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Current Gene Therapy


ISSN (Print): 1566-5232
ISSN (Online): 1875-5631

Review Article

The Therapeutic Potential of Small Activating RNAs for Colorectal Carcinoma

Author(s): Bin Zheng, QingYun Mai*, JinXing Jiang and QinQin Zhou

Volume 19 , Issue 3 , 2019

Page: [140 - 146] Pages: 7

DOI: 10.2174/1566523219666190708111404

Price: $65


Small double-strand RNAs have been recognized as master regulators of gene expression. In contrast to the evolutionary conserved RNA interference machinery, which degrades or inhibits the translation of target mRNAs, small activating RNA (saRNA) activates the specific gene in a target dependent manner through a similar mechanism as RNAi. Recently, saRNA mediated expression regulation of specific genes has been extensively studied in cancer researches. Of particular interest is the application of the RNA mediated gene activation within colorectal cancer (CRC) development, due to the high incidence of the CRC. In this review, we summarize the current knowledge of saRNA mediated genetic activation and its underlying mechanisms. Furthermore, we highlight the advantages of the utilization of saRNAs induced gene expression as an investigating tool in colorectal cancer research. Finally, the possibility and the challenge of the saRNA application as a potential therapy for colorectal cancer are addressed.

Keywords: Small non-coding RNAs, small activating RNA, colorectal cancer, therapeutic agent, siRNA, microRNA.

