环状RNA在肿瘤中的表达与功能
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摘要
环状RNA(circular RNA,circRNA)是一类闭合环状的内源RNA分子,广泛存在于不同物种及多种人体细胞中,具有丰富性、稳定性和组织特异性等特点。人体细胞中的circRNA主要可分为外显子circRNA、环状内含子RNA和外显子-内含子circRNA等。与正常组织相比,circRNA在多种肿瘤组织中异常表达,并具有作为微小RNA(microRNA,miRNA)海绵调控miRNA、结合蛋白质、参与翻译等功能。虽然circRNA在肿瘤中异常表达的具体机制尚不明确,但其在食管鳞状细胞癌、胃癌、结直肠癌、肝细胞癌、神经胶质瘤等多种肿瘤发生、发展的分子通路中具有重要作用,并有望成为全新的肿瘤标志物和治疗靶点。circRNA领域的发展日新月异,本文根据最新研究报道,就circRNA的基本特征、异常表达机制、调控肿瘤的机制及其在多种肿瘤中发挥的作用作一综述。
Circular RNAs(circRNAs) are closed circular endogenous RNA molecules in various cells of different species. They are abundant, stable and have tissue specificity. circRNAs in human cells are divided into exonic circRNA, circular intronic RNA and exon-intron circRNA. circRNAs are aberrantly expressed in a variety of tumor tissues compared with the normal counterparts, and can serve as microRNA sponges, bind to RNA-binding proteins, and even be translated into polypeptides. Although the mechanism behind the aberrant expression of circRNAs in cancer is not clear, they play a critical role in the initiation and progression of different kinds of cancer like esophageal squamous cell carcinoma, gastric cancer, colorectal cancer, hepatocellular carcinoma, and glioma. circRNAs are also expected to be novel cancer biomarkers as well as therapeutic targets. This review summarizes recent literatures, focusing on various aspects of circRNAs, including their characteristics, mechanisms of their aberrant expression, their molecular functions in cancer, and their specific roles in several kinds of cancer.
Circular RNAs(circRNAs) are closed circular endogenous RNA molecules in various cells of different species. They are abundant, stable and have tissue specificity. circRNAs in human cells are divided into exonic circRNA, circular intronic RNA and exon-intron circRNA. circRNAs are aberrantly expressed in a variety of tumor tissues compared with the normal counterparts, and can serve as microRNA sponges, bind to RNA-binding proteins, and even be translated into polypeptides. Although the mechanism behind the aberrant expression of circRNAs in cancer is not clear, they play a critical role in the initiation and progression of different kinds of cancer like esophageal squamous cell carcinoma, gastric cancer, colorectal cancer, hepatocellular carcinoma, and glioma. circRNAs are also expected to be novel cancer biomarkers as well as therapeutic targets. This review summarizes recent literatures, focusing on various aspects of circRNAs, including their characteristics, mechanisms of their aberrant expression, their molecular functions in cancer, and their specific roles in several kinds of cancer.
引文
[1] Huang G, Li S, Yang N, et al. Recent progress in circular RNAs in human cancers[J]. Cancer Lett, 2017, 404: 8-18
[2] Sanger HL, Klotz G, Riesner D, et al. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures[J]. Proc Natl Acad Sci U S A, 1976, 73(11): 3852-3856
[3] Salzman J, Gawad C, Wang PL, et al. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types[J]. PLoS One, 2012, 7(2): e30733
[4] Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges[J]. Nature, 2013, 495(7441): 384-388
[5] 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
[6] Conn SJ, Pillman KA, Toubia J, et al. The RNA binding protein quaking regulates formation of circRNAs[J]. Cell, 2015, 160(6): 1125-1134
[7] Li Z, Huang C, Bao C, et al. Exon-intron circular RNAs regulate transcription in the nucleus[J]. Nat Struct Mol Biol, 2015, 22(3): 256-264
[8] Zhang Y, Zhang XO, Chen T, et al. Circular intronic long noncoding RNAs[J]. Mol Cell, 2013, 51(6): 792-806
[9] Guarnerio J, Bezzi M, Jeong JC, et al. Oncogenic role of fusion-circRNAs derived from cancer-associated chromosomal translocations[J]. Cell, 2016, 165(2): 289-302
