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The Role of Small Interfering RNAs in Hepatocellular Carcinoma

  • Review Article
  • Published:
Journal of Gastrointestinal Cancer Aims and scope Submit manuscript

Abstract

Background

Hepatocellular carcinoma (HCC), a primary liver cancer with high mortality, is the most common malignant tumor in the world. Currently, the effect of routine treatment is poor, especially for this kind of cancer with strong heterogeneity and late detection. In the past decades, the researches of gene therapy for HCC based on small interfering RNA have blossomed everywhere. This is a promising therapeutic strategy, but the application of siRNA is limited by the discovery of effective molecular targets and the delivery system targeting HCC. As the deepening of research, scientists have developed many effective delivery systems and found more new therapeutic targets.

Conclusions

This paper mainly reviews the research on HCC treatment based on siRNA in recent years, and summarizes and classifies the HCC treatment targets and siRNA delivery systems.

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Abbreviations

siRNA:

Small interfering RNA

dsRNA:

Double-stranded RNA

RISC:

RNA-induced-silencing complex

mRNA:

Messenger RNA

S1P:

Sphygosine-1-phosphate

CLD:

Chronic liver disease

HCV:

Hepatitis C virus

HCC:

Hepatocellular carcinoma

NASH:

Nonalcoholic steatohepatitis

PEI:

Polyethyleneimine

PEG:

Polyethylene glycol

SPIO:

Superparamagnetic iron oxide

RGDfC:

Cyclic polypeptide Arg-Gly-Asp-D-Phe-Cys

STAT3:

Signal transducer and activator of transcription 3

dNTPs:

Deoxy-ribonucleoside triphosphates

ES:

Embryonic stem cell

H4K20:

H4 lysine 20

IFN:

Interferon

NPs:

Nanoparticles

References

  1. Hajiasgharzadeh K, Somi MH, Shanehbandi D, Mokhtarzadeh A, Baradaran B. Small interfering RNA-mediated gene suppression as a therapeutic intervention in hepatocellular carcinoma. J Cell Physiol. 2019;234(4):3263–76.

    Article  CAS  PubMed  Google Scholar 

  2. Lee SJ, Kim MJ, Kwon IC, Roberts TM. Delivery strategies and potential targets for siRNA in major cancer types. Adv Drug Deliv Rev. 2016;104:2–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mroweh M, Decaens T, Marche PN, Macek Jilkova Z, Clément F. Modulating the crosstalk between the tumor and its microenvironment using RNA interference: A treatment strategy for hepatocellular carcinoma. Int J Mol Sci. 2020 Jul 24;21(15):5250. https://doi.org/10.3390/ijms21155250. PMID: 32722054; PMCID: PMC7432232.

  4. Farra R, Grassi M, Grassi G, Dapas B. Therapeutic potential of small interfering RNAs/micro interfering RNA in hepatocellular carcinoma. World J Gastroenterol. 2015;21(30):8994–9001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Varshosaz J, Farzan M. Nanoparticles for targeted delivery of therapeutics and small interfering RNAs in hepatocellular carcinoma. World J Gastroenterol. 2015;21(42):12022–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Longerich T. Hepatocellular carcinoma. Pathologe. 2020;41(5):478–87.

    Article  PubMed  Google Scholar 

  7. Hwang LH. Gene therapy strategies for hepatocellular carcinoma. J Biomed Sci. 2006;13(4):453–68.

    Article  CAS  PubMed  Google Scholar 

  8. Xu C, Lee SA, Chen X. RNA interference as therapeutics for hepatocellular carcinoma. Recent Pat Anticancer Drug Discov. 2011;6(1):106–15.

    Article  CAS  PubMed  Google Scholar 

  9. Li X, Li J, Li C, Guo Q, Wu M, Su L, Dou Y, Wu X, Xiao Z, Zhang X. Aminopeptidase N-targeting nanomolecule-assisted delivery of VEGF siRNA to potentiate antitumour therapy by suppressing tumour revascularization and enhancing radiation response. J Mater Chem B. 2021;9(36):7530–43.

