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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2021, Vol. 41 Issue (11): 64-73    DOI: 10.13523/j.cb.2106023
综述     
microRNA治疗在癌症及其他疾病中的研究进展*
唐德平1,邢梦洁1,2,宋文涛1,姚慧慧1,毛爱红2,**()
1 兰州交通大学生物与制药工程学院 兰州 730070
2 甘肃省医学科学研究院 兰州 730050
Advance of microRNA Therapeutics in Cancer and Other Diseases
TANG De-ping1,XING Meng-jie1,2,SONG Wen-tao1,YAO Hui-hui1,MAO Ai-hong2,**()
1 School of Biological & Pharmaceutical Engineering, Lanzhou Jiaotong University, Lanzhou 730070,China
2 Gansu Provincial Academic Institute for Medical Research, Lanzhou 730050,China
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摘要：

microRNAs(miRNAs)是一类内源性、非编码小分子RNAs(约22 nt),在基因表达调控中发挥关键作用。已有研究表明,miRNAs失调是造成多种人类疾病的原因,如癌症、病毒感染及自身免疫性疾病等。补充或抑制miRNAs功能与活性已成为多种疾病治疗的新策略,抗肿瘤miR-34 mimics、治疗HCV感染的anti-miR-122等基于miRNAs的治疗方案已进入临床试验。重点就miRNAs治疗在癌症及其他疾病中的最新研究进展进行综述,并对目前开发安全有效miRNAs治疗策略所面临的挑战进行分析。
关键词： miRNA治疗;  癌症;  肝炎;  心血管疾病;  糖尿病    
Abstract:

microRNAs (miRNAs) are a class of endogenous, small non-coding RNAs (about 22 nt) that have critical roles in gene expression. Functional studies have identified miRNAs dysregulation as a cause in many human diseases, including cancer, viral infection, and autoimmune disorders. Restoring or suppressing miRNAs function and activity has become an attractive therapeutic method for the management of cancer and other diseases. Several miRNA-based therapeutics have reached clinical development, including a mimic of the tumor suppressor miR-34 for treating cancer and anti-miRs targeted miR-122 for treating HCV infection. In this review, we summarize the recent advances in our knowledge of miRNA therapeutics in cancer and other diseases and discuss ongoing challenges to ensure the safety and efficacy of miRNA therapeutics in vivo.
Key words: miRNA therapeutics    Cancer    Hepatitis    Cardiovascular disease    Diabetes
收稿日期: 2021-06-15 出版日期: 2021-12-01
ZTFLH:  R459.9  
基金资助: * 国家自然科学基金地区基金(12065001);甘肃省自然科学基金(20JR10RA224);甘肃省高等学校创新基金(2020A-041)
通讯作者: 毛爱红     E-mail: maoaih@aliyun.com
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引用本文:

唐德平,邢梦洁,宋文涛,姚慧慧,毛爱红. microRNA治疗在癌症及其他疾病中的研究进展*[J]. 中国生物工程杂志, 2021, 41(11): 64-73.

TANG De-ping,XING Meng-jie,SONG Wen-tao,YAO Hui-hui,MAO Ai-hong. Advance of microRNA Therapeutics in Cancer and Other Diseases. China Biotechnology, 2021, 41(11): 64-73.