[10] Meng J, Chen S, Han JX, et al. Twist1 regulates vimentin through Cul2 circular RNA to promote EMT in hepatocellular carcinoma[J]. Cancer Res, 2018, 78(15): 4150-4162
[11] Bachmayr-Heyda A, Reiner AT, Auer K, et al. Correlation of circular RNA abundance with proliferation- exemplified with colorectal and ovarian cancer, idiopathic lung fibrosis, and normal human tissues[J]. Sci Rep, 2015, 5: 8057
[12] Hansen TB, Wiklund ED, Bramsen JB, et al. miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA[J]. EMBO J, 2011, 30(21): 4414-4422
[13] Patop I L, Kadener S. circRNAs in cancer[J]. Curr Opin Genet Dev, 2018, 48:121-127
[14] Chen J, Li Y, Zheng Q, et al. Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer[J]. Cancer Lett, 2017, 388: 208-219
[15] Zheng J, Liu X, Xue Y, et al. TTBK2 circular RNA promotes glioma malignancy by regulating miR-217/HNF1beta/Derlin-1 pathway[J]. J Hematol Oncol, 2017, 10(1): 52
[16] Zhang H, Wang G, Ding C, et al. Increased circular RNA UBAP2 acts as a sponge of miR-143 to promote osteosarcoma progression[J]. Oncotarget, 2017, 8(37): 61687-61697
[17] Liu T, Liu S, Xu Y, et al. Circular RNA-ZFR inhibited cell proliferation and promoted apoptosis in gastric cancer by sponging miR-130a/miR-107 and modulating PTEN[J].Cancer Res Treat,2018, 50(4):1396-1417
[18] Xu XW, Zheng BA, Hu ZM, et al. Circular RNA hsa_circ_000984 promotes colon cancer growth and metastasis by sponging miR-106b[J]. Oncotarget, 2017, 8(53): 91674-91683
[19] Du WW, Yang W, Liu E, et al. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2[J]. Nucleic Acids Res, 2016, 44(6): 2846-2858
[20] 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
[21] 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).doi:10.1093/jnci/djx166
[22] Zhang M, Huang N, Yang X, et al. A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis[J]. Oncogene, 2018, 37(13): 1805-1814
[23] Li F, Zhang L, Li W, et al. Circular RNA ITCH has inhibitory effect on ESCC by suppressing the Wnt/beta-catenin pathway[J]. Oncotarget, 2015, 6(8): 6001-6013
[24] Su H, Lin F, Deng X, et al. Profiling and bioinformatics analyses reveal differential circular RNA expression in radioresistant esophageal cancer cells[J]. J Transl Med, 2016, 14(1): 225
[25] Xia W, Qiu M, Chen R, et al. Circular RNA hsa_circ_0067934 is upregulated in esophageal squamous cell carcinoma and promoted proliferation[J]. Sci Rep, 2016, 6: 35576
[26] Li WH, Song YC, Zhang H, et al. Decreased expression of hsa_circ_00001649 in gastric cancer and its clinical significance[J]. Dis Markers, 2017, 2017: 4587698
[27] Sun H, Tang W, Rong D, et al. Hsa_circ_0000520, a potential new circular RNA biomarker, is involved in gastric carcinoma[J]. Cancer Biomark, 2018, 21(2): 299-306
[28] Lai Z, Yang Y, Yan Y, et al. Analysis of co-expression networks for circular RNAs and mRNAs reveals that circular RNAs hsa_circ_0047905, hsa_circ_0138960 and hsa-circRNA7690-15 are candidate oncogenes in gastric cancer[J]. Cell Cycle, 2017, 16(23): 2301-2311
[29] Zhang J, Liu H, Hou L, et al. Circular RNA_LARP4 inhibits cell proliferation and invasion of gastric cancer by sponging miR-424-5p and regulating LATS1 expression[J]. Mol Cancer, 2017, 16(1): 151
[30] Wang J, Li X, Lu L, et al. Circular RNA hsa_circ_0000567 can be used as a promising diagnostic biomarker for human colorectal cancer[J]. J Clin Lab Anal, 2018, 32(5): e22379
[31] Zhuo F, Lin H, Chen Z, et al. The expression profile and clinical significance of circRNA0003906 in colorectal cancer[J]. Onco Targets Ther, 2017, 10: 5187-5193
[32] Guo JN, Li J, Zhu CL, et al. Comprehensive profile of differentially expressed circular RNAs reveals that hsa_circ_0000069 is upregulated and promotes cell proliferation, migration, and invasion in colorectal cancer[J]. Onco Targets Ther, 2016, 9: 7451-7458
