bladder cancer. Int J Mol Sci, 2024, 25(4): 2178.
42. Murshed A, Alnoud MAH, Ahmad S, et al. Genetic alchemy unveiled: microRNA-mediated gene therapy as the Artisan craft in the battlefront against hepatocellular carcinoma-a comprehensive chronicle of strategies and innovations. Front Genet, 2024, 15: 1356972.
43. Xie Y, Chen Y, Zhang L, et al. The roles of bone-derived exosomes and exosomal microRNAs in regulating bone remodelling. J Cell Mol Med, 2017, 21(5): 1033-1041.

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