Noncoding RNAs in cancer therapy resistance and targeted drug development

Noncoding RNAs (ncRNAs) represent a large segment of the human transcriptome and have been shown to play important roles in cellular physiology and disease pathogenesis. Increasing evidence on the functional roles of ncRNAs in cancer progression emphasizes the potential of ncRNAs for cancer treatment. Here, we summarize the roles of ncRNAs in disease relapse and resistance to current standard chemotherapy and radiotherapy; the current research progress on ncRNAs for clinical and/or potential translational applications, including the identification of ncRNAs as therapeutic targets; therapeutic approaches for ncRNA targeting; and ncRNA delivery strategies in potential clinical translation. Several ongoing clinical trials of novel RNA-based therapeutics were also emphasized. Finally, we discussed the perspectives and obstacles to different target combinations, delivery strategies, and system designs for ncRNA application. The next approved nucleic acid drug to treat cancer patients may realistically be on the horizon.

[1]  E. Medico,et al.  Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer. , 2011, Journal of the National Cancer Institute.

[2]  T. Fujiwara,et al.  Enhanced Oncolytic Activities of the Telomerase-Specific Replication-Competent Adenovirus Expressing Short-Hairpin RNA against Dicer , 2016, Molecular Cancer Therapeutics.

[3]  Guohao Chen,et al.  Contribution of dysregulated circRNA_100876 to proliferation and metastasis of esophageal squamous cell carcinoma , 2018, OncoTargets and therapy.

[4]  L. Timmons The long and short of siRNAs. , 2002, Molecular cell.

[5]  M. Caligiuri,et al.  Prognostic significance of expression of a single microRNA, miR-181a, in cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  C. Bloomfield,et al.  Implications of the miR-10 family in chemotherapy response of NPM1-mutated AML. , 2014, Blood.

[7]  P. Pandolfi,et al.  Oncogenic Role of Fusion-circRNAs Derived from Cancer-Associated Chromosomal Translocations , 2016, Cell.

[8]  Chunlin Zhang,et al.  Analyzing the Interactions of mRNAs and ncRNAs to Predict Competing Endogenous RNA Networks in Osteosarcoma Chemo-Resistance. , 2019, Molecular therapy : the journal of the American Society of Gene Therapy.

[9]  Hongzhan Chen,et al.  Lipid-coated calcium phosphate nanoparticle and beyond: a versatile platform for drug delivery , 2017, Journal of drug targeting.

[10]  Xinchao Wu,et al.  MicroRNA-216b reduces growth, migration and invasion of pancreatic ductal adenocarcinoma cells by directly targeting ρ-associated coiled-coil containing protein kinase 1. , 2018, Oncology letters.

[11]  Shubiao Zhang,et al.  Toxicity of cationic lipids and cationic polymers in gene delivery. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[12]  Yong Jin Choi,et al.  miR-34 miRNAs provide a barrier for somatic cell reprogramming , 2011, Nature Cell Biology.

[13]  Suzanne L Wolden,et al.  Radiation-induced micro-RNA expression changes in peripheral blood cells of radiotherapy patients. , 2011, International journal of radiation oncology, biology, physics.

[14]  Feiran Wang,et al.  miR-221 suppression through nanoparticle-based miRNA delivery system for hepatocellular carcinoma therapy and its diagnosis as a potential biomarker , 2018, International journal of nanomedicine.

[15]  Gan Zhang,et al.  The long noncoding RNA‐ROR promotes the resistance of radiotherapy for human colorectal cancer cells by targeting the p53/miR‐145 pathway , 2017, Journal of gastroenterology and hepatology.

[16]  Woo Seok Kim,et al.  Self-assembled Micelle Interfering RNA for Effective and Safe Targeting of Dysregulated Genes in Pulmonary Fibrosis* , 2016, The Journal of Biological Chemistry.

[17]  George A Calin,et al.  miRNA Deregulation in Cancer Cells and the Tumor Microenvironment. , 2016, Cancer discovery.

[18]  P. Pandolfi,et al.  Oncogenic Role of Fusion-circRNAs Derived from Cancer-Associated Chromosomal Translocations , 2016, Cell.

[19]  M. Manikandan,et al.  Dysregulation of miR-200 family microRNAs and epithelial-mesenchymal transition markers in oral squamous cell carcinoma. , 2017, Oncology letters.

[20]  S. Dhanasekaran,et al.  The Landscape of Circular RNA in Cancer , 2019, Cell.

[21]  Jingqing Yang,et al.  MiR-181a confers resistance of cervical cancer to radiation therapy through targeting the pro-apoptotic PRKCD gene , 2013, Oncogene.

