Emerging role of long non-coding RNAs in cancer chemoresistance: unravelling the multifaceted role and prospective therapeutic targeting


Chemotherapy is one of the important treatment modules in early as well as advanced stages of cancer. However, the major limitation of chemotherapy is the development of chemoresistance in the transformed cells of cancer patients, which leads to cancer recurrence. Long non-coding RNAs (lncRNA) are the transcripts longer than 200 nucleotides in length, which are reported to associate with the initiation, progression, recurrence, and metastasis of different cancers. Several lncRNAs have been implicated in the prevalence of chemoresistant phenotypes and also in the restoration of drug sensitivity in chemoresistant cells. LncRNAs such as HOTAIR, H19, and a lot more are involved in the chemoresistance of cancer cells. Therefore, targeting the lncRNAs may serve as a novel strategy for treating chemoresistant cancer. This review throws light on the role of lncRNA in chemoresistance along with the perspective of the therapeutic targets for the treatment of multiple cancers.

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  1. 1.

    Panoutsopoulou K, Avgeris M, Scorilas A (2018) miRNA and long non-coding RNA: molecular function and clinical value in breast and ovarian cancers. Expert. Rev. Mol Diagn 18:963–979

    CAS  Google Scholar 

  2. 2.

    Uchida S, Adams JC (2019) Physiological roles of non-coding RNAs. Am J Physiol Cell Physiol 317:C1–C2

    CAS  PubMed  Google Scholar 

  3. 3.

    Agostini M, Ganini C, Candi E, Melino G (2020) The role of noncoding RNAs in epithelial cancer. Cell Death Discov 6:13

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Huang T, Alvarez A, Hu B, Cheng SY (2013) Noncoding RNAs in cancer and cancer stem cells. Chin J Cancer 11:582–593

    Google Scholar 

  5. 5.

    Fang Y, Fullwood MJ (2016) Roles, functons, and mechanism of Long non-coding RNAs in Cancer. Genomics Proteomics Bioinform 14:42–54

    Google Scholar 

  6. 6.

    Singh D, Khan MA, Siddique HR (2019) Apigenin, a plant flavone playing Noble roles in Cancer prevention via modulation of key cell signaling networks. Recent Pat Anticancer Drug Discov 14:298–311

    CAS  PubMed  Google Scholar 

  7. 7.

    Brasseur K, Gévry N, Asselin E (2017) Chemoresistance and targeted therapies in ovarian and endometrial cancers. Oncotarget. 8:4008–4042

    PubMed  Google Scholar 

  8. 8.

    Bermúdez M, Aguilar-Medina M, Lizárraga-Verdugo E, Avendaño-Félix M, Silva-Benítez E, López-Camarillo C, Ramos-Payan R (2019) LncRNAs as regulators of autophagy and drug resistance in colorectal Cancer. Front Oncol 9:1008

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Liu Z, Sun M, Lu K, Liu J, Zhang M, Wu W, De W, Wang Z, Wang R (2013) The long noncoding RNA HOTAIR contributes to cisplatin resistance of human lung adenocarcinoma cells via downregualtion of p21(WAF1/CIP1) expression. PLoS ONE 8:e77293

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Liu J, Wan L, Lu K, Sun M, Pan X, Zhang P, Lu B, Liu G, Wang Z (2015) The long noncoding RNA MEG3 contributes to cisplatin resistance of human lung adenocarcinoma. PLoS ONE 10:e0114586

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Li Z, Zhao X, Zhou Y, Liu Y, Zhou Q, Ye H, Wang Y, Zeng J, Song Y, Gao W, Zheng S, Zhuang B, Chen H, Li W, Li H, Li H, Fu Z, Chen R (2015) The long non-coding RNA HOTTIP promotes progression and gemcitabine resistance by regulating HOXA13 in pancreatic cancer. J Transl Med 13(84)

  12. 12.

