Exosomal Circular RNAs Mediates Chemotherapy Resistance in Tumors
GENG Xiu-Chao1),2),3), LI Qiang1),4)*, WANG Hong2),3),5)
1)School of Medicine, Taizhou University, Taizhou 318000, Zhejiang, China; 2)Faculty of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China; 3)Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Hebei Province, Shijiazhuang 050091, China; 4)Faculty of Acupuncture-Moxibustion and Tuina, Hebei University of Chinese Medicine, Shijiazhuang 050200, China; 5)Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding 071000, Hebei, China
Abstract:As an important member of the non-coding RNA family, circRNA is a kind of single-stranded RNA with a covalently closed loop structure without a polyadenylated acid tail and 5′-3′ end, showing high stability, abundance and conservation across species characteristics. Recent studies have shown that circRNA plays an important role in many biological processes, including chemotherapy resistance and malignant progression. Exosomes are small extracellular phospholipid bilayer vesicles with a diameter of 30-150 nm that are secreted by living cells. They can be used as carriers to encapsulate and transfer functional molecules. Exosomes are important mediators of communication between tumor cells and stromal cells. They can play a role in the transmission of chemoresistance by transferring circRNA. As chemotherapy resistance is still a huge obstacle to the prognosis of cancer, the research of exosomal circRNA-mediated tumor chemotherapy resistance is at the forefront of academic research, which is a blue ocean with important significance. In this paper, we summarized the latest research progress in the aspects of exosome delivery of circRNA, the mechanism of exosome sorting non-coding RNA cargo, circRNA-mediated tumor chemotherapy resistance, exosome delivery of circRNA-mediated tumor chemotherapy resistance and its potential clinical application, which may provide a reference for the research of tumor chemotherapy resistance.
[1] Van Niel G, D′angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles[J]. Nat Rev Mol Cell Biol, 2018,19(4): 213-228 [2] Wang G, Liu W, Zou Y, et al. Three isoforms of exosomal circPTGR1 promote hepatocellular carcinoma metastasis via the miR449a-MET pathway[J]. EBioMedicine, 2019,40: 432-445 [3] Li J, Li Z, Jiang P, et al. Circular RNA IARS(circ-IARS) secreted by pancreatic cancer cells and located within exosomes regulates endothelial monolayer permeability to promote tumor metastasis[J]. J Exp Clin Cancer Res, 2018,37(1): 177 [4] Chen LL, Yang L. Regulation of circRNA biogenesis[J]. RNA Biol, 2015,12(4): 381-388 [5] Rybak-Wolf A, Stottmeister C, Glazar P, et al. Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed[J]. Mol Cell, 2015,58(5): 870-885 [6] Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges[J]. Nature, 2013,495(7441): 384-388 [7] Abdelmohsen K, Panda AC, Munk R, et al. Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1[J]. RNA Biol, 2017,14(3): 361-369 [8] Zeng Y, Du WW, Wu Y, et al. A Circular RNA Binds To and Activates AKT Phosphorylation and Nuclear Localization Reducing Apoptosis and Enhancing Cardiac Repair[J]. Theranostics, 2017,7(16): 3842-3855 [9] Wu N, Yuan Z, Du KY, et al. Translation of yes-associated protein(YAP) was antagonized by its circular RNA via suppressing the assembly of the translation initiation machinery[J]. Cell Death Differ, 2019,26(12): 2758-2773 [10] Yang Y, Gao