[33] Zhang XL, Xu LL, Wang F. Hsa_circ_0020397 regulates colorectal cancer cell viability, apoptosis and invasion by promoting the expression of the miR-138 targets TERT and PD-L1[J]. Cell Biol Int, 2017, 41(9): 1056-1064
[34] Xie H, Ren X, Xin S, et al. Emerging roles of circRNA_001569 targeting miR-145 in the proliferation and invasion of colorectal cancer[J]. Oncotarget, 2016, 7(18): 26680-26691
[35] Weng W, Wei Q, Toden S, et al. Circular RNA ciRS-7-a promising prognostic biomarker and a potential therapeutic target in colorectal cancer[J]. Clin Cancer Res, 2017, 23(14): 3918-3928
[36] Fu L, Yao T, Chen Q, et al. Screening differential circular RNA expression profiles reveals hsa_circ_ 0004018 is associated with hepatocellular carcinoma[J]. Oncotarget, 2017, 8(35): 58405-58416
[37] Han D, Li J, Wang H, et al. Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression[J]. Hepatology, 2017, 66(4): 1151-1164
[38] Xu L, Zhang M, Zheng X, et al. The circular RNA ciRS-7 (Cdr1as) acts as a risk factor of hepatic microvascular invasion in hepatocellular carcinoma[J]. J Cancer Res Clin Oncol, 2017, 143(1): 17-27
[39] Peng L, Yuan XQ, Li GC. The emerging landscape of circular RNA ciRS-7 in cancer (Review)[J]. Oncol Rep, 2015, 33(6): 2669-2674
[40] Chen G, Shi Y, Liu M, et al. circHIPK3 regulates cell proliferation and migration by sponging miR-124 and regulating AQP3 expression in hepatocellular carcinoma[J]. Cell Death Dis, 2018, 9(2): 175
[41] Yu J, Xu QG, Wang ZG, et al. Circular RNA cSMARCA5 inhibits growth and metastasis in hepatocellular carcinoma[J]. J Hepatol, 2018, 68(6): 1214-1227
[42] Li S, Gu H, Huang Y, et al. Circular RNA 101368/miR-200a axis modulates the migration of hepatocellular carcinoma through HMGB1/RAGE signaling[J]. Cell Cycle, 2018, 17(19-20): 2349-2359
[43] Hirsch S, Blatte TJ, Grasedieck S, et al. Circular RNAs of the nucleophosmin (NPM1) gene in acute myeloid leukemia[J]. Haematologica, 2017, 102(12): 2039-2047
[44] Li S, Ma Y, Tan Y, et al. Profiling and functional analysis of circular RNAs in acute promyelocytic leukemia and their dynamic regulation during all-trans retinoic acid treatment[J]. Cell Death Dis, 2018, 9(6): 651
[45] Du WW, Fang L, Yang W, et al. Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity[J]. Cell Death Differ, 2017, 24(2): 357-370
[46] Wang H, Xiao Y, Wu L, et al. Comprehensive circular RNA profiling reveals the regulatory role of the circRNA-000911/miR-449a pathway in breast carcinogenesis[J]. Int J Oncol, 2018, 52(3): 743-754
[47] Tang YY, Zhao P, Zou TN, et al. Circular RNA hsa_circ_0001982 promotes breast cancer cell carcinogenesis through decreasing miR-143[J]. DNA Cell Biol, 2017, 36(11): 901-908
[48] Yan N, Xu H, Zhang J, et al. Circular RNA profile indicates circular RNA VRK1 is negatively related with breast cancer stem cells[J]. Oncotarget, 2017, 8(56): 95704-95718
[49] Li G, Yang H, Han K, et al. A novel circular RNA, hsa_circ_0046701, promotes carcinogenesis by increasing the expression of miR-142-3p target ITGB8 in glioma[J]. Biochem Biophys Res Commun, 2018, 498(1): 254-261
[50] 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
[51] Zhou R, Chen KK, Zhang J, et al. The decade of exosomal long RNA species: an emerging cancer antagonist[J]. Mol Cancer, 2018, 17(1): 75
[2] Sanger HL, Klotz G, Riesner D, et al. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures[J]. Proc Natl Acad Sci U S A, 1976, 73(11): 3852-3856
[3] Salzman J, Gawad C, Wang PL, et al. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types[J]. PLoS One, 2012, 7(2): e30733
[4] Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges[J]. Nature, 2013, 495(7441): 384-388
[5] 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