[22]  S. Xiao,et al.  miRNA-487a Promotes Proliferation and Metastasis in Hepatocellular Carcinoma , 2016, Clinical Cancer Research.

[23]  A. Molven,et al.  Tissue MicroRNA profiles as diagnostic and prognostic biomarkers in patients with resectable pancreatic ductal adenocarcinoma and periampullary cancers , 2017, Biomarker Research.

[24]  L. Hansen,et al.  The association between miR-34 dysregulation and distant metastases formation in lung adenocarcinoma. , 2017, Experimental and molecular pathology.

[25]  P. Sharp,et al.  LincRNA-p21 activates p21 in cis to promote Polycomb target gene expression and to enforce the G1/S checkpoint. , 2014, Molecular cell.

[26]  C. Dominici,et al.  Pharmacological targeting of the ephrin receptor kinase signalling by GLPG1790 in vitro and in vivo reverts oncophenotype, induces myogenic differentiation and radiosensitizes embryonal rhabdomyosarcoma cells , 2017, Journal of Hematology & Oncology.

[27]  Seokjoong Kim,et al.  CRISPR/Cas9-Mediated Knockout of DGK Improves Antitumor Activities of Human T Cells. , 2018, Cancer research.

[28]  Y. Zu,et al.  Cellular function reinstitution of offspring red blood cells cloned from the sickle cell disease patient blood post CRISPR genome editing , 2017, Journal of Hematology & Oncology.

[29]  Luca Pinello,et al.  Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS. , 2018, Cancer cell.

[30]  Huijuan Jiang,et al.  Downregulation of lncRNA ANRIL inhibits proliferation, induces apoptosis, and enhances radiosensitivity in nasopharyngeal carcinoma cells through regulating miR-125a , 2017, Cancer biology & therapy.

[31]  G. Calin,et al.  Noncoding RNAs and immune checkpoints—clinical implications as cancer therapeutics , 2017, The FEBS journal.

[32]  M. Sobrinho-Simões,et al.  Effect of miR-128 in DNA damage of HL-60 acute myeloid leukemia cells. , 2014, Current pharmaceutical biotechnology.

[33]  P. Iversen,et al.  c-MYC antisense phosphosphorodiamidate morpholino oligomer inhibits lung metastasis in a murine tumor model. , 2008, Lung cancer.

[34]  V. Erdmann,et al.  Design of antisense oligonucleotides stabilized by locked nucleic acids. , 2002, Nucleic acids research.

[35]  Zhongwei Cao,et al.  miR-181a sensitizes resistant leukaemia HL-60/Ara-C cells to Ara-C by inducing apoptosis , 2011, Journal of Cancer Research and Clinical Oncology.

[36]  Wei Xiong,et al.  MicroRNA-125b Confers the Resistance of Breast Cancer Cells to Paclitaxel through Suppression of Pro-apoptotic Bcl-2 Antagonist Killer 1 (Bak1) Expression* , 2010, The Journal of Biological Chemistry.

[37]  Runsheng Chen,et al.  The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling. , 2015, Cell stem cell.

[38]  F. Fan,et al.  Expression and function of miRNA in postoperative radiotherapy sensitive and resistant patients of non-small cell lung cancer. , 2011, Lung cancer.

[39]  R. Fort,et al.  An integrated view of the role of miR-130b/301b miRNA cluster in prostate cancer , 2018, Experimental Hematology & Oncology.

[40]  Geoff Delaney,et al.  The role of radiotherapy in cancer treatment , 2005, Cancer.

[41]  A. Harris,et al.  miR-139-5p Modulates Radiotherapy Resistance in Breast Cancer by Repressing Multiple Gene Networks of DNA Repair and ROS Defense. , 2018, Cancer research.

[42]  Hsiang-Cheng Chi,et al.  Roles of Long Noncoding RNAs in Recurrence and Metastasis of Radiotherapy-Resistant Cancer Stem Cells , 2017, International journal of molecular sciences.

[43]  J. Rossi,et al.  Gene activation of CEBPA using saRNA: Preclinical studies of the first in human saRNA drug candidate for liver cancer , 2018, Oncogene.

[44]  M. De Carvalho Bittencourt,et al.  Curative or pre-emptive adenovirus-specific T cell transfer from matched unrelated or third party haploidentical donors after HSCT, including UCB transplantations: a successful phase I/II multicenter clinical trial , 2017, Journal of Hematology & Oncology.

[45]  K. Kelnar,et al.  Quantification of Therapeutic miRNA Mimics in Whole Blood from Nonhuman Primates , 2014, Analytical chemistry.