    Takahashi K, Yan IK, Kogure T, Haga H, Patel T (2014) Extracellular vesicle-mediated transfer of long non-coding RNA ROR modulates chemosensitivity in human hepatocellular cancer. FEBS Open Bio 4:458–467

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Niazi F, Valadkhan S (2012) Computational analysis of functional long noncoding RNAs reveals lack of peptide coding capacity and parallels with 3′ UTRs. RNA. 18:825–843

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Novikova IV, Hennelly SP, Sanbonmatsu KY (2012) Sizing up long non-coding RNAs: do lncRNAs have secondary and tertiary structure. Bioarchitecture. 2:189–199

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, Wang Y, Brzoska P, Kong B, Li R, West RB, van de Vijver MJ, Sukumar S, Chang HY (2010) Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 464:1071–1076

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Laurent GS, Wahlestedt C, Kapranov P (2015) The landscape of long noncoding RNA classification. Trends Genet 31:239–251

    Google Scholar 

  17. 17.

    Zheng HC (2017) The molecular mechanisms of chemoresistance in cancers. Oncotarget. 8:59950–59964

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Liu K, Gao L, Ma X, Huang JJ, Chen J, Zeng L, Ashby CR, Zou C, Chen ZS (2020) Long non-coding RNAs regulate drug resistance in cancer. Mol Cancer 19:54

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Ozes AR, Miller DF, Ozes ON, Fang F, Liu Y, Matei D, Huang T, Nephew KP (2016) NF-kappa-HOTAIR axis links DNA damage response, chemoresistance and cellular senescence in ovarian cancer. Oncogene. 35:5350–5361

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Fang S, Gao H, Tong Y, Yang J, Tang R, Niu Y, Li M, Guo L (2016) Long noncoding RNA-HOTAIR affects chemoresistance by regulating HOXA1 methylation in small cell lung cancer cells. Lab Investig 96:60–68

    CAS  PubMed  Google Scholar 

  21. 21.

    Xue X, Yang YA, Zhang A, Fong KW, Kim J, Song B, Li S, Zhao JC, Yu J (2016) LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer. Oncogene. 35:2746–2755

    CAS  PubMed  Google Scholar 

  22. 22.

    Wang Y, Zhang D, Wu K, Zhao Q, Nie Y, Fan D (2014) Long noncoding RNA MRUL promotes ABCB1 expression in multidrug-resistant gastric cancer cell sublines. Mol Cell Biol 34:3182–3193

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Dong S, Qu X, Li W, Zhong X, Li P, Yang S, Chen X, Shao M, Zhang L (2015) The long non-coding RNA, GAS5, enhances gefitinib-induced cell death in innate EGFR tyrosine kinase inhibitor-resistant lung adenocarcinoma cells with wide-type EGFR via downregulation of the IGF-1R expression. J Hematol Oncol 8:43

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Gao ZQ, Wang JF, Chen DH, Ma XS, Yang W, Zhe T, Dang XW (2018) Long non-coding RNA GAS5 antagonizes the chemoresistance of pancreatic cancer cells through down-regulation of miR-181c-5p. Biomed Pharmacother 97:809–817

    CAS  PubMed  Google Scholar 

  25. 25.

    Cheng N, Cai W, Ren S, Li X, Wang Q, Pan H, Zhao M, Li J, Zhang Y, Zhao C, Chen X, Fei K, Zhou C, Hirsch FR (2015) Long non-coding RNA UCA1 induces non-T790M acquired resistance to EGFR-TKIs by activating the AKT/mTOR pathway in EGFR-mutant non-small cell lung cancer. Oncotarget. 6:23582–23593

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Wang H, Guan Z, He K, Qian J, Cao J, Teng L (2017) LncRNA UCA1 in anti-cancer drug resistance. Oncotarget. 8:64638–64650

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Bian Z, Jin L, Zhang J, Yin Y, Quan C, Hu Y, Feng Y, Liu H, Fei B, Mao Y, Zhou L, Qi X, Huang S, Hua D, Xing C, Huang Z (2016) LncRNA—UCA1 enhances cell proliferation and 5-fluorouracil resistance in colorectal cancer by inhibiting miR-204-5p. Sci Rep UK 6:23892

    CAS  Google Scholar 

  28. 28.