    Article  CAS  PubMed  Google Scholar 

  10. Xia Y, Wang C, Xu T, Li Y, Guo M, Lin Z, Zhao M, Zhu B. Targeted delivery of HES5-siRNA with novel polypeptide-modified nanoparticles for hepatocellular carcinoma therapy. RSC Adv. 2018;8(4):1917–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yang Z, Duan J, Wang J, Liu Q, Shang R, Yang X, Lu P, Xia C, Wang L, Dou K. Superparamagnetic iron oxide nanoparticles modified with polyethylenimine and galactose for siRNA targeted delivery in hepatocellular carcinoma therapy. Int J Nanomed. 2018;13:1851–65.

    Article  CAS  Google Scholar 

  12. Xia Y, Tang G, Chen Y, Wang C, Guo M, Xu T, Zhao M, Zhou Y. Tumor-targeted delivery of siRNA to silence Sox2 gene expression enhances therapeutic response in hepatocellular carcinoma. Bioact Mater. 2021;6(5):1330–40.

    CAS  PubMed  Google Scholar 

  13. Zhang J, Ma H, Yang L, Yang H, He Z. Silencing of the TROP2 gene suppresses proliferation and invasion of hepatocellular carcinoma HepG2 cells. J Int Med Res. 2019;47(3):1319–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Liu Y, Tan M, Fang C, Chen X, Liu H, Feng Y, Zhang Y, Min W. A novel multifunctional gold nanorod-mediated and tumor-targeted gene silencing of GPC-3 synergizes photothermal therapy for liver cancer. Nanotechnology. 2021;32(17): 175101.

    Article  PubMed  Google Scholar 

  15. Zhao B, Zhou B, Shi K, Zhang R, Dong C, Xie D, Tang L, Tian Y, Qian Z, Yang L. Sustained and targeted delivery of siRNA/DP7-C nanoparticles from injectable thermosensitive hydrogel for hepatocellular carcinoma therapy. Cancer Sci. 2021;112(6):2481–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang M, Weng Y, Cao Z, Guo S, Hu B, Lu M, Guo W, Yang T, Li C, Yang X, et al. ROS-activatable siRNA-engineered polyplex for NIR-triggered synergistic cancer treatment. ACS Appl Mater Interfaces. 2020;12(29):32289–300.

    Article  CAS  PubMed  Google Scholar 

  17. Khan AA, Alanazi AM, Jabeen M, Chauhan A, Ansari MA. Therapeutic potential of functionalized siRNA nanoparticles on regression of liver cancer in experimental mice. Sci Rep. 2019;9(1):15825.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Liu Y, Tan M, Zhang Y, Huang W, Min L, Peng S, Yuan K, Qiu L, Min W. Targeted gene silencing BRAF synergized photothermal effect inhibits hepatoma cell growth using new GAL-GNR-siBRAF nanosystem. Nanoscale Res Lett. 2020;15(1):116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bamodu OA, Chang HL, Ong JR, Lee WH, Yeh CT, Tsai JT. Elevated PDK1 expression drives PI3K/AKT/MTOR signaling promotes radiation-resistant and dedifferentiated phenotype of hepatocellular carcinoma. Cells. 2020;9(3):746. Published 2020 Mar 18. https://doi.org/10.3390/cells9030746.

  20. Guo Y, Wu Z, Shen S, Guo R, Wang J, Wang W, Zhao K, Kuang M, Shuai X. Nanomedicines reveal how PBOV1 promotes hepatocellular carcinoma for effective gene therapy. Nat Commun. 2018;9(1):3430.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Vivero-Escoto JL, Vadarevu H, Juneja R, Schrum LW, Benbow JH. Nanoparticle mediated silencing of tenascin C in hepatic stellate cells: effect on inflammatory gene expression and cell migration. J Mater Chem B. 2019;7(46):7396–405.

    Article  CAS  PubMed  Google Scholar 

  22. Woitok MM, Zoubek ME, Doleschel D, Bartneck M, Mohamed MR, Kiessling F, Lederle W, Trautwein C, Cubero FJ. Lipid-encapsulated siRNA for hepatocyte-directed treatment of advanced liver disease. Cell Death Dis. 2020;11(5):343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Xiang-Chun D, Xiao-Qing Y, Ting-Ting Y, Zhen-Hui L, Xiao-Yan L, Xia L, Yan-Chao H, Yi-Xuan Y, Li-Na M. Alpha-enolase regulates hepatitis B virus replication through suppression of the interferon signalling pathway. J Viral Hepat. 2018;25(3):289–95.