Graphical Abstract
Hangauer MJ, Vaughn IW, McManus MT. Pervasive transcription of the human genome produces thousands of previously unidentified long intergenic noncoding RNAs. PLoS Genet 2013; 9(6)e1003569
[] [PMID: 23818866]
Shahrouki P, Larsson E. The non-coding oncogene: A case of missing DNA evidence? Front Genet 2012; 3: 170.
[] [PMID: 22988449]
Vagin VV, Sigova A, Li C, Seitz H, Gvozdev V, Zamore PD. A distinct small RNA pathway silences selfish genetic elements in the germline. Sci 2006; 313(5785): 320-4.
[] [PMID: 16809489]
Lau NC, Seto AG, Kim J, et al. Characterization of the piRNA complex from rat testes. Sci 2006; 313(5785): 363-7.
[] [PMID: 16778019]
Li J, Wu C, Wang W, et al. Structurally modulated codelivery of siRNA and Argonaute 2 for enhanced RNA interference. Proc Natl Acad Sci USA 2018; 115(12): E2696-705.
[] [PMID: 29432194]
Deerberg A, Willkomm S, Restle T. Minimal mechanistic model of siRNA-dependent target RNA slicing by recombinant human Argonaute 2 protein. Proc Natl Acad Sci USA 2013; 110(44): 17850-5.
[] [PMID: 24101500]
Cummins JM, He Y, Leary RJ, et al. The colorectal microRNAome. Proc Natl Acad Sci USA 2006; 103(10): 3687-92.
[] [PMID: 16505370]
Huang V, Place RF, Portnoy V, et al. Upregulation of Cyclin B1 by miRNA and its implications in cancer. Nucleic Acids Res 2012; 40(4): 1695-707.
[] [PMID: 22053081]
Place RF, Li LC, Pookot D, Noonan EJ, Dahiya R. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci USA 2008; 105(5): 1608-13.
[] [PMID: 18227514]
Li LC, Okino ST, Zhao H, et al. Small dsRNAs induce transcriptional activation in human cells. Proc Natl Acad Sci USA 2006; 103(46): 17337-42.
[] [PMID: 17085592]
Janowski BA, Younger ST, Hardy DB, Ram R, Huffman KE, Corey DR. Activating gene expression in mammalian cells with promoter-targeted duplex RNAs. Nat Chem Biol 2007; 3(3): 166-73.
[] [PMID: 17259978]
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018; 68(1): 7-30.
[] [PMID: 29313949]
Gu MJ, Huang QC, Bao CZ, et al. Attributable causes of colorectal cancer in China. BMC Cancer 2018; 18(1): 38.
[] [PMID: 29304763]
Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin 2016; 66(2): 115-32.
[] [PMID: 26808342]
Sameer AS. Colorectal cancer: Molecular mutations and polymorphisms. Front Oncol 2013; 3: 114.
[] [PMID: 23717813]
Huang D, Sun W, Zhou Y, et al. Mutations of key driver genes in colorectal cancer progression and metastasis. Cancer Metastasis Rev 2018; 37(1): 173-87.
[] [PMID: 29322354]
Slattery ML, Herrick JS, Mullany LE, et al. The co-regulatory networks of tumor suppressor genes, oncogenes, and miRNAs in colorectal cancer. Genes Chromosomes Cancer 2017; 56(11): 769-87.
[] [PMID: 28675510]
Mansoori B, Sandoghchian SS, Baradaran B. RNA interference and its role in cancer therapy. Adv Pharm Bull 2014; 4(4): 313-21.
[PMID: 25436185]
Prados J, Melguizo C, Roldan H, et al. RNA interference in the treatment of colon cancer. Bio Dru Clin Imm, Biopharm. Gene Ther 2013; 27(4): 317-27.
Jagannath A, Wood MJ. Localization of double-stranded small interfering RNA to cytoplasmic processing bodies is Ago2 dependent and results in up-regulation of GW182 and Argonaute-2. Mol Biol Cell 2009; 20(1): 521-9.
[] [PMID: 18946079]
Portnoy V, Huang V, Place RF, Li LC. Small RNA and transcriptional upregulation. Wiley Interdiscip Rev RNA 2011; 2(5): 748-60.
[] [PMID: 21823233]
Place RF, Noonan EJ, Földes-Papp Z, Li LC. Defining features and exploring chemical modifications to manipulate RNAa activity. Curr Pharm Biotechnol 2010; 11(5): 518-26.
[] [PMID: 20662764]
Guo D, Barry L, Lin SS, Huang V, Li LC. RNAa in action: From the exception to the norm. RNA Biol 2014; 11(10): 1221-5.
[] [PMID: 25602906]
Zheng L, Wang L, Gan J, Zhang H. RNA activation: Promise as a new weapon against cancer. Cancer Lett 2014; 355(1): 18-24.
[] [PMID: 25261049]
Matsui M, Sakurai F, Elbashir S, Foster DJ, Manoharan M, Corey DR. Activation of LDL receptor expression by small RNAs complementary to a noncoding transcript that overlaps the LDLR promoter. Chem Biol 2010; 17(12): 1344-55.
[] [PMID: 21168770]
Meng X, Jiang Q, Chang N, et al. Small activating RNA binds to the genomic target site in a seed-region-dependent manner. Nucleic Acids Res 2016; 44(5): 2274-82.
[] [PMID: 26873922]
Cao H, Meng X, Wang X, Liang Z. Target-recognition mechanism and specificity of RNA activation. Adv Exp Med Biol 2017; 983: 41-51.
[] [PMID: 28639190]