    Shi SJ, Wang LJ, Yu B, Li YH, Jin Y, Bai XZ (2015) LncRNA-ATB promotes trastuzumab resistance and invasion-metastasis cascade in breast cancer. Oncotarget. 6:11652–11663

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Han P, Li JW, Zhang BM, Lv JC, Li YM, Gu XY, Yu ZW, Jia YH, Bai XF, Li L, Liu YL, Cui BB (2017) The lncRNA CRNDE promotes colorectal cancer cell proliferation and chemoresistance via miR-181a-5p-mediated regulation of Wnt/β-catenin signalling. Mol Cancer 16:9

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Niu Y, Ma F, Huang W, Fang S, Li M, Wei T, Guo L (2017) Long non-coding RNA TUG1 is involved in cell growth and chemoresistance of small cell lung cancer by regulating LIMK2b via EZH2. Mol Cancer 16:5

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Ren K, Xu R, Huang J, Zhao J, Shi W (2017) Knockdown of long non-coding RNA KCNQ1OT1 depressed chemoresistance to paclitaxel in lung adenocarcinoma. Cancer Chemother Pharmacol 80:243–250

    CAS  PubMed  Google Scholar 

  32. 32.

    Jiang YZ, Liu YR, Xu XE, Jin X, Hu X, Yu KD, Shao ZM (2016) Transcriptome analysis of triple-negative breast Cancer reveals an integrated mRNA-lncRNA signature with predictive and prognostic value. Cancer Res 76:2105–2114

    CAS  PubMed  Google Scholar 

  33. 33.

    Zhang C, Zhu K, Shen G, Zhu Z (2016) A long non-coding RNA contributes to doxorubicin resistance of osteosarcoma. Tumor Biol 37:2737–2748

    CAS  Google Scholar 

  34. 34.

    Lee H, Kim C, Ku J, Kim W, Yoon SK, Kuh HJ, Lee JH, Nam SW, Lee EK (2014) A Long non-coding RNA snaR contributes to 5-fluorouracil resistance in human Colon Cancer cells. Mol Cells 37:540–546

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Ma Y, Yang Y, Wang F, Moyer MP, Wei Q, Zhang P, Yang Z, Liu W, Zhang H, Chen N, Wang H, Wang H, Qin H (2015) Long non-coding RNA CCAL regulates colorectal cancer progression by activating Wnt/ -catenin signalling pathway via suppression of activator protein 2. Gut. 65:1494–1504

    PubMed  Google Scholar 

  36. 36.

    Qu L, Ding J, Chen C, Wu Z, Liu B, Gao Y, Chen W, Liu F, Sun W, Li XF, Wang X, Wang Y, Xu ZY, Gao L, Yang Q, Xu B, Li YM, Fang ZY, Xu ZP, Bao Y, Wu DS, Miao X, Sun HY, Sun YH, Wang HY, Wang LH (2016) Exosome-transmitted lncARSR promotes Sunitinib resistance in renal Cancer by acting as a competing endogenous RNA. Cancer Cell 29:653–668

    CAS  PubMed  Google Scholar 

  37. 37.

    Pan Y, Li C, Chen J, Zhang K, Chur X, Wang R, Chen L (2016) The emerging roles of Long noncoding RNA ROR (lincRNA-ROR) and its possible mechanisms in human cancers. Cell Physiol Biochem 40:219–229

    CAS  PubMed  Google Scholar 

  38. 38.

    Liu E, Liu Z, Zhou Y, Mi R, Wang D (2015) Overexpression of long non-coding RNA PVT1 in ovarian cancer cells promotes cisplatin resistance by regulating apoptotic pathways. Int J Clin Exp Med 8:20565–20572

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Sun ZY, Jian YK, Zhu HY, Li B (2019) lncRNAPVT1 targets miR-152 to enhance chemoresistance of osteosarcoma to gemcitabine through activating c-MET/PI3K/AKT pathway. Pathol Res Pract 215:555–563

    CAS  PubMed  Google Scholar 

  40. 40.