X, Zhang M, et al. Novel Role of FBXW7 Circular RNA in Repressing Glioma Tumorigenesis[J]. J Natl Cancer Inst, 2018,110(3): 304-315 [11] Geng X, Jia Y, Zhang Y, et al. Circular RNA: biogenesis, degradation, functions and potential roles in mediating resistance to anticarcinogens[J]. Epigenomics, 2020,12(3): 267-283 [12] Zhang Y, Lin X, Geng X, et al. Advances in circular RNAs and their role in glioma(Review)[J]. Int J Oncol, 2020,57(1): 67-79 [13] Zhang Z, Yin J, Lu C, et al. Exosomal transfer of long non-coding RNA SBF2-AS1 enhances chemoresistance to temozolomide in glioblastoma[J]. J Exp Clin Cancer Res, 2019,38(1): 166 [14] Zhao Z, Ji M, Wang Q, et al. Circular RNA Cdr1as Upregulates SCAI to Suppress Cisplatin Resistance in Ovarian Cancer via miR-1270 Suppression[J]. Mol Ther Nucleic Acids, 2019,18: 24-33 [15] Xie M, Yu T, Jing X, et al. Exosomal circSHKBP1 promotes gastric cancer progression via regulating the miR-582-3p/HUR/VEGF axis and suppressing HSP90 degradation[J]. Mol Cancer, 2020,19(1): 112 [16] Li Y, Zheng Q, Bao C, et al. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis[J]. Cell Res, 2015,25(8): 981-984 [17] Dou Y, Cha DJ, Franklin JL, et al. Circular RNAs are down-regulated in KRAS mutant colon cancer cells and can be transferred to exosomes[J]. Sci Rep, 2016,6: 37982 [18] Jeck WR, Sorrentino JA, Wang K, et al. Circular RNAs are abundant, conserved, and associated with ALU repeats[J]. RNA, 2013,19(2): 141-157 [19] Lasda E, Parker R. Circular RNAs Co-Precipitate with Extracellular Vesicles: A Possible Mechanism for circRNA Clearance[J]. PLoS One, 2016,11(2): e0148407 [20] Chen C, Zong S, Wang Z, et al. Visualization and intracellular dynamic tracking of exosomes and exosomal miRNAs using single molecule localization microscopy[J]. Nanoscale, 2018,10(11): 5154-5162 [21] Clancy JW, Zhang Y, Sheehan C, et al. An ARF6-Exportin-5 axis delivers pre-miRNA cargo to tumour microvesicles[J]. Nat Cell Biol, 2019,21(7): 856-866 [22] Melo SA, Sugimoto H, O′connell JT, et al. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis[J]. Cancer Cell, 2014,26(5): 707-721 [23] Mckenzie AJ, Hoshino D, Hong NH, et al. KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes[J]. Cell Rep, 2016,15(5): 978-987 [24] Villarroya-Beltri C, Gutierrez-Vazquez C, Sanchez-Cabo F, et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs[J]. Nat Commun, 2013,4: 2980 [25] Qu L, Ding J, Chen C, et al. Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA[J]. Cancer Cell, 2016,29(5): 653-668 [26] Shurtleff MJ, Temoche-Diaz MM, Karfilis KV, et al. Y-box protein 1 is required to sort microRNAs into exosomes in cells and in a cell-free reaction[J]. Elife, 2016,5: e19276 [27] Preusser C, Hung LH, Schneider T, et al. Selective release of circRNAs in platelet-derived extracellular vesicles[J]. J Extracell Vesicles, 2018,7(1): 1424473 [28] Hong W, Xue M, Jiang J, et al. Circular RNA circ-CPA4/ let-7 miRNA/PD-L1 axis regulates cell growth, stemness, drug resistance and immune evasion in non-small cell lung cancer(NSCLC)[J]. J Exp Clin Cancer Res, 2020,39(1): 149 [29] Xu J, Wan Z, Tang M, et al. N(6)-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling[J]. Mol Cancer, 2020,19(1): 163 [30] Su Y, Yang W, Jiang N, et al. Hypoxia-elevated circELP3 contributes to bladder cancer progression and cisplatin resistance[J]. Int J Biol Sci, 2019,15(2): 441-452 [31] Huang W, Yang Y, Wu J, et al. Circular RNA cESRP1 sensitises small cell