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https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2106023    或    https://manu60.magtech.com.cn/biotech/CN/Y2021/V41/I11/64

miRNAs 递送载体 调控靶mRNA 临床前模型 疾病
抑癌miRNAs(miRNA mimics 为治疗剂)
Ler-7 中性脂质乳剂 MYC,BCLXL,RAS,EZH2,HMGA2,FAS,P21,PGRMC1, DICER1 肺癌(orthotopic)KrasG12DGEM 实体瘤(乳腺、结直肠、卵巢、肺、肝和胶质瘤)、B细胞淋巴瘤
miR-34a 脂质纳米颗粒载体
中性脂质乳剂		 BCL2,MET,MYC,CDK6,CD44,SRC,E2F1,JAG1,FOXP1,PDGFRA,PDL1, SIRT1 肺癌(xenograft/ orthotopic )KrasG12DGEM胰腺癌(orthotopic)
前列腺癌(orthotopic)		 实体瘤(肺、肝、结直肠、脑、前列腺、胰腺、膀胱和宫颈癌)、骨髓瘤、B细胞淋巴瘤
miR-143
miR-145		 脂质体
PEI		 KRAS,ERK5,VEGF,NFKB1,MYC,MMPs,PLK1,CDH2,EGFR 结直肠癌(orthotopic)
胰腺癌(orthotopic)		 实体瘤(膀胱、肺、乳腺、结直肠、胰腺、宫颈和头颈部肿瘤)
淋巴性白血病
miR-200家族 脂质体
DOPC中性脂质		 ZEB1,ZEB2 BMI1,SUZ12,JAG1,SOX2,SP1,CDH1,KRAS 肺癌(orthotopic)
卵巢癌(orthotopic)
乳腺癌(orthotopic)		 实体瘤(乳腺、卵巢和肺)
致癌miRNAs(antimiRs 为治疗剂)
miR-10b LNA antimiRs NF1,CDH1,E2F1,PIK3CA,ZEB1,HOXD10 恶性胶质瘤(orthotopic)
乳腺癌(orthotopic)		 实体瘤(乳腺和胶质瘤)
miR-155 pHIP 共轭antimiR SHIP,SPI1,HDAC4,RHOA,SOCS1,BCL2,JMJD1A,SOX6,SMAD2,SMAD5, TP53INP1 淋巴瘤(miR-155过表达 GEM) 实体瘤(肝、肺、肾、胰腺和神经胶质瘤)、B细胞淋巴瘤、淋巴性白血病
miR-221
miR-222		 胆固醇- antimiR CDKN1B,CDKN1C,BMF, RB1,WEE1,APAF1,ANXA1, CTCF 肝细胞癌 实体瘤(肝、胰腺和肺)
其他
MiR-122 硫代磷酸DNA-LNA antimiR HCV5'-RNA, CAT1, CD320, ALDOA, PPARB HCV小鼠模型 HCV感染相关肝脏疾病
miR-33 2'-F或MOE 硫代磷酸DNA antimiR
LNA antimiR		 SREBF2, ABCA1, CROT, CPT1A, HADHB, PRKAA1 HFD小鼠 动脉粥样硬化
miR-208 LNA antimiR MED13, SOX6, MYH7B Dahl高血压大鼠 心脏病
心脏负荷
心肌梗死
miR-21 LNA antimiR PTEN, PDCD4, SMAD7, SPRY, PPAR 心脏病(压力超负荷模型) 肾纤维化
心肌纤维化
miR-192 LNA-miRNA mimic Collagens-I, ZEB1, ZEB2 链脲霉素诱导的Ⅰ型糖尿病小鼠 糖尿病相关的肾并发症
miR-29c 裸antagomiRs HDAC4, MMPs db/db小鼠 糖尿病相关的肾并发症
miR-103
miR-107		 LNA-antimiR CAV1 ob/ob小鼠
HFD小鼠		 糖尿病
miR-15 LNA-antimiR CHEK1 缺血-再灌注损伤小鼠 心肌梗死
表1  临床前研究阶段的miRNAs
名 称(开发公司) 治疗剂 递送方式 疾病 临床试验
Mirvirasen
(Santaris Pharma A/S
Hoffmann La Roche)		 AntimiR-122 LNA-修饰的反义抑制 慢性感染诱导的丙肝 Ⅱ期,多-中心(NCT01200420)
Ⅱ期,多-中心(NCT01872936)
Ⅱ期,单-中心(NCT02031133)
Ⅱ期,单-中心(NCT02508090)
RG-101
(Regulus Therapeutics)		 AntimiR-122 GalNAc-共轭antimiR 慢性丙肝 Ⅰ期,单-中心
Ⅱ期,多-中心
RG-125/AZD4076
(Regulus Therapeutics)		 AntimiR-103/107 GalNAc-共轭antimiR 2型糖尿病
非酒精性脂肪肝		 Ⅰ期,单-中心(NCT02612662)
Ⅰ/Ⅱa期,单-中心(NCT02826525)
MRG-106
(mirage Therapeutics)		 AntimiR-155 LNA-修饰的反义抑制 皮肤T细胞淋巴瘤
真菌病		 Ⅰ期,多-中心(NCT02580552)
MRG-201
(mirage Therapeutics)		 miR-29 mimic 胆固醇-连接的miRNA双链 硬皮病 Ⅰ期,单-中心(NCT02603224)
MesomiR-1
(EnGeneIC)		 miR-16 mimic EnGeneIC递送载体 间皮瘤
非小细胞肺癌		 Ⅰ期,多-中心(NCT02369198)
MRX34
(Mirna Therapeutics)		 miR-34 mimic LNPs (Smarticles) 多种实体瘤 Ⅰ期,多-中心(NCT01829971)
表2  临床试验阶段的miRNA治疗
图1  基于miRNA 治疗的化学修饰及递送载体
[1] Iorio M V, Croce C M. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Molecular Medicine, 2012, 4(3):143-159.
