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LNA Inhibitor in microRNA miR-23b as a Potential Anti-proliferative Option in Human Hepatocellular Carcinoma

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Abstract

Purpose

Dysregulation of microRNAs (miRNAs) has been shown to be involved in the pathogenesis and progression of many malignancies. Human hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and the third cause of cancer-related deaths. Recent data suggest that microRNA-23b (miR-23b) is significantly high in different types of cancer, specifically human hepatocellular carcinoma. Locked nucleic acid (LNA)–modified oligonucleotides have recently been suggested as a novel approach for targeting miRNAs as antisense-based gene silencing. The aim of this study was to explore the functional role of LNA-anti-miR-23b in a HepG2 (hepatocarcinoma) cell line.

Methods

HepG2 cells were transfected with LNA-anti-miR-23b for 24, 48, and 72 h. Quantitative real-time reverse transcriptase-PCR (qRT-PCR) was performed to assess miR-23b expression by LNA-anti-miR-23b. The viability of the cells was evaluated by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay.

Results

LNA-anti-miR-23b was successfully transfected into human HepG2 cells and suppressed the miR-23b. LNA-anti-miR-23b reduced the invasive behaviors of HepG2 cells after 24 h, compared to untreated cells and scrambled LNA-transfected cells, and this effect was more pronounced after 72 h.

Conclusions

Our findings suggest that inhibition of miR-23b could be used as a novel approach in inhibition of HCC proliferation.

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References

  1. Sinha S, Boila LD, Chatterjee SS, Sengupta A. miRNA and cancer: a deadly liaison? Cancer noncoding RNAs. Amsterdam: Elsevier; 2018. p. 27–46.

    Google Scholar 

  2. Rottiers V, Näär AM. MicroRNAs in metabolism and metabolic disorders. Nat Rev Mol Cell Biol. 2012;13:239.

    Article  CAS  Google Scholar 

  3. Chakraborty C, Sharma AR, Sharma G, Sarkar BK, Lee S-S. The novel strategies for next-generation cancer treatment: miRNA combined with chemotherapeutic agents for the treatment of cancer. Oncotarget. 2018;9:10164.

    Article  Google Scholar 

  4. Gibb EA, Brown CJ, Lam WL. The functional role of long non-coding RNA in human carcinomas. Mol Cancer. 2011;10:38.

    Article  CAS  Google Scholar 

  5. O’Connell RM, Rao DS, Baltimore D. microRNA regulation of inflammatory responses. Annu Rev Immunol. 2012;30:295–312.

    Article  Google Scholar 

  6. Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 2006;20:515–24.

    Article  CAS  Google Scholar 

  7. Najafi Z, Sharifi M, Javadi G. Degradation of miR-21 induces apoptosis and inhibits cell proliferation in human hepatocellular carcinoma. Cancer Gene Ther. 2015;22:530.

    Article  CAS  Google Scholar 

  8. Sharifi M, Salehi R, Gheisari Y, Kazemi M. MikroRNA miR-92a Inhibisyonu İnsan Akut Promyelositik Lösemide Hücre Proliferasyonunu İnhibe Eder.

  9. Spizzo R, Rushworth D, Guerrero M, Calin GA. RNA inhibition, microRNAs, and new therapeutic agents for cancer treatment. Clin Lymphoma Myeloma. 2009;9:S313–8.

    Article  CAS  Google Scholar 

  10. Ruan K, Fang X, Ouyang G. MicroRNAs: novel regulators in the hallmarks of human cancer. Cancer Lett. 2009;285:116–26.

    Article  CAS  Google Scholar 

  11. Baulies A, Montero J, Matías N, Insausti N, Terrones O, Basañez G, et al. The 2-oxoglutarate carrier promotes liver cancer by sustaining mitochondrial GSH despite cholesterol loading. Redox Biol. 2018;14:164–77.