lung cancer cells to chemotherapy by sponging miR-93-5p to inhibit TGF-β signalling[J]. Cell Death Differ, 2020,27(5): 1709-1727 [32] Liu J, Du F, Chen C, et al. CircRNA ITCH increases bortezomib sensitivity through regulating the miR-615-3p/PRKCD axis in multiple myeloma[J]. Life Sci, 2020,262: 118506 [33] Xu N, Chen S, Liu Y, et al. Profiles and Bioinformatics Analysis of Differentially Expressed Circrnas in Taxol-Resistant Non-Small Cell Lung Cancer Cells[J]. Cell Physiol Biochem, 2018,48(5): 2046-2060 [34] Li X, Feng Y, Yang B, et al. A novel circular RNA, hsa_circ_0030998 suppresses lung cancer tumorigenesis and Taxol resistance by sponging miR-558[J]. Mol Oncol, 2020, Nov 15 [Epub ahead of print] [35] Li X, Yang B, Ren H, et al. Hsa_circ_0002483 inhibited the progression and enhanced the Taxol sensitivity of non-small cell lung cancer by targeting miR-182-5p[J]. Cell Death Dis, 2019,10(12): 953 [36] Li J, Fan R, Xiao H. Circ_ZFR contributes to the paclitaxel resistance and progression of non-small cell lung cancer by upregulating KPNA4 through sponging miR-195-5p[J]. Cancer Cell Int, 2021,21(1): 15 [37] Joseph NA, Chiou SH, Lung Z, et al. The role of HGF-MET pathway and CCDC66 cirRNA expression in EGFR resistance and epithelial-to-mesenchymal transition of lung adenocarcinoma cells[J]. J Hematol Oncol, 2018,11(1): 74 [38] Zhu X, Han J, Lan H, et al. A novel circular RNA hsa_circRNA_103809/miR-377-3p/GOT1 pathway regulates cisplatin-resistance in non-small cell lung cancer(NSCLC)[J]. BMC Cancer, 2020,20(1): 1190 [39] Chen C, Zhang M, Zhang Y. Circ_0000079 Decoys the RNA-Binding Protein FXR1 to Interrupt Formation of the FXR1/PRCKI Complex and Decline Their Mediated Cell Invasion and Drug Resistance in NSCLC[J]. Cell Transplant, 2020,29: 963689720961070 [40] Zhao Y, Zheng R, Chen J, et al. CircRNA CDR1as/miR-641/HOXA9 pathway regulated stemness contributes to cisplatin resistance in non-small cell lung cancer(NSCLC)[J]. Cancer Cell Int, 2020,20: 289 [41] Zhang W, Song C, Ren X. Circ_0003998 Regulates the Progression and Docetaxel Sensitivity of DTX-Resistant Non-Small Cell Lung Cancer Cells by the miR-136-5p/CORO1C Axis[J]. Technol Cancer Res Treat, 2021,20: 1533033821990040 [42] Zhou Y, Zheng X, Xu B, et al. Circular RNA hsa_circ_0004015 regulates the proliferation, invasion, and TKI drug resistance of non-small cell lung cancer by miR-1183/PDPK1 signaling pathway[J]. Biochem Biophys Res Commun, 2019,508(2): 527-535 [43] Zheng F, Xu R. CircPVT1 contributes to chemotherapy resistance of lung adenocarcinoma through miR-145-5p/ABCC1 axis[J]. Biomed Pharmacother, 2020,124: 109828 [44] Mao Y, Xu R. Circular RNA CDR1-AS contributes to pemetrexed and cisplatin chemoresistance through EGFR/PI3K signaling pathway in lung adenocarcinoma[J]. Biomed Pharmacother, 2020,123: 109771 [45] Hong X, Liu N, Liang Y, et al. Circular RNA CRIM1 functions as a ceRNA to promote nasopharyngeal carcinoma metastasis and docetaxel chemoresistance through upregulating FOXQ1[J]. Mol Cancer, 2020,19(1): 33 [46] Sang Y, Chen B, Song X, et al. circRNA_0025202 Regulates Tamoxifen Sensitivity and Tumor Progression via Regulating the miR-182-5p/FOXO3a Axis in Breast Cancer[J]. Mol Ther, 2019,27(9): 1638-1652 [47] Gao D, Zhang X, Liu B, et al. Screening circular RNA related to chemotherapeutic resistance in breast cancer[J]. Epigenomics, 2017,9(9): 1175-1188 [48] Li H, Xu W, Xia Z, et al. Hsa_circ_0000199 facilitates chemo-tolerance