doi: 10.1002/emmm.v4.3
[2] Baek J, Kang S, Min H. MicroRNA-targeting therapeutics for hepatitis C. Archives of Pharmacal Research, 2014, 37(3):299-305.
doi: 10.1007/s12272-013-0318-9
[3] Gurha P. MicroRNAs in cardiovascular disease. Current Opinion in Cardiology, 2016, 31(3):249-254.
doi: 10.1097/HCO.0000000000000280
[4] Rupaimoole R, Slack F J. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nature Reviews Drug Discovery, 2017, 16(3):203-222.
doi: 10.1038/nrd.2016.246 pmid: 28209991
[5] Li Z H, Rana T M. Therapeutic targeting of microRNAs: current status and future challenges. Nature Reviews Drug Discovery, 2014, 13(8):622-638.
doi: 10.1038/nrd4359
[6] To K K W, Fong W, Tong C W S, et al. Advances in the discovery of microRNA-based anticancer therapeutics: latest tools and developments. Expert Opinion on Drug Discovery, 2020, 15(1):63-83.
doi: 10.1080/17460441.2020.1690449
[7] Okada N, Lin C P, Ribeiro M C, et al. A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression. Genes & Development, 2014, 28(5):438-450.
doi: 10.1101/gad.233585.113
[8] Wang X, Li J G, Dong K, et al. Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia. Cellular Signalling, 2015, 27(3):443-452.
doi: 10.1016/j.cellsig.2014.12.003 pmid: 25499621
[9] Cortez M A, Ivan C, Valdecanas D, et al. PDL1 Regulation by p53 via miR-34. JNCI: Journal of the National Cancer Institute, 2016, 108(1). DOI: 10.1093/jnci/djv303.
doi: 10.1093/jnci/djv303
[10] Wiggins J F, Ruffino L, Kelnar K, et al. Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Research, 2010, 70(14):5923-5930.
doi: 10.1158/0008-5472.CAN-10-0655 pmid: 20570894
[11] Trang P, Wiggins J F, Daige C L, et al. Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice. Molecular Therapy, 2011, 19(6):1116-1122.
doi: 10.1038/mt.2011.48
[12] Kasinski A L, Slack F J. miRNA-34 prevents cancer initiation and progression in a therapeutically resistant K-ras and p53-induced mouse model of lung adenocarcinoma. Cancer Research, 2012, 72(21):5576-5587.
doi: 10.1158/0008-5472.CAN-12-2001 pmid: 22964582
[13] Pramanik D, Campbell N R, Karikari C, et al. Restitution of tumor suppressor microRNAs using a systemic nanovector inhibits pancreatic cancer growth in mice. Molecular Cancer Therapeutics, 2011, 10(8):1470-1480.
doi: 10.1158/1535-7163.MCT-11-0152
[14] Liu C, Kelnar K, Liu B G, et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nature Medicine, 2011, 17(2):211-215.
doi: 10.1038/nm.2284
[15] Gregory P A, Bert A G, Paterson E L, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nature Cell Biology, 2008, 10(5):593-601.
doi: 10.1038/ncb1722 pmid: 18376396
[16] Korpal M, Lee E S, Hu G H, et al. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. Journal of Biological Chemistry, 2008, 283(22):14910-14914.
doi: 10.1074/jbc.C800074200 pmid: 18411277
[17] Gregory P A, Bracken C P, Smith E, et al. An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. Molecular Biology of the Cell, 2011, 22(10):1686-1698.
doi: 10.1091/mbc.E11-02-0103 pmid: 21411626
[18] Pecot C V, Rupaimoole R, Yang D, et al. Tumour angiogenesis regulation by the miR-200 family. Nature Communications, 2013, 4:2427.