[6] Conn SJ, Pillman KA, Toubia J, et al. The RNA binding protein quaking regulates formation of circRNAs[J]. Cell, 2015, 160(6): 1125-1134
[7] Li Z, Huang C, Bao C, et al. Exon-intron circular RNAs regulate transcription in the nucleus[J]. Nat Struct Mol Biol, 2015, 22(3): 256-264
[8] Zhang Y, Zhang XO, Chen T, et al. Circular intronic long noncoding RNAs[J]. Mol Cell, 2013, 51(6): 792-806
[9] Guarnerio J, Bezzi M, Jeong JC, et al. Oncogenic role of fusion-circRNAs derived from cancer-associated chromosomal translocations[J]. Cell, 2016, 165(2): 289-302
[10] Meng J, Chen S, Han JX, et al. Twist1 regulates vimentin through Cul2 circular RNA to promote EMT in hepatocellular carcinoma[J]. Cancer Res, 2018, 78(15): 4150-4162
[11] Bachmayr-Heyda A, Reiner AT, Auer K, et al. Correlation of circular RNA abundance with proliferation- exemplified with colorectal and ovarian cancer, idiopathic lung fibrosis, and normal human tissues[J]. Sci Rep, 2015, 5: 8057
[12] Hansen TB, Wiklund ED, Bramsen JB, et al. miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA[J]. EMBO J, 2011, 30(21): 4414-4422
[13] Patop I L, Kadener S. circRNAs in cancer[J]. Curr Opin Genet Dev, 2018, 48:121-127
[14] Chen J, Li Y, Zheng Q, et al. Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer[J]. Cancer Lett, 2017, 388: 208-219
[15] Zheng J, Liu X, Xue Y, et al. TTBK2 circular RNA promotes glioma malignancy by regulating miR-217/HNF1beta/Derlin-1 pathway[J]. J Hematol Oncol, 2017, 10(1): 52
[16] Zhang H, Wang G, Ding C, et al. Increased circular RNA UBAP2 acts as a sponge of miR-143 to promote osteosarcoma progression[J]. Oncotarget, 2017, 8(37): 61687-61697
[17] Liu T, Liu S, Xu Y, et al. Circular RNA-ZFR inhibited cell proliferation and promoted apoptosis in gastric cancer by sponging miR-130a/miR-107 and modulating PTEN[J].Cancer Res Treat,2018, 50(4):1396-1417
[18] Xu XW, Zheng BA, Hu ZM, et al. Circular RNA hsa_circ_000984 promotes colon cancer growth and metastasis by sponging miR-106b[J]. Oncotarget, 2017, 8(53): 91674-91683
[19] Du WW, Yang W, Liu E, et al. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2[J]. Nucleic Acids Res, 2016, 44(6): 2846-2858
[20] 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
[21] 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).doi:10.1093/jnci/djx166
[22] Zhang M, Huang N, Yang X, et al. A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis[J]. Oncogene, 2018, 37(13): 1805-1814
[23] Li F, Zhang L, Li W, et al. Circular RNA ITCH has inhibitory effect on ESCC by suppressing the Wnt/beta-catenin pathway[J]. Oncotarget, 2015, 6(8): 6001-6013
[24] Su H, Lin F, Deng X, et al. Profiling and bioinformatics analyses reveal differential circular RNA expression in radioresistant esophageal cancer cells[J]. J Transl Med, 2016, 14(1): 225
[25] Xia W, Qiu M, Chen R, et al. Circular RNA hsa_circ_0067934 is upregulated in esophageal squamous cell carcinoma and promoted proliferation[J]. Sci Rep, 2016, 6: 35576
[26] Li WH, Song YC, Zhang H, et al. Decreased expression of hsa_circ_00001649 in gastric cancer and its clinical significance[J]. Dis Markers, 2017, 2017: 4587698
[27] Sun H, Tang W, Rong D, et al. Hsa_circ_0000520, a potential new circular RNA biomarker, is involved in gastric carcinoma[J]. Cancer Biomark, 2018, 21(2): 299-306
[28] Lai Z, Yang Y, Yan Y, et al. Analysis of co-expression networks for circular RNAs and mRNAs reveals that circular RNAs hsa_circ_0047905, hsa_circ_0138960 and hsa-circRNA7690-15 are candidate oncogenes in gastric cancer[J]. Cell Cycle, 2017, 16(23): 2301-2311
[29] Zhang J, Liu H, Hou L, et al. Circular RNA_LARP4 inhibits cell proliferation and invasion of gastric cancer by sponging miR-424-5p and regulating LATS1 expression[J]. Mol Cancer, 2017, 16(1): 151
[30] Wang J, Li X, Lu L, et al. Circular RNA hsa_circ_0000567 can be used as a promising diagnostic biomarker for human colorectal cancer[J]. J Clin Lab Anal, 2018, 32(5): e22379
