AAV-mediated combination gene therapy of inducible Caspase 9 and miR-199a-5p is therapeutic in hepatocellular carcinoma

Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–63.

Article  PubMed  Google Scholar 

Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Prim. 2021;7:6.

Article  PubMed  Google Scholar 

Yuen VW, Wong CC. Hypoxia-inducible factors and innate immunity in liver cancer. J Clin Invest. 2020;130:5052–62.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gilkes DM, Semenza GL, Wirtz D. Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat Rev Cancer. 2014;14:430–9.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001;107:43–54.

Article  CAS  PubMed  Google Scholar 

Kaelin WG Jr, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30:393–402.

Article  CAS  PubMed  Google Scholar 

Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA. 1995;92:5510–4.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wigerup C, Pahlman S, Bexell D. Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharm Ther. 2016;164:152–69.

Article  CAS  Google Scholar 

Walsh JC, Lebedev A, Aten E, Madsen K, Marciano L, Kolb HC. The clinical importance of assessing tumor hypoxia: relationship of tumor hypoxia to prognosis and therapeutic opportunities. Antioxid Redox Signal. 2014;21:1516–54.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Phillips RM, Hendriks HR, Peters GJ, Pharmacology E. Molecular Mechanism G. EO9 (Apaziquone): from the clinic to the laboratory and back again. Br J Pharm. 2013;168:11–18.

Article  CAS  Google Scholar 

Singh V, Khan N, Jayandharan GR. Vector engineering, strategies and targets in cancer gene therapy. Cancer Gene Ther. 2022;29:402–17.

Article  CAS  PubMed  Google Scholar 

Santiago-Ortiz JL, Schaffer DV. Adeno-associated virus (AAV) vectors in cancer gene therapy. J Control Release. 2016;240:287–301.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bulcha JT, Wang Y, Ma H, Tai PWL, Gao G. Viral vector platforms within the gene therapy landscape. Signal Transduct Target Ther. 2021;6:53.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sun X, Jiang H, Jiang X, Tan H, Meng Q, Sun B, et al. Antisense hypoxia-inducible factor-1alpha augments transcatheter arterial embolization in the treatment of hepatocellular carcinomas in rats. Hum Gene Ther. 2009;20:314–24.

Article  CAS  PubMed  Google Scholar 

Liu F, Wang P, Jiang X, Tan G, Qiao H, Jiang H, et al. Antisense hypoxia-inducible factor 1alpha gene therapy enhances the therapeutic efficacy of doxorubicin to combat hepatocellular carcinoma. Cancer Sci. 2008;99:2055–61.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ma S, Sun J, Guo Y, Zhang P, Liu Y, Zheng D, et al. Combination of AAV-TRAIL with miR-221-Zip Therapeutic Strategy Overcomes the Resistance to TRAIL Induced Apoptosis in Liver Cancer. Theranostics. 2017;7:3228–42.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Khan N, Bammidi S, Chattopadhyay S, Jayandharan GR. Combination Suicide Gene Delivery with an Adeno-Associated Virus Vector Encoding Inducible Caspase-9 and a Chemical Inducer of Dimerization Is Effective in a Xenotransplantation Model of Hepatocellular Carcinoma. Bioconjug Chem. 2019;30:1754–62.

Article  CAS  PubMed  Google Scholar 

Khan N, Maurya S, Bammidi S, Jayandharan GR. AAV6 Vexosomes Mediate Robust Suicide Gene Delivery in a Murine Model of Hepatocellular Carcinoma. Mol Ther Methods Clin Dev. 2020;17:497–504.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Otmani K, Lewalle P. Tumor Suppressor miRNA in Cancer Cells and the Tumor Microenvironment: Mechanism of Deregulation and Clinical Implications. Front Oncol. 2021;11:708765.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Raue R, Frank AC, Syed SN, Brune B Therapeutic Targeting of MicroRNAs in the Tumor Microenvironment. Int J Mol Sci. 2021;22.

Shu J, Xia Z, Li L, Liang ET, Slipek N, Shen D, et al. Dose-dependent differential mRNA target selection and regulation by let-7a-7f and miR-17-92 cluster microRNAs. RNA Biol. 2012;9:1275–87.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Diener C, Keller A, Meese E. Emerging concepts of miRNA therapeutics: from cells to clinic. Trends Genet. 2022;38:613–26.

Article  CAS  PubMed  Google Scholar 

Kota J, Chivukula RR, O’Donnell KA, Wentzel EA, Montgomery CL, Hwang HW, et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell. 2009;137:1005–17.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hou J, Lin L, Zhou W, Wang Z, Ding G, Dong Q, et al. Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma. Cancer Cell. 2011;19:232–43.

Article  CAS  PubMed  Google Scholar 

Yin L, Keeler GD, Zhang Y, Hoffman BE, Ling C, Qing K, et al. AAV3-miRNA vectors for growth suppression of human hepatocellular carcinoma cells in vitro and human liver tumors in a murine xenograft model in vivo. Gene Ther. 2021;28:422–34.

Article  CAS  PubMed  Google Scholar 

Xu H, Zhao L, Fang Q, Sun J, Zhang S, Zhan C, et al. MiR-338-3p inhibits hepatocarcinoma cells and sensitizes these cells to sorafenib by targeting hypoxia-induced factor 1alpha. PLoS One. 2014;9:e115565.

Article  PubMed  PubMed Central  Google Scholar 

Wang C, Song B, Song W, Liu J, Sun A, Wu D, et al. Underexpressed microRNA-199b-5p targets hypoxia-inducible factor-1alpha in hepatocellular carcinoma and predicts prognosis of hepatocellular carcinoma patients. J Gastroenterol Hepatol. 2011;26:1630–7.

Article  CAS  PubMed  Google Scholar 

Agarwal V, Bell GW, Nam JW, Bartel DP Predicting effective microRNA target sites in mammalian mRNAs. Elife. 2015;4.

Paraskevopoulou MD, Georgakilas G, Kostoulas N, Vlachos IS, Vergoulis T, Reczko M, et al. DIANA-microT web server v5.0: service integration into miRNA functional analysis workflows. Nucleic Acids Res. 2013;41:W169–W173.

Article  PubMed  PubMed Central  Google Scholar 

Chen Y, Wang X. miRDB: an online database for prediction of functional microRNA targets. Nucleic Acids Res. 2020;48:D127–D131.

Article  CAS  PubMed  Google Scholar 

Vejnar CE, Zdobnov EM. MiRmap: comprehensive prediction of microRNA target repression strength. Nucleic Acids Res. 2012;40:11673–83.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Comments (0)

No login
gif