doi: 10.1038/ncomms3427 pmid: 24018975
[19] Cortez M A, Valdecanas D, Zhang X C, et al. Therapeutic delivery of miR-200c enhances radiosensitivity in lung cancer. Molecular Therapy, 2014, 22(8):1494-1503.
doi: 10.1038/mt.2014.79
[20] Bahreyni A, Rezaei M, Bahrami A, et al. Diagnostic, prognostic, and therapeutic potency of microRNA 21 in the pathogenesis of colon cancer, current status and prospective. Journal of Cellular Physiology, 2019, 234(6):8075-8081.
doi: 10.1002/jcp.v234.6
[21] Wang Y, Zhou S Y, Fan K F, et al. MicroRNA-21 and its impact on signaling pathways in cervical cancer. Oncology Letters, 2019, 17(3):3066-3070.
[22] Sekar D, Mani P, Biruntha M, et al. Dissecting the functional role of microRNA 21 in osteosarcoma. Cancer Gene Therapy, 2019, 26(7):179-182.
doi: 10.1038/s41417-019-0092-z
[23] Medina P P, Nolde M, Slack F J. OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature, 2010, 467(7311):86-90.
doi: 10.1038/nature09284
[24] Hatley M E, Patrick D M, Garcia M R, et al. Modulation of K-ras-dependent lung tumorigenesis by MicroRNA-21. Cancer Cell, 2010, 18(3):282-293.
doi: 10.1016/j.ccr.2010.08.013 pmid: 20832755
[25] Krichevsky A M, Gabriely G. miR-21: a small multi-faceted RNA. Journal of Cellular and Molecular Medicine, 2008, 13(1):39-53.
doi: 10.1111/j.1582-4934.2008.00556.x
[26] Campbell J D, Alexandrov A, Kim J, et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nature Genetics, 2016, 48(6):607-616.
doi: 10.1038/ng.3564 pmid: 27158780
[27] Saheb Sharif-Askari N, Saheb Sharif-Askari F, Guraya S Y, et al. Integrative systematic review meta-analysis and bioinformatics identifies MicroRNA-21 and its target genes as biomarkers for colorectal adenocarcinoma. International Journal of Surgery, 2020, 73:113-122.
doi: S1743-9191(19)30338-3 pmid: 31756546
[28] Javanmardi S, Aghamaali M R, Abolmaali S S, et al. miR-21, an oncogenic target miRNA for cancer therapy: molecular mechanisms and recent advancements in chemo and radio-resistance. Current Gene Therapy, 2017, 16(6):375-389.
doi: 10.2174/1566523217666170102105119 pmid: 28042781
[29] Jiang S, Zhang H W, Lu M H, et al. MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Research, 2010, 70(8):3119-3127.
doi: 10.1158/0008-5472.CAN-09-4250
[30] Chang S, Wang R H, Akagi K, et al. Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155. Nature Medicine, 2011, 17(10):1275-1282.
doi: 10.1038/nm.2459
[31] Due H, Schönherz A A, Ryø L, et al. MicroRNA-155 controls vincristine sensitivity and predicts superior clinical outcome in diffuse large B-cell lymphoma. Blood Advances, 2019, 3(7):1185-1196.
doi: 10.1182/bloodadvances.2018029660
[32] Tili E, Michaille J J, Wernicke D, et al. Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer. PNAS, 2011, 108(12):4908-4913.
doi: 10.1073/pnas.1101795108
[33] Kong W, He L, Richards E J, et al. Upregulation of miRNA-155 promotes tumour angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative breast cancer. Oncogene, 2014, 33(6):679-689.
doi: 10.1038/onc.2012.636 pmid: 23353819
[34] Babar I A, Cheng C J, Booth C J, et al. Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma. PNAS, 2012, 109(26):E1695-E1704. DOI: 10.1073/pnas.1201516109.
doi: 10.1073/pnas.1201516109
[35] Cheng C J, Bahal R, Babar I A, et al. MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature, 2015, 518(7537):107-110.
doi: 10.1038/nature13905
[36] Sarnow P, Sagan S M. Unraveling the mysterious interactions between hepatitis C virus RNA and liver-specific MicroRNA-122. Annual Review of Virology, 2016, 3(1):309-332.