    Kun-Peng Z, Xiao-Long M, Chun-Lin Z (2018) Overexpressed circPVT1, a potential new circular RNA biomarker, contributes to doxorubicin and cisplatin resistance of osteosarcoma cells by regulating ABCB1. Int J Biol Sci 14:321–330

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, Lajoie BR, Protacio A, Flynn RA, Gupta RA, Wysocka J, Lei M, Dekker J, Helms JA, Chang HY (2011) A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 472:120–124

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Yang F, Deng X, Ma W, Berletch JB, Rabaia N, Wei G, Moore JM, Filippova GN, Xu J, Liu Y, Noble WS, Shendure J, Disteche CM (2015) The lncRNA Firre anchors the inactive X chromosome to the nucleolus by binding CTCF and maintains H3K27me3 methylation. Genome Biol 16:52

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Do H, Kim W (2018) Roles of oncogenic Long non-coding RNAs in Cancer development. Genomics Inform 4:e18

    Google Scholar 

  44. 44.

    Li Y, Wang Z, Shi H, Li H, Li L, Fang R, Cai X, Liu B, Zhang X, Ye L (2015) HBXIP and LSD1 Scaffolded by lncRNA hotair mediate transcriptional activation by c-Myc. Cancer Res 76:293

    PubMed  Google Scholar 

  45. 45.

    Nie W, Ge HJ, Yang XQ, Sun X, Huang H, Tao X, Chen WS, Li B (2016) LncRNA-UCA1 exerts oncogenic functions in non-small cell lung cancer by targeting miR-193a-3p. Cancer Lett 371:99–106

    CAS  PubMed  Google Scholar 

  46. 46.

    Peng W, Si S, Zhang Q, Li C, Zhao F, Wang F, Yu J, Ma R (2015) Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate gastric cancer progression. J Exp Clin Cancer Res 34:79

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Deng L, Yang SB, Xu FF, Zhang JH (2015) Long noncoding RNA CCAT1 promotes hepatocellular carcinoma progression by functioning as let-7 sponge. J Exp Clin Cancer Res 34:18

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Lee S, Kopp F, Chang TC, Sataluri A, Chen B, Sivakumar S, Yu H, Xie Y, Mendell JT (2015) Noncoding RNA NORAD regulates genomic stability by sequestering PUMILIO proteins. Cell. 164:69

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Inamura K (2017) Major tumor suppressor and oncogenic non-coding RNAs: clinical relevance in lung Cancer. Cells. 6:12

    PubMed Central  Google Scholar 

  50. 50.

    Fatma H, Siddique HR (2020) Role of long non-coding RNAs and MYC interaction in cancer metastasis: a possible target for therapeutic intervention. Tox App Pharmacol 399

  51. 51.

    Guo F, Guo L, Li Y, Zhou Q, Li Z (2015) MALAT1 is an oncogenic long non-coding RNA associated with tumor invasion in non-small cell lung cancer regulated by DNA methylation. Int J Clin Exp Pathol 8:15903–15910

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Liu XH, Sun M, Nie FQ, Ge YB, Zhang EB, Yin DD, Kong R, Xia R, Lu KH, Li JH, De W, Wang KM, Wang ZX (2014) LncRNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. Mol Cancer 13:92

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Liu Y, Sun M, Xia R, Zhang EB, Liu XH, Zhang ZH, Xu TP, De W, Liu BR, Wang ZX (2015) LincHOTAIR epigenetically silences miR34a by binding to PRC2 to promote the epithelial-to-mesenchymal transition in human gastric cancer. Cell Death Disease 6:e1802

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Hajjari M, Salavaty A (2015) HOTAIR: an oncogenic long non-coding RNA in different cancers. Cancer Biol Med 12:1–9

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Zhang A, Zhao JC, Kim J, Fong K, Yang YA, Chakravarti D, Mo YY, Yu JI (2015) HOTAIR enhances the androgen-receptor-mediated transcriptional program and drives castration-resistant prostate cancer. Cell Rep 13:209–221

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Godinho M, Meijer D, Setyono-Han B, Dorssers LCJ, Van Agthoven T (2011) Characterization of BCAR4, a novel oncogene causing endocrine resistance in human breast cancer cells. J Cell Physiol 226:1741–1749

    CAS  PubMed  Google Scholar 

  57. 57.