[31] Zhuo F, Lin H, Chen Z, et al. The expression profile and clinical significance of circRNA0003906 in colorectal cancer[J]. Onco Targets Ther, 2017, 10: 5187-5193
[32] Guo JN, Li J, Zhu CL, et al. Comprehensive profile of differentially expressed circular RNAs reveals that hsa_circ_0000069 is upregulated and promotes cell proliferation, migration, and invasion in colorectal cancer[J]. Onco Targets Ther, 2016, 9: 7451-7458
[33] Zhang XL, Xu LL, Wang F. Hsa_circ_0020397 regulates colorectal cancer cell viability, apoptosis and invasion by promoting the expression of the miR-138 targets TERT and PD-L1[J]. Cell Biol Int, 2017, 41(9): 1056-1064
[34] Xie H, Ren X, Xin S, et al. Emerging roles of circRNA_001569 targeting miR-145 in the proliferation and invasion of colorectal cancer[J]. Oncotarget, 2016, 7(18): 26680-26691
[35] Weng W, Wei Q, Toden S, et al. Circular RNA ciRS-7-a promising prognostic biomarker and a potential therapeutic target in colorectal cancer[J]. Clin Cancer Res, 2017, 23(14): 3918-3928
[36] Fu L, Yao T, Chen Q, et al. Screening differential circular RNA expression profiles reveals hsa_circ_ 0004018 is associated with hepatocellular carcinoma[J]. Oncotarget, 2017, 8(35): 58405-58416
[37] Han D, Li J, Wang H, et al. Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression[J]. Hepatology, 2017, 66(4): 1151-1164
[38] Xu L, Zhang M, Zheng X, et al. The circular RNA ciRS-7 (Cdr1as) acts as a risk factor of hepatic microvascular invasion in hepatocellular carcinoma[J]. J Cancer Res Clin Oncol, 2017, 143(1): 17-27
[39] Peng L, Yuan XQ, Li GC. The emerging landscape of circular RNA ciRS-7 in cancer (Review)[J]. Oncol Rep, 2015, 33(6): 2669-2674
[40] Chen G, Shi Y, Liu M, et al. circHIPK3 regulates cell proliferation and migration by sponging miR-124 and regulating AQP3 expression in hepatocellular carcinoma[J]. Cell Death Dis, 2018, 9(2): 175
[41] Yu J, Xu QG, Wang ZG, et al. Circular RNA cSMARCA5 inhibits growth and metastasis in hepatocellular carcinoma[J]. J Hepatol, 2018, 68(6): 1214-1227
[42] Li S, Gu H, Huang Y, et al. Circular RNA 101368/miR-200a axis modulates the migration of hepatocellular carcinoma through HMGB1/RAGE signaling[J]. Cell Cycle, 2018, 17(19-20): 2349-2359
[43] Hirsch S, Blatte TJ, Grasedieck S, et al. Circular RNAs of the nucleophosmin (NPM1) gene in acute myeloid leukemia[J]. Haematologica, 2017, 102(12): 2039-2047
[44] Li S, Ma Y, Tan Y, et al. Profiling and functional analysis of circular RNAs in acute promyelocytic leukemia and their dynamic regulation during all-trans retinoic acid treatment[J]. Cell Death Dis, 2018, 9(6): 651
[45] Du WW, Fang L, Yang W, et al. Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity[J]. Cell Death Differ, 2017, 24(2): 357-370
[46] Wang H, Xiao Y, Wu L, et al. Comprehensive circular RNA profiling reveals the regulatory role of the circRNA-000911/miR-449a pathway in breast carcinogenesis[J]. Int J Oncol, 2018, 52(3): 743-754
[47] Tang YY, Zhao P, Zou TN, et al. Circular RNA hsa_circ_0001982 promotes breast cancer cell carcinogenesis through decreasing miR-143[J]. DNA Cell Biol, 2017, 36(11): 901-908
[48] Yan N, Xu H, Zhang J, et al. Circular RNA profile indicates circular RNA VRK1 is negatively related with breast cancer stem cells[J]. Oncotarget, 2017, 8(56): 95704-95718
[49] Li G, Yang H, Han K, et al. A novel circular RNA, hsa_circ_0046701, promotes carcinogenesis by increasing the expression of miR-142-3p target ITGB8 in glioma[J]. Biochem Biophys Res Commun, 2018, 498(1): 254-261
[50] 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
[51] Zhou R, Chen KK, Zhang J, et al. The decade of exosomal long RNA species: an emerging cancer antagonist[J]. Mol Cancer, 2018, 17(1): 75