pmid: 27578438
[37] Luna J M, Scheel T K H, Danino T, et al. Hepatitis C virus RNA functionally sequesters miR-122. Cell, 2015, 160(6):1099-1110.
doi: 10.1016/j.cell.2015.02.025
[38] Elmén J, Lindow M, Silahtaroglu A, et al. Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver. Nucleic Acids Research, 2008, 36(4):1153-1162.
doi: 10.1093/nar/gkm1113
[39] Tsai W C, Hsu S D, Hsu C S, et al. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. The Journal of Clinical Investigation, 2012, 122(8):2884-2897.
doi: 10.1172/JCI63455
[40] Elmén J, Lindow M, Schütz S, et al. LNA-mediated microRNA silencing in non-human Primates. Nature, 2008, 452(7189):896-899.
doi: 10.1038/nature06783
[41] Bejerano T, Etzion S, Elyagon S, et al. Nanoparticle delivery of miRNA-21 mimic to cardiac macrophages improves myocardial remodeling after myocardial infarction. Nano Letters, 2018, 18(9):5885-5891.
doi: 10.1021/acs.nanolett.8b02578 pmid: 30141949
[42] Xin M, Small E M, Sutherland L B, et al. MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury. Genes & Development, 2009, 23(18):2166-2178.
doi: 10.1101/gad.1842409
[43] Ikeda S, He A B, Kong S W, et al. MicroRNA-1 negatively regulates expression of the hypertrophy-associated calmodulin and Mef2a genes. Molecular and Cellular Biology, 2009, 29(8):2193-2204.
doi: 10.1128/MCB.01222-08
[44] Shan Z X, Lin Q X, Fu Y H, et al. Upregulated expression of miR-1/miR-206 in a rat model of myocardial infarction. Biochemical and Biophysical Research Communications, 2009, 381(4):597-601.
doi: 10.1016/j.bbrc.2009.02.097
[45] Thanikachalam P V, Ramamurthy S, Wong Z W, et al. Current attempts to implement microRNA-based diagnostics and therapy in cardiovascular and metabolic disease: a promising future. Drug Discovery Today, 2018, 23(3):460-480.
doi: S1359-6446(17)30222-2 pmid: 29107764
[46] Price N L, Miguel V, Ding W, et al. Genetic deficiency or pharmacological inhibition of miR-33 protects from kidney fibrosis. JCI Insight, 2019, 4(22). DOI: 10.1172/jci.insight.131102.
doi: 10.1172/jci.insight.131102
[47] Rayner K J, Esau C C, Hussain F N, et al. Inhibition of miR-33a/b in non-human Primates raises plasma HDL and lowers VLDL triglycerides. Nature, 2011, 478(7369):404-407.
doi: 10.1038/nature10486
[48] Goedeke L, Salerno A, Ramírez C M, et al. Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice. EMBO Molecular Medicine, 2014, 6(9):1133-1141.
doi: 10.15252/emmm.201404046 pmid: 25038053
[49] Belgardt B F, Ahmed K, Spranger M, et al. The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes. Nature Medicine, 2015, 21(6):619-627.
doi: 10.1038/nm.3862
[50] McArthur K, Feng B, Wu Y, et al. MicroRNA-200b regulates vascular endothelial growth factor-mediated alterations in diabetic retinopathy. Diabetes, 2011, 60(4):1314-1323.
doi: 10.2337/db10-1557 pmid: 21357793
[51] Wang B, Herman-Edelstein M, Koh P, et al. E-cadherin expression is regulated by miR-192/215 by a mechanism that is independent of the profibrotic effects of transforming growth factor-beta. Diabetes, 2010, 59(7):1794-1802.
doi: 10.2337/db09-1736 pmid: 20393144
[52] Ślusarz A, Pulakat L. The two faces of miR-29. Journal of Cardiovascular Medicine, 2015, 16(7):480-490.
doi: 10.2459/JCM.0000000000000246 pmid: 25689084
[53] Agarwal V, Bell G W, Nam J W, et al. Predicting effective microRNA target sites in mammalian mRNAs. eLife, 2015, 4:e05005. DOI: 10.7554/eLife.05005.
doi: 10.7554/eLife.05005
[54] Eulalio A, Mano M, Ferro M D, et al. Functional screening identifies miRNAs inducing cardiac regeneration. Nature, 2012, 492(7429):376-381.
doi: 10.1038/nature11739
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