    Article  CAS  PubMed  Google Scholar 

  24. Hasan MT, Campbell E, Sizova O, et al. Multi-drug/gene NASH therapy delivery and selective hyperspectral NIR imaging using chirality-sorted single-walled carbon nanotubes. Cancers (Basel). 2019;11(8):1175. Published 2019 Aug 14. https://doi.org/10.3390/cancers11081175.

  25. Fu N, Du H, Li D, Lu Y, Li W, Wang Y, Kong L, Du J, Zhao S, Ren W, et al. Clusterin contributes to hepatitis C virus-related hepatocellular carcinoma by regulating autophagy. Life Sci. 2020;256: 117911.

    Article  CAS  PubMed  Google Scholar 

  26. Azimi A, Majidinia M, Shafiei-Irannejad V, Jahanban-Esfahlan R, Ahmadi Y, Karimian A, Mir SM, Karami H, Yousefi B. Suppression of p53R2 gene expression with specific siRNA sensitizes HepG2 cells to doxorubicin. Gene. 2018;642:249–55.

    Article  CAS  PubMed  Google Scholar 

  27. Wu J, Qiao K, Du Y, Zhang X, Cheng H, Peng L, Guo Z. Downregulation of histone methyltransferase SET8 inhibits progression of hepatocellular carcinoma. Sci Rep. 2020;10(1):4490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li M, Zhao P, Fan T, Chen Y, Zhang X, He C, Yang T, Lee RJ, Khan MW, Raza SM, et al. Biocompatible co-loading vehicles for delivering both nanoplatin cores and siRNA to treat hepatocellular carcinoma. Int J Pharm. 2019;572: 118769.

    Article  CAS  PubMed  Google Scholar 

  29. Chen X, Chen T, Zhang L, Wang Z, Zhou Q, Huang T, Ge C, Xu H, Zhu M, Zhao F, et al. Cyclodextrin-mediated formation of porous RNA nanospheres and their application in synergistic targeted therapeutics of hepatocellular carcinoma. Biomaterials. 2020;261:120304.

    Article  CAS  PubMed  Google Scholar 

  30. Younis MA, Khalil IA, Elewa YHA, Kon Y, Harashima H. Ultra-small lipid nanoparticles encapsulating sorafenib and midkine-siRNA selectively-eradicate sorafenib-resistant hepatocellular carcinoma in vivo. J Control Release. 2021;331:335–49.

    Article  CAS  PubMed  Google Scholar 

  31. El-sherbeni AR, Ghattas MH, Shehata HH, Mohamad MI. Silencing the epitranscriptomic writer METTL3 in Hepatocellular carcinoma cells: A prospective therapeutic approach. Gene Rep. 2021;25:101359, ISSN 2452-0144. https://doi.org/10.1016/j.genrep.2021.101359.

  32. Liang J, Zhang X, He S, Miao Y, Wu N, Li J, Gan Y. Sphk2 RNAi nanoparticles suppress tumor growth via downregulating cancer cell derived exosomal microRNA. J Control Release. 2018;286:348–57.

    Article  CAS  PubMed  Google Scholar 

  33. Dong D, Gao W, Liu Y, Qi XR. Therapeutic potential of targeted multifunctional nanocomplex co-delivery of siRNA and low-dose doxorubicin in breast cancer. Cancer Lett. 2015;359(2):178–86.

    Article  CAS  PubMed  Google Scholar 

  34. Doan CC, Le LT, Hoang SN, Do SM, Le DV. Simultaneous silencing of VEGF and KSP by siRNA cocktail inhibits proliferation and induces apoptosis of hepatocellular carcinoma Hep3B cells. Biol Res. 2014;47:70.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Zheng G, Zhao R, Xu A, Shen Z, Chen X, Shao J. Co-delivery of sorafenib and siVEGF based on mesoporous silica nanoparticles for ASGPR mediated targeted HCC therapy. Eur J Pharm Sci. 2018;111:492–502.

    Article  CAS  PubMed  Google Scholar 

  36. Qu Y, Sun F, He F, Yu C, Lv J, Zhang Q, Liang D, Yu C, Wang J, Zhang X, et al. Glycyrrhetinic acid-modified graphene oxide mediated siRNA delivery for enhanced liver-cancer targeting therapy. Eur J Pharm Sci. 2019;139: 105036.