[46]  T. CrookeStanley Molecular Mechanisms of Antisense Oligonucleotides. , 2017 .

[47]  L. Collette,et al.  Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. , 2014, The Lancet. Oncology.

[48]  Imran Babar,et al.  MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy. , 2007, Cancer research.

[49]  S. Inoue,et al.  Nanobiopolymer for Direct Targeting and Inhibition of EGFR Expression in Triple Negative Breast Cancer , 2012, PloS one.

[50]  M. Esteller Non-coding RNAs in human disease , 2011, Nature Reviews Genetics.

[51]  anastasia. khvorova,et al.  The chemical evolution of oligonucleotide therapies of clinical utility , 2017, Nature Biotechnology.

[52]  Q. Lu,et al.  The role of MALAT1/miR-1/slug axis on radioresistance in nasopharyngeal carcinoma , 2016, Tumor Biology.

[53]  A. Bader miR-34 – a microRNA replacement therapy is headed to the clinic , 2012, Front. Gene..

[54]  F. Slack,et al.  MicroRNA therapeutics: towards a new era for the management of cancer and other diseases , 2017, Nature Reviews Drug Discovery.

[55]  Lili Wang,et al.  hsa_circ_0081143 promotes cisplatin resistance in gastric cancer by targeting miR-646/CDK6 pathway , 2019, Cancer Cell International.

[56]  Bo W. Han,et al.  Down-regulated miR-331–5p and miR-27a are associated with chemotherapy resistance and relapse in leukaemia , 2011, Journal of cellular and molecular medicine.

[57]  Yunching Chen,et al.  Galactose Derivative-Modified Nanoparticles for Efficient siRNA Delivery to Hepatocellular Carcinoma. , 2018, Biomacromolecules.

[58]  Jingting Jiang,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. , 2019, Biochemical and biophysical research communications.

[59]  S. Crooke Molecular Mechanisms of Antisense Oligonucleotides , 2017, Nucleic acid therapeutics.

[60]  Xucong Teng,et al.  Antisense Oligonucleotide-Conjugated Nanostructure-Targeting lncRNA MALAT1 Inhibits Cancer Metastasis. , 2018, ACS applied materials & interfaces.

[61]  Xiang Li,et al.  The Biogenesis, Functions, and Challenges of Circular RNAs. , 2018, Molecular cell.

[62]  H. Greinix,et al.  Infections in patients with acute myeloid leukemia treated with low-intensity therapeutic regimens: Risk factors and efficacy of antibiotic prophylaxis. , 2016, Leukemia research.

[63]  Yan Xin,et al.  Circular RNAs: a new frontier for cancer diagnosis and therapy , 2018, Journal of Hematology & Oncology.

[64]  Fangting Wu,et al.  LncRNA loc285194 is a p53-regulated tumor suppressor , 2013, Nucleic acids research.

[65]  S. Raguz,et al.  Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. , 2010, Molecular cell.

[66]  S. Aerts,et al.  p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity , 2016, Nature Medicine.

[67]  Li-li Wang,et al.  Clinical implications of genome-wide DNA methylation studies in acute myeloid leukemia , 2017, Journal of Hematology & Oncology.

[68]  Y. Kopelman,et al.  Mutant KRAS is a druggable target for pancreatic cancer , 2013, Proceedings of the National Academy of Sciences.

[69]  M. Shi,et al.  Cancer-associated Fibroblast–promoted LncRNA DNM3OS Confers Radioresistance by Regulating DNA Damage Response in Esophageal Squamous Cell Carcinoma , 2018, Clinical Cancer Research.

[70]  Amy Chan,et al.  Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. , 2014, Journal of the American Chemical Society.

[71]  J. Mah An Overview of Recent Therapeutics Advances for Duchenne Muscular Dystrophy. , 2018, Methods in molecular biology.

[72]  Jindan Yu,et al.  LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer , 2015, Oncogene.

[73]  S. Volinia,et al.  The Network of Non-coding RNAs in Cancer Drug Resistance , 2018, Front. Oncol..

[74]  Lili Qin,et al.  The role of long noncoding RNA HOTAIR in the acquired multidrug resistance to imatinib in chronic myeloid leukemia cells , 2017, Hematology.

[75]  L. Johnson,et al.  An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy , 2000, Nature Medicine.

[76]  S. Lipkin,et al.  A long non-coding RNA targets microRNA miR-34a to regulate colon cancer stem cell asymmetric division , 2016, eLife.

[77]  P. Tassone,et al.  MALAT1: a druggable long non-coding RNA for targeted anti-cancer approaches , 2018, Journal of Hematology & Oncology.