of triple-negative breast cancer by interfering with miR-206/613-led PI3K/Akt/mTOR signaling[J]. Aging(Albany NY), 2021,12[Epub ahead of print] [49] Luo Y, Fu Y, Huang R, et al. CircRNA_101505 sensitizes hepatocellular carcinoma cells to cisplatin by sponging miR-103 and promotes oxidored-nitro domain-containing protein 1 expression[J]. Cell Death Discov, 2019,5: 121 [50] Chen H, Liu S, Li M, et al. circ_0003418 Inhibits Tumorigenesis And Cisplatin Chemoresistance Through Wnt/β-Catenin Pathway In Hepatocellular Carcinoma[J]. Onco Targets Ther, 2019,12: 9539-9549 [51] Huang X, Li Z, Zhang Q, et al. Circular RNA AKT3 upregulates PIK3R1 to enhance cisplatin resistance in gastric cancer via miR-198 suppression[J]. Mol Cancer, 2019,18(1): 71 [52] Zhang Z, Yu X, Zhou B, et al. Circular RNA circ_0026359 Enhances Cisplatin Resistance in Gastric Cancer via Targeting miR-1200/POLD4 Pathway[J]. Biomed Res Int, 2020,2020: 5103272 [53] Zhang Q, Miao Y, Fu Q, et al. CircRNACCDC66 regulates cisplatin resistance in gastric cancer via the miR-618/BCL2 axis[J]. Biochem Biophys Res Commun, 2020,526(3): 713-720 [54] Zhong Y, Wang D, Ding Y, et al. Circular RNA circ_0032821 contributes to oxaliplatin(OXA) resistance of gastric cancer cells by regulating SOX9 via miR-515-5p[J]. Biotechnol Lett, 2021,43(2): 339-351 [55] Xu QY, Xie MJ, Huang J, et al. Effect of circ MTHFD2 on resistance to pemetrexed in gastric cancer through regulating expression of miR-124[J]. Eur Rev Med Pharmacol Sci, 2019,23(23): 10290-10299 [56] Liu YY, Zhang LY, Du WZ. Circular RNA circ-PVT1 contributes to paclitaxel resistance of gastric cancer cells through the regulation of ZEB1 expression by sponging miR-124-3p[J]. Biosci Rep, 2019,39(12): BSR20193045 [57] Xu C, Yu Y, Ding F. Microarray analysis of circular RNA expression profiles associated with gemcitabine resistance in pancreatic cancer cells[J]. Oncol Rep, 2018,40(1): 395-404 [58] Chi BJ, Zhao DM, Liu L, et al. Downregulation of hsa_circ_0000285 serves as a prognostic biomarker for bladder cancer and is involved in cisplatin resistance[J]. Neoplasma, 2019,66(2): 197-202 [59] Chen H, Pei L, Xie P, et al. Circ-PRKDC Contributes to 5-Fluorouracil Resistance of Colorectal Cancer Cells by Regulating miR-375/FOXM1 Axis and Wnt/β-Catenin Pathway[J]. Onco Targets Ther, 2020,13: 5939-5953 [60] Wang X, Zhang H, Yang H, et al. Exosome-delivered circRNA promotes glycolysis to induce chemoresistance through the miR-122-PKM2 axis in colorectal cancer[J]. Mol Oncol, 2020,14(3): 539-555 [61] Li S, Zheng S. Down-Regulation of Circ_0032833 Sensitizes Colorectal Cancer to 5-Fluorouracil and Oxaliplatin Partly Depending on the Regulation of miR-125-5p and MSI1[J]. Cancer Manag Res, 2020,12: 11257-11269 [62] Lai M, Liu G, Li R, et al. Hsa_circ_0079662 induces the resistance mechanism of the chemotherapy drug oxaliplatin through the TNF-α pathway in human colon cancer[J]. J Cell Mol Med, 2020,24(9): 5021-5027 [63] Jian X, He H, Zhu J, et al. Hsa_circ_001680 affects the proliferation and migration of CRC and mediates its chemoresistance by regulating BMI1 through miR-340[J]. Mol Cancer, 2020,19(1): 20 [64] Yan L, Liu G, Cao H, et al. Hsa_circ_0035483 sponges hsa-miR-335 to promote the gemcitabine-resistance of human renal cancer cells by autophagy regulation[J]. Biochem Biophys Res Commun, 2019,519(1): 172-178 [65] Ding C, Yi X, Wu X, et al. Exosome-mediated transfer of circRNA CircNFIX enhances temozolomide resistance