    Article  CAS  Google Scholar 

  12. Pollutri D, Patrizi C, Marinelli S, Giovannini C, Trombetta E, Giannone FA, et al. The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma. Cell Death Dis. 2018;9:4.

    Article  Google Scholar 

  13. Ringelhan M, Pfister D, O’Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma. Nat Immunol. 2018;1.

  14. Rani B, Malfettone A, Dituri F, Soukupova J, Lupo L, Mancarella S, et al. Galunisertib suppresses the staminal phenotype in hepatocellular carcinoma by modulating CD44 expression. Cell Death Dis. 2018;9:373.

    Article  Google Scholar 

  15. Papadopoulou N, Wainwright L, Lacey V, Wrigley J, Wood J, Malhi S, et al. Abstract A010: interrogation of checkpoint inhibitors in bioluminescent orthotopic syngeneic models of hepatocellular carcinoma. AACR. 2018.

  16. Buonfiglioli F, Brillanti S. Direct antiviral therapy for hepatitis C and hepatocellular carcinoma: facing the conundrum. 2018

  17. García ER, Gutierrez EA, de Melo FCSA, Novaes RD, Gonçalves RV. Flavonoids effects on hepatocellular carcinoma in murine models: a systematic review. Evid Based Complement Alternat Med. 2018;2018:1–23.

    Article  Google Scholar 

  18. Manka P, Coombes JD, Boosman R, Gauthier K, Papa S, Syn WK. Thyroid hormone in the regulation of hepatocellular carcinoma and its microenvironment. Cancer Lett. 2018;419:175–86.

    Article  CAS  Google Scholar 

  19. Yang X, Pang Y-Y, He R-Q, Lin P, Cen J-M, Yang H, et al. Diagnostic value of strand-specific miRNA-101-3p and miRNA-101-5p for hepatocellular carcinoma and a bioinformatic analysis of their possible mechanism of action. FEBS Open Bio. 2018.

  20. Rogler CE, LeVoci L, Ader T, Massimi A, Tchaikovskaya T, Norel R, et al. MicroRNA-23b cluster microRNAs regulate transforming growth factor-beta/bone morphogenetic protein signaling and liver stem cell differentiation by targeting Smads. Hepatology. 2009;50:575–84.

    Article  CAS  Google Scholar 

  21. Zhang H, Hao Y, Yang J, Zhou Y, Li J, Yin S, et al. Genome-wide functional screening of miR-23b as a pleiotropic modulator suppressing cancer metastasis. Nat Commun. 2011;2:554.

    Article  Google Scholar 

  22. Saunders MA, Lim LP. (micro) Genomic medicine: microRNAs as therapeutics and biomarkers. RNA Biol. 2009;6:324–8.

    Article  CAS  Google Scholar 

  23. Sabatel C, Malvaux L, Bovy N, Deroanne C, Lambert V, Gonzalez M-LA, et al. MicroRNA-21 exhibits antiangiogenic function by targeting RhoB expression in endothelial cells. PLoS One. 2011;6:e16979.

    Article  CAS  Google Scholar 

  24. Yelamanchili SV, Chaudhuri AD, Chen L-N, Xiong H, Fox HS. MicroRNA-21 dysregulates the expression of MEF2C in neurons in monkey and human SIV/HIV neurological disease. Cell Death Dis. 2010;1:e77.

    Article  CAS  Google Scholar 

  25. Reddy SDN, Gajula RP, Pakala SB, Kumar R. MicroRNAs and cancer therapy: the next wave or here to stay? Cancer Biol Ther. 2010;9:479–82.

    Article  CAS  Google Scholar 

  26. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264–73.

    Article  Google Scholar 

  27. Whittaker S, Marais R, Zhu AX. The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene. 2010;29:4989.

    Article  CAS  Google Scholar 

  28. Xue X, Zhao Y, Wang X, Qin L, Hu R. Development and validation of serum exosomal microRNAs as diagnostic and prognostic biomarkers for hepatocellular carcinoma. J Cell Biochem. 2019;120:135–42.