[78]  C. Leonetti,et al.  The future of antisense therapy: combination with anticancer treatments , 2003, Oncogene.

[79]  M. Spiess,et al.  The asialoglycoprotein receptor: a model for endocytic transport receptors. , 1990, Biochemistry.

[80]  C. Chim,et al.  High applicability of ASO-RQPCR for detection of minimal residual disease in multiple myeloma by entirely patient-specific primers/probes , 2016, Journal of Hematology & Oncology.

[81]  Wei Zheng,et al.  miR-125b acts as a tumor suppressor in chondrosarcoma cells by the sensitization to doxorubicin through direct targeting the ErbB2-regulated glucose metabolism , 2016, Drug design, development and therapy.

[82]  P. Iversen,et al.  Efficacy of antisense morpholino oligomer targeted to c-myc in prostate cancer xenograft murine model and a Phase I safety study in humans. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[83]  J. Ju,et al.  microRNA based prognostic biomarkers in pancreatic Cancer , 2018, Biomarker Research.

[84]  Xian-Jun Qu,et al.  CXCL12/CXCR4 axis induced miR-125b promotes invasion and confers 5-fluorouracil resistance through enhancing autophagy in colorectal cancer , 2017, Scientific Reports.

[85]  S. Yip,et al.  Long non-coding RNAs in hematological malignancies: translating basic techniques into diagnostic and therapeutic strategies , 2018, Journal of Hematology & Oncology.

[86]  Mei-Juan Tu,et al.  RNA therapy: Are we using the right molecules? , 2019, Pharmacology & therapeutics.

[87]  Bin Li,et al.  Circular RNAs in cancer: an emerging key player , 2017, Journal of Hematology & Oncology.

[88]  Hong Chang,et al.  Role of epigenetics-microRNA axis in drug resistance of multiple myeloma , 2017, Journal of Hematology & Oncology.

[89]  A. Parker,et al.  Designer Oncolytic Adenovirus: Coming of Age , 2018, Cancers.

[90]  V. Herrera,et al.  Nucleic acid nanomedicines in Phase II/III clinical trials: translation of nucleic acid therapies for reprogramming cells. , 2018, Nanomedicine.

[91]  Kazuhisa Takahashi,et al.  Chemotherapy-Regulated microRNA-125–HER2 Pathway as a Novel Therapeutic Target for Trastuzumab-Mediated Cellular Cytotoxicity in Small Cell Lung Cancer , 2015, Molecular Cancer Therapeutics.

[92]  Yingnan Sun,et al.  A cytoplasmic long noncoding RNA LINC00470 as a new AKT activator to mediate glioblastoma cell autophagy , 2018, Journal of Hematology & Oncology.

[93]  Anne-Kathrin Garz,et al.  A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers , 2016, Clinical Epigenetics.

[94]  M. Chaudhry,et al.  Transcriptional modulation of micro-RNA in human cells differing in radiation sensitivity , 2010, International journal of radiation biology.

[95]  Simon W. Jones,et al.  Lung delivery studies using siRNA conjugated to TAT(48-60) and penetratin reveal peptide induced reduction in gene expression and induction of innate immunity. , 2007, Bioconjugate chemistry.

[96]  Min Young Kim,et al.  Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation , 2017, Molecular Cancer.

[97]  Xu Zhou,et al.  ncDR: a comprehensive resource of non-coding RNAs involved in drug resistance , 2017, Bioinform..

[98]  P. Hrdlicka,et al.  Pyrene-functionalized oligonucleotides and locked nucleic acids (LNAs): tools for fundamental research, diagnostics, and nanotechnology. , 2011, Chemical Society reviews.

[99]  Anna M. Krichevsky,et al.  Genome Editing Reveals Glioblastoma Addiction to MicroRNA-10b. , 2017, Molecular Therapy.

[100]  Qing Tang,et al.  HOTAIR: An Oncogenic Long Non-Coding RNA in Human Cancer , 2018, Cellular Physiology and Biochemistry.

[101]  S. Lawler,et al.  MicroRNAs in cancer: biomarkers, functions and therapy. , 2014, Trends in molecular medicine.

[102]  Yingying Liu,et al.  MiR-146b-5p overexpression attenuates stemness and radioresistance of glioma stem cells by targeting HuR/lincRNA-p21/β-catenin pathway , 2016, Oncotarget.

[103]  P. Sætrom,et al.  Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo , 2014, Hepatology.

[104]  L. Jia,et al.  Long non-coding RNA-SNHG7 acts as a target of miR-34a to increase GALNT7 level and regulate PI3K/Akt/mTOR pathway in colorectal cancer progression , 2018, Journal of Hematology & Oncology.