    Van Agthoven T, Dorssers LC, Lehmann U, Kreipe H, Looijenga LH, Christgen M (2015) Breast Cancer anti-Estrogen resistance 4 (BCAR4) drives proliferation of IPH-926 lobular carcinoma cells. PLoS ONE 10:e136845

    Google Scholar 

  58. 58.

    Han Y, Ye J, Wu D, Wu P, Chen Z, Chen J, Gao S, Huang J (2014) LEIGC long non-coding RNA acts as a tumor suppressor in gastric carcinoma by inhibiting the epithelial-to-mesenchymal transition. BMC Cancer 14:932

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Fang X, Pan H, Leng R, Ye D (2015) Long noncoding RNAs: novel insights into gastric cancer. Can Lett 356:357–366

    CAS  Google Scholar 

  60. 60.

    Mohammad RM, Muqbil I, Lowe L, Yedjou C, Hsu HY, Lin LT, Siegelin MD, Fimognari C, Kumar NB, Dou QP, Yang H, Samadi AK, Russo GL, Spagnuolo C, Ray SK, Chakrabarti M, Morre JD, Coley HM, Honoki K, Fujii H et al (2015) Broad targeting of resistance to apoptosis in cancer. Semin Cancer Biol 35:S78–S103

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Zhang X, Bu P, Liu L, Zhang X, Li J (2015) Overexpression of long non-coding RNA PVT1 in gastric cancer cells promotes the development of multidrug resistance. Biochem Biophys Res Commun 462:227–232

    CAS  PubMed  Google Scholar 

  62. 62.

    Shang C, Guo Y, Zhang J, Huang B (2016) Silence of long noncoding RNA UCA1 inhibits malignant proliferation and chemotherapy resistance to adriamycin in gastric cancer. Cancer Chemoth Pharm 77:1061–1067

    CAS  Google Scholar 

  63. 63.

    Wang F, Li X, Xie X, Zhao L, Chen W (2008) UCA1, a non-protein-coding RNA up-regulated in bladder carcinoma and embryo, influencing cell growth and promoting invasion. FEBS Lett 582:1919–1927

    CAS  PubMed  Google Scholar 

  64. 64.

    Wang Y, Chen W, Yang C, Wu W, Wu S, Qin X, Li X (2012) Long non-coding RNA UCA1a(CUDR) promotes proliferation and tumorigenesis of bladder cancer. Int J Oncol 41:276–284

    CAS  PubMed  Google Scholar 

  65. 65.

    Lan WG, Xu DH, Xu C, Ding CL, Ning FL, Zhou YL, Ma LB, Liu CM, Han X (2016) Silencing of long non-coding RNA ANRIL inhibits the development of multidrug resistance in gastric cancer cells. Oncol Rep 36:263–270

    CAS  PubMed  Google Scholar 

  66. 66.

    Wan L, Sun M, Liu GJ, Wei CC, Zhang EB, Kong R, Xu TP, Huang MD, Wang ZX (2016) Long non-coding RNA PVT1 promotes non-small cell lung cancer cell proliferation through epigenetically regulating LATS2 expression. Mol Cancer Ther 15:1082–1094

    CAS  PubMed  Google Scholar 

  67. 67.

    Cheng N, Li X, Zhao C, Ren S, Chen X, Cai W, Zhao M, Zhang Y, Li J, Wang Q, Zhou C (2015) Microarray expression profile of long non-coding RNAs in EGFR-TKIs resistance of human non-small cell lung cancer. Oncol Rep 33:833–839

    CAS  PubMed  Google Scholar 

  68. 68.

    Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM (2013) Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology. 144:512–527

    PubMed  PubMed Central  Google Scholar 

  69. 69.