Schwartz JC, Younger ST, Nguyen NB, et al. Antisense transcripts are targets for activating small RNAs. Nat Struct Mol Biol 2008; 15(8): 842-8.
[] [PMID: 18604220]
Wu Z, Li Y, Li Z, et al. Transcriptional regulation of E-cadherin by small activating RNA: A new double-stranded RNA. Int J Oncol 2016; 49(4): 1620-8.
[] [PMID: 27498620]
Noland CL, Doudna JA. Multiple sensors ensure guide strand selection in human RNAi pathways. RNA 2013; 19(5): 639-48.
[] [PMID: 23531496]
Ohrt T, Muetze J, Svoboda P, Schwille P. Intracellular localization and routing of miRNA and RNAi pathway components. Curr Top Med Chem 2012; 12(2): 79-88.
[] [PMID: 22196276]
Zamudio JR, Kelly TJ, Sharp PA. Argonaute-bound small RNAs from promoter-proximal RNA polymerase II. Cell 2014; 156(5): 920-34.
[] [PMID: 24581493]
Xia Z, Huynh T, Ren P, Zhou R. Large domain motions in Ago protein controlled by the guide DNA-strand seed region determine the Ago-DNA-mRNA complex recognition process. PLoS One 2013; 8(1)e54620
[] [PMID: 23382927]
Portnoy V, Lin SH, Li KH, et al. saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription. Cell Res 2016; 26(3): 320-35.
[] [PMID: 26902284]
Yue X, Schwartz JC, Chu Y, et al. Transcriptional regulation by small RNAs at sequences downstream from 3 gene termini. Nat Chem Biol 2010; 6(8): 621-9.
[] [PMID: 20581822]
Core LJ, Lis JT. Transcription regulation through promoter-proximal pausing of RNA polymerase II. Sci 2008; 319(5871): 1791-2.
[] [PMID: 18369138]
Huang V, Qin Y, Wang J, et al. RNAa is conserved in mammalian cells. PLoS One 2010; 5(1)e8848
[] [PMID: 20107511]
Wang LL, Feng CL, Zheng WS, et al. Tumor-selective lipopolyplex encapsulated small active RNA hampers colorectal cancer growth in vitro and in orthotopic murine. Biomat 2017; 141: 13-28.
[] [PMID: 28666099]
Zhou Q, Fan D, Huang K, Chen X, Chen Y, Mai Q. Activation of KLF4 expression by small activating RNA promotes migration and invasion in colorectal epithelial cells. Cell Biol Int 2018; 42(4): 495-503.
[] [PMID: 29274293]
Kosaka M, Kang MR, Yang G, Li LC. Targeted p21WAF1/CIP1 activation by RNAa inhibits hepatocellular carcinoma cells. Nucleic Acid Ther 2012; 22(5): 335-43.
[] [PMID: 22909100]
Zhang Z, Wang Z, Liu X, et al. Up-regulation of p21WAF1/CIP1 by small activating RNA inhibits the in vitro and in vivo growth of pancreatic cancer cells. Tumori 2012; 98(6): 804-11.
[] [PMID: 23389370]
Xie D, Shang L, Peng L, Li L. Up-regulation of VEZT by small activating RNA inhibits the proliferation, invasion and migration of gastric cancer cells. Biochem Biophys Res Commun 2017; 482(4): 542-8.
[] [PMID: 27856244]
Wang C, Ge Q, Zhang Q, et al. Targeted p53 activation by saRNA suppresses human bladder cancer cells growth and metastasis. J Exp Clin Cancer Res 2016; 35: 53.
Kwok A, Raulf N, Habib N. Developing small activating RNA as a therapeutic: Current challenges and promises. Ther Deliv 2019; 10(3): 151-64.
[] [PMID: 30909853]
Stewart-Ornstein J, Lahav G. Dynamics of CDKN1A in single cells defined by an endogenous fluorescent tagging toolkit. Cell Rep 2016; 14(7): 1800-11.
[] [PMID: 26876176]
Wu Z, Huang H, Liu Z, et al. Activation of p21(WAF1/CIP1) by small activating RNA inhibits cell proliferation and induces apoptosis in BEL-7402 hepatoma cell. Zhonghua Yi Xue Za Zhi 2014; 94(20): 1534-8.
[PMID: 25146739]
Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131(5): 861-72.
[] [PMID: 18035408]
Zhang L, Zhang L, Xia X, He S, He H, Zhao W. Krüppel-like factor 4 promotes human osteosarcoma growth and metastasis via regulating CRYAB expression. Oncotarget 2016; 7(21): 30990-1000.
[] [PMID: 27105535]
Wang B, Zhao MZ, Cui NP, et al. Krüppel-like factor 4 induces apoptosis and inhibits tumorigenic progression in SK-BR-3 breast cancer cells. FEBS Open Bio 2015; 5: 147-54.
[] [PMID: 25834779]
Wang J, Place RF, Huang V, et al. Prognostic value and function of KLF4 in prostate cancer: RNAa and vector-mediated overexpression identify KLF4 as an inhibitor of tumor cell growth and migration. Cancer Res 2010; 70(24): 10182-91.
[] [PMID: 21159640]
Yet SF, McA’Nulty MM, Folta SC, et al. Human EZF, a Krüppel-like zinc finger protein, is expressed in vascular endothelial cells and contains transcriptional activation and repression domains. J Biol Chem 1998; 273(2): 1026-31.
[] [PMID: 9422764]
Shields JM, Christy RJ, Yang VW. Identification and characterization of a gene encoding a gut-enriched Krüppel-like factor expressed during growth arrest. J Biol Chem 1996; 271(33): 20009-17.
[] [PMID: 8702718]