[105]  D. Corey,et al.  Non-coding RNAs as drug targets , 2016, Nature Reviews Drug Discovery.

[106]  Lisheng He,et al.  Dual targeting delivery of miR-328 by functionalized mesoporous silica nanoparticles for colorectal cancer therapy. , 2018, Nanomedicine.

[107]  Xingxu Huang,et al.  Nucleofection with Plasmid DNA for CRISPR/Cas9-Mediated Inactivation of Programmed Cell Death Protein 1 in CD133-Specific CAR T Cells. , 2018, Human gene therapy.

[108]  Pei-Ling Hsieh,et al.  Berberine-targeted miR-21 chemosensitizes oral carcinomas stem cells , 2017, Oncotarget.

[109]  Claus Belka,et al.  MicroRNA expression profiles in human cancer cells after ionizing radiation , 2011, Radiation oncology.

[110]  M. Caligiuri,et al.  Lenalidomide-mediated enhanced translation of C/EBPα-p30 protein up-regulates expression of the antileukemic microRNA-181a in acute myeloid leukemia. , 2013, Blood.

[111]  Tao Yu,et al.  Knockdown of Long Non-Coding RNA XIST Inhibited Doxorubicin Resistance in Colorectal Cancer by Upregulation of miR-124 and Downregulation of SGK1 , 2018, Cellular Physiology and Biochemistry.

[112]  A. Krainer,et al.  Abstract PR11: Differentiation of mammary tumors and reduction in metastasis upon Malat1 LncRNA loss , 2016 .

[113]  U. Gezer,et al.  Do circulating long non-coding RNAs (lncRNAs) (LincRNA-p21, GAS 5, HOTAIR) predict the treatment response in patients with head and neck cancer treated with chemoradiotherapy? , 2016, Tumor Biology.

[114]  Zhonghan Li,et al.  Therapeutic targeting of microRNAs: current status and future challenges , 2014, Nature Reviews Drug Discovery.

[115]  R. Eliakim,et al.  RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients , 2015, Oncotarget.

[116]  D. Spector,et al.  The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. , 2013, Cancer research.

[117]  Lin Zhang,et al.  Long noncoding RNA LINP1 regulates double strand DNA break repair in triple negative breast cancer , 2016, Nature Structural &Molecular Biology.

[118]  D. Watson,et al.  MicroRNAs and Their Impact on Radiotherapy for Cancer , 2016, Radiation Research.

[119]  Miran Kim,et al.  Alcohol‐mediated miR‐34a modulates hepatocyte growth and apoptosis , 2018, Journal of cellular and molecular medicine.

[120]  D. Bartel MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[121]  Jennifer A. Doudna,et al.  CRISPR-Cas guides the future of genetic engineering , 2018, Science.

[122]  J. Rinn,et al.  Modular regulatory principles of large non-coding RNAs , 2012, Nature.

[123]  Kyuri Lee,et al.  The cutting-edge technologies of siRNA delivery and their application in clinical trials , 2018, Archives of pharmacal research.

[124]  C. Croce,et al.  CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia. , 2013, The Journal of clinical investigation.

[125]  Zhijun Li,et al.  Long noncoding RNA MALAT1 affects the efficacy of radiotherapy for esophageal squamous cell carcinoma by regulating Cks1 expression , 2017, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[126]  A. Schmidt,et al.  Alteration of miRNA expression in a sulfur mustard resistant cell line. , 2017, Toxicology letters.

[127]  T. Liang,et al.  Delivery of miR-212 by chimeric peptide-condensed supramolecular nanoparticles enhances the sensitivity of pancreatic ductal adenocarcinoma to doxorubicin. , 2019, Biomaterials.

[128]  S. Milstein,et al.  Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates , 2018, Molecular therapy : the journal of the American Society of Gene Therapy.

[129]  J. Rossi,et al.  Therapeutic Potential of small Activating RNAs (saRNAs) in Human Cancers , 2018, Current pharmaceutical biotechnology.

[130]  Michael H. Shuman,et al.  Assessing cellular toxicities in fibroblasts upon exposure to lipid-based nanoparticles: a high content analysis approach , 2011, Nanotechnology.

[131]  N. Raulf,et al.  MicroRNA‐196a promotes an oncogenic effect in head and neck cancer cells by suppressing annexin A1 and enhancing radioresistance , 2015, International journal of cancer.

[132]  Hao Li,et al.  miR-181a sensitizes a multidrug-resistant leukemia cell line K562/A02 to daunorubicin by targeting BCL-2. , 2012, Acta biochimica et biophysica Sinica.