    Jiang M, Huang O, Xie Z, Wu S, Zhang X, Shen A, Liu H, Chen X, Wu J, Lou Y, Mao Y, Sun K, Hu S, Geng M, Shen K (2014) A novel long non-coding RNA-ARA: Adriamycin resistance-associated. Biochem Pharmacol 87:254–283

    CAS  PubMed  Google Scholar 

  70. 70.

    Souza PS, Madigan JP, Gillet JP, Kapoor K, Ambudkar SV, Maia RC, Gottesman MM, Fung KL (2015) Expression of the multidrug transporter P-glycoprotein is inversely related to that of apoptosis-associated endogenous TRAIL. Exp Cell Res 336:318–328

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Tsang WP, Kwok TT (2007) Riboregulator H19 induction of MDR1-associated drug resistance in human hepatocellular carcinoma cells. Oncogene. 26:4877–4881

    CAS  PubMed  Google Scholar 

  72. 72.

    Huang L, Zeng L, Chu J, Xu P, Lv M, Xu J, Wen J, Li W, Wang L, Wu X, Fu Z, Xie H, Wang S (2018) Chemoresistance-related long non-coding RNA expression profiles in human breast cancer cells. Mol Med Rep 18:243–253

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Vendrell JA, Thollet A, Nguyen NT, Ghayad SE, Vinot S, Ivan B, Evelyne G, Veronique J, Jean-Luc C, Pierre R, Laura C, Isabelle T, Ruth R, Pascale C (2012) ZNF217 is a marker of poor prognosis in breast cancer that drives epithelial-mesenchymal transition and invasion. Cancer Res 72:3593–3606

    CAS  PubMed  Google Scholar 

  74. 74.

    Yang Y, Li H, Hou S, Hu B, Liu J, Wang J (2013) The noncoding RNA expression profile and the effect of lncRNA AK126698 on cisplatin resistance in non-small- cell lung Cancer cell. PLoS ONE 8:e65309

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Cai Y, He J, Zhang D (2016) Suppression of long non-coding RNA CCAT2 improves tamoxifen-resistant breast cancer cells’ response to tamoxifen. Mol Biol (Mosk) 50(821–7)

  76. 76.

    Li Z, Qian J, Li J, Zhu C (2019) Knockdown of lncRNA-HOTAIR downregulates the drug-resistance of breast cancer cells to doxorubicin via the PI3K/AKT/mTOR signaling pathway. Exp Ther Med 18:435–442

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Li W, Zhai L, Wang H, Liu C, Zhang J, Chen W, Wei Q (2016) Downregulation of LncRNA GAS5 causes trastuzumab resistance in breast cancer. Oncotarget. 7:27778–27786

    PubMed  PubMed Central  Google Scholar 

  78. 78.

    Kimura T, Aikata H, Takahashi S, Takahashi I, Nishibuchi I, Doi Y, Kenjo M, Murakami Y, Honda Y, Kakizawa H, Awai K, Chayama K, Nagata Y (2015) Stereotactic body radiotherapy for patients with small hepatocellular carcinoma ineligible for resection or ablation therapies. Hepatol Res 45:378–386

    PubMed  Google Scholar 

  79. 79.

    Arjmand F, Afsan Z, Sharma S, Parveen S, Yousuf I, Sartaj S, Siddique HR, Tabassum S (2019) Recent advances in Metallodrug-like molecules targeting non-coding RNAs (ncRNAs) in cancer chemotherapy. Coord Chem Rev 387:47–59

    CAS  Google Scholar 

  80. 80.

    Nishimura M, Jung EJ, Shah MY, Lu C, Spizzo R, Shimizu M, Han HD, Ivan C, Rossi S, Zhang X, Nicoloso MS, Wu SY, Almeida MI, Bottsford-Miller J, Pecot CV, Zand B, Matsuo K, Shahzad MM, Jennings NB, Rodriguez-Aguayo C, Lopez-Berestein G, Sood AK, Calin GA (2013) Therapeutic synergy between microRNA and siRNA in ovarian cancer treatment. Cancer Discov 3:1302–1315

    CAS  PubMed  Google Scholar 

  81. 81.