in glioma[J]. Cancer Lett, 2020,479: 1-12 [66] Yin H, Cui X. Knockdown of circHIPK3 Facilitates Temozolomide Sensitivity in Glioma by Regulating Cellular Behaviors Through miR-524-5p/KIF2A-Mediated PI3K/AKT Pathway[J]. Cancer Biother Radiopharm, 2020[Epub ahead of print] [67] Deng Y, Zhu H, Xiao L, et al. Circ_0005198 enhances temozolomide resistance of glioma cells through miR-198/TRIM14 axis[J]. Aging(Albany NY), 2020,13(2): 2198-2211 [68] Shang J, Chen WM, Wang ZH, et al. CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p-XIAP axis[J]. Exp Hematol, 2019,70: 42-54.e43 [69] Shang J, Chen WM, Liu S, et al. CircPAN3 contributes to drug resistance in acute myeloid leukemia through regulation of autophagy[J]. Leuk Res, 2019,85: 106198 [70] Cao HX, Miao CF, Sang LN, et al. Circ_0009910 promotes imatinib resistance through ULK1-induced autophagy by sponging miR-34a-5p in chronic myeloid leukemia[J]. Life Sci, 2020,243: 117255 [71] Song Y, Hu N, Song X, et al. Hsa_Circ_0007841 Enhances Multiple Myeloma Chemotherapy Resistance Through Upregulating ABCG2[J]. Technol Cancer Res Treat, 2020,19: 1533033820928371 [72] Zhang H, Yan J, Lang X, et al. Expression of circ_001569 is upregulated in osteosarcoma and promotes cell proliferation and cisplatin resistance by activating the Wnt/beta-catenin signaling pathway[J]. Oncol Lett, 2018,16(5): 5856-5862 [73] Zhang J, Ma X, Zhou R, et al. TRPS1 and YAP1 Regulate Cell Proliferation and Drug Resistance of Osteosarcoma via Competitively Binding to the Target of circTADA2A - miR-129-5p[J]. Onco Targets Ther, 2020,13: 12397-12407 [74] Zhu KP, Zhang CL, Ma XL, et al. Analyzing the Interactions of mRNAs and ncRNAs to Predict Competing Endogenous RNA Networks in Osteosarcoma Chemo-Resistance[J]. Mol Ther, 2019,27(3): 518-530 [75] Kun-Peng Z, Xiao-Long M, Chun-Lin Z. Overexpressed circPVT1, a potential new circular RNA biomarker, contributes to doxorubicin and cisplatin resistance of osteosarcoma cells by regulating ABCB1[J]. Int J Biol Sci, 2018,14(3): 321-330 [76] Kun-Peng Z, Xiao-Long M, Lei Z, et al. Screening circular RNA related to chemotherapeutic resistance in osteosarcoma by RNA sequencing[J]. Epigenomics, 2018,10(10): 1327-1346 [77] Guo M, Li S, Zhao X, et al. Knockdown of Circular RNA Hsa_circ_0000714 Can Regulate RAB17 by Sponging miR-370-3p to Reduce Paclitaxel Resistance of Ovarian Cancer Through CDK6/RB Pathway[J]. Onco Targets Ther, 2020,13: 13211-13224 [78] Zhang S, Cheng J, Quan C, et al. circCELSR1(hsa_circ_0063809) Contributes to Paclitaxel Resistance of Ovarian Cancer Cells by Regulating FOXR2 Expression via miR-1252[J]. Mol Ther Nucleic Acids, 2020,19: 718-730 [79] Liu F, Zhang J, Qin L, et al. Circular RNA EIF6(Hsa_circ_0060060) sponges miR-144-3p to promote the cisplatin-resistance of human thyroid carcinoma cells by autophagy regulation[J]. Aging(Albany NY), 2018,10(12): 3806-3820 [80] Zheng X, Carstens JL, Kim J, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer[J]. Nature, 2015,527(7579): 525-530 [81] Kharkar PS. Cancer Stem Cell(CSC) Inhibitors in Oncology-A Promise for a Better Therapeutic Outcome: State of the Art and Future Perspectives[J]. J Med Chem, 2020,63(24): 15279-15307 [82] Prieto-Vila M, Takahashi RU, Usuba W, et al. Drug Resistance Driven by Cancer Stem Cells and Their Niche[J]. Int J Mol Sci, 2017,18(12): 2574 [83] Wang Y, Wang Y, Qin Z, et al. The role of non-coding RNAs in ABC transporters regulation and their clinical