    Article  CAS  PubMed  Google Scholar 

  37. Xu B, Xu Y, Su G, Zhu H, Zong L. A multifunctional nanoparticle constructed with a detachable albumin outer shell and a redox-sensitive inner core for efficient siRNA delivery to hepatocellular carcinoma cells. J Drug Target. 2018;26(10):941–54.

    Article  CAS  PubMed  Google Scholar 

  38. Zhu G, Shi W, Fan H, Zhang X, Xu J, Chen Y, Xu Z, Tao T, Cheng C. HES5 promotes cell proliferation and invasion through activation of STAT3 and predicts poor survival in hepatocellular carcinoma. Exp Mol Pathol. 2015;99(3):474–84.

    Article  CAS  PubMed  Google Scholar 

  39. Gu S, Zhang R, Gu J, Li X, Lv L, Jiang J, Xu Z, Wang S, Shi C, Wang DP, et al. HES5 promotes cellular proliferation of non-small cell lung cancer through STAT3 signaling. Oncol Rep. 2017;37(1):474–82.

    Article  PubMed  Google Scholar 

  40. Xia Y, Guo M, Xu T, Li Y, Wang C, Lin Z, Zhao M, Zhu B. siRNA-loaded selenium nanoparticle modified with hyaluronic acid for enhanced hepatocellular carcinoma therapy. Int J Nanomed. 2018;13:1539–52.

    Article  CAS  Google Scholar 

  41. Xia Y, Zhao M, Chen Y, Hua L, Xu T, Wang C, Li Y, Zhu B. Folate-targeted selenium nanoparticles deliver therapeutic siRNA to improve hepatocellular carcinoma therapy. RSC Adv. 2018;8(46):25932–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Puri N, Ahmed S, Janamanchi V, Tretiakova M, Zumba O, Krausz T, Jagadeeswaran R, Salgia R. c-Met is a potentially new therapeutic target for treatment of human melanoma. Clin Cancer Res. 2007;13(7):2246–53.

    Article  CAS  PubMed  Google Scholar 

  43. Xie B, Xing R, Chen P, Gou Y, Li S, Xiao J, Dong J. Down-regulation of c-Met expression inhibits human HCC cells growth and invasion by RNA interference. J Surg Res. 2010;162(2):231–8.

    Article  CAS  PubMed  Google Scholar 

  44. Cheng J, Wu LM, Deng XS, Wu J, Lv Z, Zhao HF, Yang Z, Ni Y. MicroRNA-449a suppresses hepatocellular carcinoma cell growth via G1 phase arrest and the HGF/MET c-Met pathway. Hepatobiliary Pancreat Dis Int. 2018;17(4):336–44.

    Article  CAS  PubMed  Google Scholar 

  45. Yang MH, Baek SH, Um JY, Ahn KS. Anti-neoplastic effect of Ginkgolide C through modulating c-Met phosphorylation in hepatocellular carcinoma cells. Int J Mol Sci. 2020;21(21):8303. Published 2020 Nov 5. https://doi.org/10.3390/ijms21218303.

  46. Wu B, Shang H, Liu J, Liang X, Yuan Y, Chen Y, Wang C, Jing H, Cheng W. Quantitative proteomics analysis of FFPE tumor samples reveals the influences of NET-1 siRNA nanoparticles and sonodynamic therapy on tetraspanin protein involved in HCC. Front Mol Biosci. 2021;8: 678444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wang M, Sun X, Jiang Y, Tan Z. NET-1 promotes invasion, adhesion and growth of hepatocellular carcinoma by regulating the expression of BAX, caspase 3, caspase 8 and BCL2. Cell Mol Biol (Noisy-le-grand). 2018;64(12):37–41.

    Article  PubMed  Google Scholar 

  48. Shang H, Wu B, Liang X, Sun Y, Han X, Zhang L, Wang Q, Cheng W. Evaluation of therapeutic effect of targeting nanobubbles conjugated with NET-1 siRNA by shear wave elastography: an in vivo study of hepatocellular carcinoma bearing mice model. Drug Deliv. 2019;26(1):944–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wu B, Shang H, Liang X, Sun Y, Jing H, Han X, Cheng W. Preparation of novel targeting nanobubbles conjugated with small interfering RNA for concurrent molecular imaging and gene therapy in vivo. FASEB J. 2019;33(12):14129–36.