    Aslan B, Monroig P, Hsu MC, Pena GA, Rodriguez-Aguayo C (2015) The ZNF304-integrin axis protects against anoikis in cancer. Nat Commun 6:7351

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Ozpolat B, Sood AK, Lopez-Berestein G (2014) Liposomal siRNA nanocarriers for cancer therapy. Adv Drug Deliv Rev 66:110–116

    CAS  PubMed  Google Scholar 

  83. 83.

    Gutschner T, Hämmerle M, Eissmann M, Hsu J, Kim Y, Hung G, Revenko A, Arun G, Stentrup M, Gross M, Zörnig M, MacLeod AR, Spector DL, Diederichs S (2013) The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res 73:1180–1189

    CAS  PubMed  Google Scholar 

  84. 84.

    Kotake Y, Nakagawa T, Kitagawa K, Suzuki S, Liu N, Kitagawa M, Xiong Y (2011) Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene. Oncogene. 30:1956–1962

    CAS  PubMed  Google Scholar 

  85. 85.

    Geary RS, Norris D, Yu R, Bennett CF (2015) Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Adv Drug Deliv Rev 87:46–51

    CAS  PubMed  Google Scholar 

  86. 86.

    Shen X, Corey DR (2018) Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs. Nucleic Acids Res 46:1584–1600

    CAS  PubMed  Google Scholar 

  87. 87.

    Yang G, Lu X, Yuan L (2014) LncRNA: a link between RNA and cancer. Biochim Biophys Acta 1839:1097–1109

    CAS  PubMed  Google Scholar 

  88. 88.

    Iden M, Fye S, Li K, Chowdhury T, Ramchandran R, Rader JS (2016) The lncRNA PVT1 contributes to the cervical cancer phenotype and associates with poor patient prognosis. PLoS ONE 11:e0156274

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Durig J, Duhrsen U, Klein-Hitpass L, Worm J, Hansen JB, Orum H, Wissenbach M (2011) The novel antisense Bcl-2 inhibitor SPC2996 causes rapid leukemic cell clearance and immune activation in chronic lymphocytic leukemia. Leukemia. 25:638–647

    CAS  PubMed  Google Scholar 

  90. 90.

    Carlevaro-Fita J, Rahim A, Guigó R, Vardy LA, Johnson R (2016) Cytoplasmic long noncoding RNAs are frequently bound to and degraded at ribosomes in human cells. RNA. 22:867–882

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Pavco PA, Bouhana KS, Gallegos AM, Agrawal A, Blanchard KS, Grimm SL, Jensen KL, Andrews LE, Wincott FE, Pitot PA, Tressler RJ, Cushman C, Reynolds MA, Parry TJ (2000) Antitumor and antimetastatic activity of ribozymes targeting the messenger RNA of vascular endothelial growth factor receptors. Clin Cancer Res 6:2094–2130

    CAS  PubMed  Google Scholar 

  92. 92.

    Charles Richard JL, Eichhorn PJA (2018) Platforms for investigating LncRNA functions. SLAS Technol 23:493–506

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Vitiello M, Tuccoli A, Poliseno L (2015) Long non-coding RNAs in cancer: implications for personalized therapy. Cell Oncol (Dordr) 38(17–28)

  94. 94.

    Rivas E, Clements J, Eddy SR (2017) A statistical test for conserved RNA structure shows lack of evidence for structure in lncRNAs. Nat Methods 14:45–48

    CAS  PubMed  Google Scholar 

  95. 95.

    Brown JA, Kinzig CG, DeGregorio SJ, Steitz JA (2014) Methyltransferase-like protein 16 binds the 3′-terminal triple helix of MALAT1 long noncoding RNA. Proc Natl Acad Sci U S A 113:14013–14018

    Google Scholar 

  96. 96.

    Desoize B (2004) Metals and metal compounds in cancer treatment. Anticancer Res 24:1529–1544

    CAS  PubMed  Google Scholar 

  97. 97.