Yu T, Chen X, Zhang W, et al. Krüppel-like factor 4 regulates intestinal epithelial cell morphology and polarity. PLoS One 2012; 7(2): e32492-2.
[] [PMID: 22384261]
Zhao W, Hisamuddin IM, Nandan MO, Babbin BA, Lamb NE, Yang VW. Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer. Oncogene 2004; 23(2): 395-402.
[] [PMID: 14724568]
Lv H, Zhang Z, Wang Y, Li C, Gong W, Wang X. Microrna-92a promotes colorectal cancer cell growth and migration by inhibiting KLF4. Oncol Res 2016; 23(6): 283-90.
Tang W, Zhu Y, Gao J, et al. MicroRNA-29a promotes colorectal cancer metastasis by regulating matrix metalloproteinase 2 and E-cadherin via KLF4. Br J Cancer 2014; 110(2): 450-8.
[] [PMID: 24281002]
Lee HY, Ahn JB, Rha SY, et al. High KLF4 level in normal tissue predicts poor survival in colorectal cancer patients. World J Surg Oncol 2014; 12: 232.
[] [PMID: 25060774]
Van Roy F, Berx G. The cell-cell adhesion molecule E-cadherin. Cell Mol Life Sci 2008; 65(23): 3756-88.
[] [PMID: 18726070]
Qu J, Jiang Y, Liu H, et al. Prognostic value of e-cadherin-, CD44-, and MSH2-associated nomograms in patients with stage ii and iii colorectal cancer. Transl Oncol 2017; 10(2): 121-31.
[] [PMID: 28126685]
Junxia W, Ping G, Yuan H, et al. Double strand RNA-guided endogeneous E-cadherin up-regulation induces the apoptosis and inhibits proliferation of breast carcinoma cells in vitro and in vivo. Cancer Sci 2010; 101(8): 1790-6.
[] [PMID: 20518789]
Mao Q, Zheng X, Yang K, et al. Suppression of migration and invasion of PC3 prostate cancer cell line via activating E-cadherin expression by small activating RNA. Cancer Invest 2010; 28(10): 1013-8.
[] [PMID: 20690797]
Mao Q, Li Y, Zheng X, et al. Up-regulation of E-cadherin by small activating RNA inhibits cell invasion and migration in 5637 human bladder cancer cells. Biochem Biophys Res Commun 2008; 375(4): 566-70.
[] [PMID: 18725195]
Wang J, Place RF, Portnoy V, et al. Inducing gene expression by targeting promoter sequences using small activating RNAs. J Biol Methods 2015; 2(1)e14
[] [PMID: 25839046]
Hwang HW, Wentzel EA, Mendell JT. A hexanucleotide element directs microRNA nuclear import. Science 2007; 315(5808): 97-100.
[] [PMID: 17204650]
Liao JY, Ma LM, Guo YH, et al. Deep sequencing of human nuclear and cytoplasmic small RNAs reveals an unexpectedly complex subcellular distribution of miRNAs and tRNA 3′ trailers. PLoS One 2010; 5(5)e10563
[] [PMID: 20498841]
Novina CD, Sharp PA. The RNAi revolution. Nature 2004; 430(6996): 161-4.
[] [PMID: 15241403]
Baretti M, Azad NS. The role of epigenetic therapies in colorectal cancer. Curr Probl Cancer 2018; 42(6): 530-47.
[] [PMID: 29625794]
Wang J, Huang V, Ye L, et al. Identification of small activating RNAs that enhance endogenous OCT4 expression in human mesenchymal stem cells. Stem Cells Dev 2015; 24(3): 345-53.
[] [PMID: 25232932]
Meng Z, Lu M. RNA interference-induced innate immunity, off-target effect, or immune adjuvant? Front Immunol 2017; 8: 331.
[] [PMID: 28386261]
Yoneyama M, Kikuchi M, Natsukawa T, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 2004; 5(7): 730-7.
[] [PMID: 15208624]
Voutila J, Sætrom P, Mintz P, et al. Gene expression profile changes after short-activating RNA-mediated induction of endogenous pluripotency factors in human mesenchymal stem cells. Mol Ther Nucleic Acids 2012; 1e35
[] [PMID: 23344177]
Zou GM. RNAi technique in stem cell research: Current status and future perspectives. Methods Mol Biol 2017; 1622: 3-14.
[] [PMID: 28674797]
Nasrallah A, Saykali B, Al Dimassi S, Khoury N, Hanna S, El-Sibai M. Effect of StarD13 on colorectal cancer proliferation, motility and invasion. Oncol Rep 2014; 31(1): 505-15.
[] [PMID: 24253896]
Wang K, Liang Q, Li X, et al. MDGA2 is a novel tumour suppressor cooperating with DMAP1 in gastric cancer and is associated with disease outcome. Gut 2016; 65(10): 1619-31.
[] [PMID: 26206665]
Voutila J, Reebye V, Roberts TC, et al. Development and mechanism of small activating RNA targeting CEBPA, a novel therapeutic in clinical trials for liver cancer. Mol Ther 2017; 25(12): 2705-14.
[] [PMID: 28882451]
ClinicalTrialsgovFirst-in-human safety and tolerability study of MTLCEBPA in patients with advanced liver cancer Available from:
Reebye V, Huang KW, Lin V, et al. Gene activation of CEBPA using saRNA: Preclinical studies of the first in human saRNA drug candidate for liver cancer. Oncogene 2018; 37(24): 3216-28.
[] [PMID: 29511346]

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