implications of multidrug resistance in cancer[J]. Expert Opin Drug Metab Toxicol, 2021[Epub ahead of print] [84] Smith AG, Macleod KF. Autophagy, cancer stem cells and drug resistance[J]. J Pathol, 2019,247(5): 708-718 [85] Sun Y. Tumor microenvironment and cancer therapy resistance[J]. Cancer Lett, 2016,380(1): 205-215 [86] Xu X, Tao R, Sun L, et al. Exosome-transferred hsa_circ_0014235 promotes DDP chemoresistance and deteriorates the development of non-small cell lung cancer by mediating the miR-520a-5p/CDK4 pathway[J]. Cancer Cell Int, 2020,20(1): 552 [87] Hon KW, Ab-Mutalib NS, Abdullah NMA, et al. Extracellular Vesicle-derived circular RNAs confers chemoresistance in Colorectal cancer[J]. Sci Rep, 2019,9(1): 16497 [88] Yao W, Guo P, Mu Q, et al. Exosome-Derived Circ-PVT1 Contributes to Cisplatin Resistance by Regulating Autophagy, Invasion, and Apoptosis Via miR-30a-5p/YAP1 Axis in Gastric Cancer Cells[J]. Cancer Biother Radiopharm, 2020[Epub ahead of print] [89] Han C, Wang S, Wang H, et al. Exosomal Circ-HIPK3 Facilitates Tumor Progression and Temozolomide Resistance by Regulating miR-421/ZIC5 Axis in Glioma[J]. Cancer Biother Radiopharm, 2020[Epub ahead of print] [90] Pan Y, Lin Y, Mi C. Cisplatin-resistant osteosarcoma cell-derived exosomes confer cisplatin resistance to recipient cells in an exosomal circ_103801-dependent manner[J]. Cell Biol Int, 2020[Epub ahead of print] [91] Luo Y, Gui R. Circulating exosomal circFoxp1 confers cisplatin resistance in epithelial ovarian cancer cells[J]. J Gynecol Oncol, 2020,31(5): e75 [92] Hu K, Liu X, Li Y, et al. Exosomes Mediated Transfer of Circ_UBE2D2 Enhances the Resistance of Breast Cancer to Tamoxifen by Binding to MiR-200a-3p[J]. Med Sci Monit, 2020,26: e922253 [93] Syeda MM, Wiggins JM, Corless BC, et al. Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study[J]. Lancet Oncol, 2021, 22(3): 370-380 [94] Geng X, Lin X, Zhang Y, et al. Exosomal circular RNA sorting mechanisms and their function in promoting or inhibiting cancer[J]. Oncol Lett, 2020,19(5): 3369-3380 [95] Eguchi A, Kostallari E, Feldstein AE, et al. Extracellular vesicles, the liquid biopsy of the future[J]. J Hepatol, 2019,70(6): 1292-1294 [96] Geng X, Zhang Y, Li Q, et al. Screening and functional prediction of differentially expressed circular RNAs in human glioma of different grades[J]. Aging(Albany NY), 2020,13(2): 1989-2014 [97] Lu J, Wang YH, Yoon C, et al. Circular RNA circ-RanGAP1 regulates VEGFA expression by targeting miR-877-3p to facilitate gastric cancer invasion and metastasis[J]. Cancer Lett, 2020,471: 38-48 [98] Fan Q, Yang L, Zhang X, et al. The emerging role of exosome-derived non-coding RNAs in cancer biology[J]. Cancer Lett, 2018,414: 107-115 [99] Fareh M, Almairac F, Turchi L, et al. Cell-based therapy using miR-302-367 expressing cells represses glioblastoma growth[J]. Cell Death Dis, 2017,8(3): e2713 [100] Munoz JL, Bliss SA, Greco SJ, et al. Delivery of Functional Anti-miR-9 by Mesenchymal Stem Cell-derived Exosomes to Glioblastoma Multiforme Cells Conferred Chemosensitivity[J]. Mol Ther Nucleic Acids, 2013,2(10): e126 [101] Kim MS, Haney MJ, Zhao Y, et al. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells[J]. Nanomedicine, 2016,12(3): 655-664 [102] Liang G, Zhu Y, Ali DJ, et al. Engineered exosomes for targeted co-delivery of miR-21 inhibitor and chemotherapeutics to reverse drug resistance in colon cancer[J]. J Nanobiotechnology, 2020,18(1): 10