    Celander DW, Nussbaum JM (1996) The porphyrin handbook. Biochemistry. 35:12061–12069

    CAS  PubMed  Google Scholar 

  98. 98.

    Moulton JD (2017) Using morpholinos to control gene expression. Curr Protoc Nucleic Acid Chem 68:1–4

    Google Scholar 

  99. 99.

    Blum M, De Robertis EM, Wallingford JB, Niehrs C (2015) Morpholinos: antisense and sensibility. Dev Cell 35:145–149

    CAS  PubMed  Google Scholar 

  100. 100.

    Goemans NM, Tulinius M, Van den Akker JT, Burm BE, Ekhart PF, Heuvelmans N, Holling T, Janson AA, Platenburg GJ, Sipkens JA, Sitsen JM, Aartsma-Rus A, van Ommen GJ, Buyse G, Darin N, Verschuuren JJ, Campion GV, de Kimpe SJ, van Deutekom JC (2011) Systemic administration of PRO051 in Duchenne’s muscular dystrophy. N Engl J Med 364:1513–1522

    CAS  PubMed  Google Scholar 

  101. 101.

    Siddique HR (2016) CRISPR/Cas9 technology: a revolutionary molecular scissors for genome editing and genetic research. MOJ Cell Sci Rep 3:21–24

    Google Scholar 

  102. 102.

    Tseng YY, Moriarity BS, Gong W, Akiyama R, Tiwari A, Kawakami H, Ronning P, Reuland B, Guenther K, Beadnell TC, Essig J, Otto GM, O'Sullivan MG, Largaespada DA, Schwertfeger KL, Marahrens Y, Kawakami Y, Bagchi A (2014) PVT1 dependence in cancer with MYC copy-number increase. Nature. 512:82–86

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Zhen S, Hua L, Liu YH, Sun XM, Jiang MM, Chen W, Zhao L, Li X (2017) Inhibition of long non-coding RNA UCA1 by CRISPR/Cas9 attenuated malignant phenotypes of bladder cancer. Oncotarget. 8:9634–9646

    PubMed  Google Scholar 

  104. 104.

    Goyal A, Myacheva K, Gross M, Klingenberg M, Duran Arque B, Diederichs S (2017) Challenges of CRISPR/Cas9 applications for long non-coding RNA genes. Nucleic Acids Res 45:e12

    PubMed  Google Scholar 

  105. 105.

    Jiang W, Xia J, Xie S, Zou R, Pan S, Wang ZW, Assaraf YG, Zhu X (2020) Long non-coding RNAs as a determinant of cancer drug resistance: towards the overcoming of chemoresistance via modulation of lncRNAs. Drug Res Updates 50:100683

    Google Scholar 

  106. 106.

    Huarte M (2015) The emerging role of lncRNAs in cancer. Nat Med 21:1253–1261

    CAS  Google Scholar 

  107. 107.

    Rocha CR, Silva MM, Quinet A, Cabral-Neto JB, Menck CF (2018) DNA repair pathways and cisplation resistance: an intimate relationship. Clinics 73(e478s)

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We apologize to the eminent researches working in this field whose work has not been cited due to space limitations. The authors are thankful to the Chairman, Department of Zoology, Aligarh Muslim University for his necessary help. DS and MAK express their gratitude to the Council of Scientific and Industrial Research, New Delhi for fellowship.


This study was funded by the University Grants Commission [F.30-377/2017(BSR)], Department of Science and Technology, Government of India) [EMR/2017/001758] and Council of Scientific and Industrial Research, India [524/(CSIR-UGC-NET) June 2019].

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Singh, D., Khan, M.A. & Siddique, H.R. Emerging role of long non-coding RNAs in cancer chemoresistance: unravelling the multifaceted role and prospective therapeutic targeting. Mol Biol Rep (2020). https://doi.org/10.1007/s11033-020-05609-x

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  • LncRNA
  • Cancer
  • Chemoresistance
  • Signalling pathways
  • Therapeutic challenges