    Article  CAS  Google Scholar 

  29. Paul P, Chakraborty A, Sarkar D, Langthasa M, Rahman M, Bari M, et al. Interplay between miRNAs and human diseases. J Cell Physiol. 2018;233:2007–18.

    Article  CAS  Google Scholar 

  30. Xiang Y, Huang Y, Sun H, Pan Y, Wu M, Zhang J. Deregulation of miR-520d-3p promotes hepatocellular carcinoma development via lncRNA MIAT regulation and EPHA2 signaling activation. Biomed Pharmacother. 2019;109:1630–9.

    Article  CAS  Google Scholar 

  31. Zare M, Bastami M, Solali S, Alivand MR. Aberrant miRNA promoter methylation and EMT-involving miRNAs in breast cancer metastasis: diagnosis and therapeutic implications. J Cell Physiol. 2018;233:3729–44.

    Article  CAS  Google Scholar 

  32. Deb B, Uddin A, Chakraborty S. miRNAs and ovarian cancer: an overview. J Cell Physiol. 2018;233:3846–54.

    Article  CAS  Google Scholar 

  33. Dong C, Ji M, Ji C. Micro-RNAs and their potential target genes in leukemia pathogenesis. Cancer Biol Ther. 2009;8:200–5.

    Article  CAS  Google Scholar 

  34. Donadelli M, Dando I, Fiorini C, Palmieri M. Regulation of miR-23b expression and its dual role on ROS production and tumour development. Cancer Lett. 2014;349:107–13.

    Article  CAS  Google Scholar 

  35. Huang T-T, Ping Y-H, Wang A-M, Ke C-C, Fang W-L, Huang K-H, et al. The reciprocal regulation loop of Notch2 pathway and miR-23b in controlling gastric carcinogenesis. Oncotarget. 2015;6:18012.

    PubMed  PubMed Central  Google Scholar 

  36. Chen L, Han L, Zhang K, Shi Z, Zhang J, Zhang A, et al. VHL regulates the effects of miR-23b on glioma survival and invasion via suppression of HIF-1α/VEGF and β-catenin/Tcf-4 signaling. Neuro-Oncol. 2012;14:1026–36.

    Article  CAS  Google Scholar 

  37. Liu W, Zabirnyk O, Wang H, Shiao YH, Nickerson ML, Khalil S, et al. miR-23b* targets proline oxidase, a novel tumor suppressor protein in renal cancer. Oncogene. 2010;29:4914.

    Article  CAS  Google Scholar 

  38. Zhu S, Pan W, Song X, Liu Y, Shao X, Tang Y, et al. The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-α. Nat Med. 2012;18:1077.

    Article  CAS  Google Scholar 

  39. Pellegrino L, Stebbing J, Braga VM, Frampton AE, Jacob J, Buluwela L, et al. miR-23b regulates cytoskeletal remodeling, motility and metastasis by directly targeting multiple transcripts. Nucleic Acids Res. 2013;41:5400–12.

    Article  CAS  Google Scholar 

  40. Ørum H. Locked nucleic acids as microRNA therapeutics. MicroRNAs Med. 2013:663–72.

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Correspondence to Mohammadreza Sharifi.

Ethics declarations

This study was approved by the local ethics committee of Isfahan University of Medical Sciences (Iran), and the studies have been approved by the appropriate institutional and/or national research ethics committee and have been performed in accordance with the ethical standards, as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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The authors declare that they have no conflict of interest.

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Najafi, Z., Sharifi, M. & Javadi, G. LNA Inhibitor in microRNA miR-23b as a Potential Anti-proliferative Option in Human Hepatocellular Carcinoma. J Gastrointest Canc 51, 109–115 (2020). https://doi.org/10.1007/s12029-019-00215-y

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