    Article  CAS  PubMed  Google Scholar 

  50. Liang X, Wu B, Shang H, Han X, Jing H, Sun Y, Cheng W. VTIQ evaluates antitumor effects of NET-1 siRNA by UTMD in HCC xenograft models. Oncol Lett. 2018;16(3):2893–902.

    PubMed  PubMed Central  Google Scholar 

  51. Wu F, Ye X, Wang P, Jung K, Wu C, Douglas D, Kneteman N, Bigras G, Ma Y, Lai R. Sox2 suppresses the invasiveness of breast cancer cells via a mechanism that is dependent on Twist1 and the status of Sox2 transcription activity. BMC Cancer. 2013;13:317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Yang N, Wang Y, Hui L, Li X, Jiang X. Silencing SOX2 expression by RNA interference inhibits proliferation, invasion and metastasis, and induces apoptosis through MAP4K4/JNK signaling pathway in human laryngeal cancer TU212 Cells. J Histochem Cytochem. 2015;63(9):721–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lei L, Dou L. Wang H-y: The defined siRNAs suppress Nanog and Sox2 expressions in mouse ES cells. Agric Sci China. 2011;10(9):1475–81.

    Article  CAS  Google Scholar 

  54. Liu T, Liu Y, Bao X, Tian J, Liu Y, Yang X. Overexpression of TROP2 predicts poor prognosis of patients with cervical cancer and promotes the proliferation and invasion of cervical cancer cells by regulating ERK signaling pathway. PLoS ONE. 2013;8(9): e75864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gao XY, Zhu YH, Zhang LX, Lu HY, Jiang AG. siRNA targeting of Trop2 suppresses the proliferation and invasion of lung adenocarcinoma H460 cells. Exp Ther Med. 2015;10(2):429–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wang XD, Wang Q, Chen XL, Huang JF, Yin Y, Da P, Wu H. Trop2 inhibition suppresses the proliferation and invasion of laryngeal carcinoma cells via the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. Mol Med Rep. 2015;12(1):865–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wu B, Yu C, Zhou B, Huang T, Gao L, Liu T, Yang X. Overexpression of TROP2 promotes proliferation and invasion of ovarian cancer cells. Exp Ther Med. 2017;14(3):1947–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Akutsu N, Yamamoto H, Sasaki S, Taniguchi H, Arimura Y, Imai K, Shinomura Y. Association of glypican-3 expression with growth signaling molecules in hepatocellular carcinoma. World J Gastroenterol. 2010;16(28):3521–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hu P, Cheng B, He Y, Wei Z, Wu D, Meng Z. Autophagy suppresses proliferation of HepG2 cells via inhibiting glypican-3/wnt/beta-catenin signaling. Onco Targets Ther. 2018;11:193–200.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Shao L, Yu X, Han Q, Zhang X, Lu N, Zhang C. Enhancing anti-tumor efficacy and immune memory by combining 3p-GPC-3 siRNA treatment with PD-1 blockade in hepatocellular carcinoma. Oncoimmunology. 2022;11(1):2010894. Published 2022 Jan 2. https://doi.org/10.1080/2162402X.2021.2010894.

  61. Kanaoka R, Kushiyama A, Seno Y, Nakatsu Y, Matsunaga Y, Fukushima T, Tsuchiya Y, Sakoda H, Fujishiro M, Yamamotoya T, et al. Pin1 Inhibitor juglone exerts anti-oncogenic effects on LNCaP and DU145 cells despite the patterns of gene regulation by Pin1 differing between these cell lines. PLoS ONE. 2015;10(6): e0127467.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Pang RW, Lee TK, Man K, Poon RT, Fan ST, Kwong YL, Tse E. PIN1 expression contributes to hepatic carcinogenesis. J Pathol. 2006;210(1):19–25.

    Article  CAS  PubMed  Google Scholar 

  63. Gao J, Chen H, Yu Y, Song J, Song H, Su X, Li W, Tong X, Qian W, Wang H, et al. Inhibition of hepatocellular carcinoma growth using immunoliposomes for co-delivery of adriamycin and ribonucleotide reductase M2 siRNA. Biomaterials. 2013;34(38):10084–98.

    Article  CAS  PubMed  Google Scholar 

  64. Kitab B, Satoh M, Ohmori Y, Munakata T, Sudoh M, Kohara M, Tsukiyama-Kohara K. Ribonucleotide reductase M2 promotes RNA replication of hepatitis C virus by protecting NS5B protein from hPLIC1-dependent proteasomal degradation. J Biol Chem. 2019;294(15):5759–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Khosravi N, Shahgoli VK, Amini M, Safaei S, Mokhtarzadeh A, Mansoori B, Derakhshani A, Baghbanzadeh A, Baradaran B. Suppression of Nanog inhibited cell migration and increased the sensitivity of colorectal cancer cells to 5-fluorouracil. Eur J Pharmacol. 2021;894: 173871.

    Article  CAS  PubMed  Google Scholar 

  66. Zhou JJ, Deng XG, He XY, Zhou Y, Yu M, Gao WC, Zeng B, Zhou QB, Li ZH, Chen RF. Knockdown of NANOG enhances chemosensitivity of liver cancer cells to doxorubicin by reducing MDR1 expression. Int J Oncol. 2014;44(6):2034–40.

    Article  CAS  PubMed  Google Scholar 

  67. Alemohammad H, Motafakkerazad R, Asadzadeh Z, Farsad N, Hemmat N, Najafzadeh B, Vasefifar P, Baradaran B. siRNA-mediated silencing of Nanog reduces stemness properties and increases the sensitivity of HepG2 cells to cisplatin. Gene. 2022;821: 146333.

    Article  CAS  PubMed  Google Scholar 

  68. Xia Y, Xu T, Wang C, Li Y, Lin Z, Zhao M, Zhu B. Novel functionalized nanoparticles for tumor-targeting co-delivery of doxorubicin and siRNA to enhance cancer therapy. Int J Nanomed. 2017;13:143–59.

    Article  Google Scholar 

  69. Chang HL, Chen HA, Bamodu OA, Lee KF, Tzeng YM, Lee WH, Tsai JT. Ovatodiolide suppresses yes-associated protein 1-modulated cancer stem cell phenotypes in highly malignant hepatocellular carcinoma and sensitizes cancer cells to chemotherapy in vitro. Toxicol In Vitro. 2018;51:74–82.

    Article  CAS  PubMed  Google Scholar 

  70. Guo L, Zheng J, Luo J, Zhang Z, Shao G. Targeting Yes1 associated transcriptional regulator inhibits hepatocellular carcinoma progression and improves sensitivity to sorafenib: an in vitro and in vivo study. Onco Targets Ther. 2020;13:11071–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhang Q, Zhao W, Cheng J, Deng Z, Zhang P, Zhang A, Xu Z, Pan S, Liao X, Cui D. Heat-induced manganese-doped magnetic nanocarriers combined with Yap-siRNA for MRI/NIR-guided mild photothermal and gene therapy of hepatocellular carcinoma. Chem Eng J. 2021;426:130746, ISSN 1385-8947. https://doi.org/10.1016/j.cej.2021.130746.

  72. Tang B, Liang X, Tang F, Zhang J, Zeng S, Jin S, Zhou L, Kudo Y, Qi G. Expression of USP22 and Survivin is an indicator of malignant behavior in hepatocellular carcinoma. Int J Oncol. 2015;47(6):2208–16.

    Article  CAS  PubMed  Google Scholar 

  73. Wu Z, Xu XL, Zhang JZ, et al. Magnetic cationic amylose nanoparticles used to deliver survivin-small interfering RNA for gene therapy of hepatocellular carcinoma in vitro. Nanomaterials (Basel). 2017;7(5):110. Published 2017 May 11. https://doi.org/10.3390/nano7050110.

  74. Liu W, Zhu F, Jiang Y, Sun D, Yang B, Yan H. siRNA targeting survivin inhibits the growth and enhances the chemosensitivity of hepatocellular carcinoma cells. Oncol Rep. 2013;29(3):1183–8.

    Article  CAS  PubMed  Google Scholar 

  75. Zhang H, Deng L, Liu H, Mai S, Cheng Z, Shi G, Zeng H, Wu Z. Enhanced fluorescence/magnetic resonance dual imaging and gene therapy of liver cancer using cationized amylose nanoprobe. Mater Today Bio. 2022;13: 100220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yang S, Wang D, Zhang X, Sun Y, Zheng B. cRGD peptide-conjugated polyethylenimine-based lipid nanoparticle for intracellular delivery of siRNA in hepatocarcinoma therapy. Drug Deliv. 2021;28(1):995–1006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhao Y, Lee RJ, Liu L, Dong S, Zhang J, Zhang Y, Yao Y, Lu J, Meng Q, Xie J, et al. Multifunctional drug carrier based on PEI derivatives loaded with small interfering RNA for therapy of liver cancer. Int J Pharm. 2019;564:214–24.

    Article  CAS  PubMed  Google Scholar 

  78. Xiao D, Li Y, Tian T, Zhang T, Shi S, Lu B, Gao Y, Qin X, Zhang M, Wei W, et al. Tetrahedral framework nucleic acids loaded with aptamer AS1411 for siRNA delivery and gene silencing in malignant melanoma. ACS Appl Mater Interfaces. 2021;13(5):6109–18.

    Article  CAS  PubMed  Google Scholar 

  79. Liu D, Liu Z, Condouris S, Xing M. BRAF V600E maintains proliferation, transformation, and tumorigenicity of BRAF-mutant papillary thyroid cancer cells. J Clin Endocrinol Metab. 2007;92(6):2264–71.

    Article  CAS  PubMed  Google Scholar 

  80. Zhang Y, Zhan X, Peng S, Cai Y, Zhang YS, Liu Y, Wang Z, Yu Y, Wang Y, Shi Q, et al. Targeted-gene silencing of BRAF to interrupt BRAF/MEK/ERK pathway synergized photothermal therapeutics for melanoma using a novel FA-GNR-siBRAF nanosystem. Nanomedicine. 2018;14(5):1679–93.

    Article  CAS  PubMed  Google Scholar 

  81. Chung JH, Kim DH, Kim YS, Son BS, Kim D, Hwang C, Shin D, Noh SG, Han JH, Kim DK, et al. Upregulation of P21-activated kinase 1 (PAK1)/CREB axis in squamous non-small cell lung carcinoma. Cell Physiol Biochem. 2018;50(1):304–16.

    Article  CAS  PubMed  Google Scholar 

  82. Yuan L, Santi M, Rushing EJ, Cornelison R, MacDonald TJ. ERK activation of p21 activated kinase-1 (Pak1) is critical for medulloblastoma cell migration. Clin Exp Metastasis. 2010;27(7):481–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Al-Azayzih A, Gao F, Somanath PR. P21 activated kinase-1 mediates transforming growth factor beta1-induced prostate cancer cell epithelial to mesenchymal transition. Biochim Biophys Acta. 2015;1853(5):1229–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zheng QC, Jiang S, Wu YZ, Shang D, Zhang Y, Hu SB, Cheng X, Zhang C, Sun P, Gao Y, et al. Dual-targeting nanoparticle-mediated gene therapy strategy for hepatocellular carcinoma by delivering small interfering RNA. Front Bioeng Biotechnol. 2020;8:512.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Ye XW, Yu H, Jin YK, Jing XT, Xu M, Wan ZF, Zhang XY. miR-138 inhibits proliferation by targeting 3-phosphoinositide-dependent protein kinase-1 in non-small cell lung cancer cells. Clin Respir J. 2015;9(1):27–33.

    Article  CAS  PubMed  Google Scholar 

  86. Zhang X, Yu Z. Expression of PDK1 in malignant pheochromocytoma as a new promising potential therapeutic target. Clin Transl Oncol. 2019;21(10):1312–8.

    Article  CAS  PubMed  Google Scholar 

  87. Yu J, Chen KS, Li YN, Yang J, Zhao L. Silencing of PDK1 gene expression by RNA interference suppresses growth of esophageal cancer. Asian Pac J Cancer Prev. 2012;13(8):4147–51.

    Article  PubMed  Google Scholar 

  88. Pan T, Wu R, Liu B, Wen H, Tu Z, Guo J, Yang J, Shen G. PBOV1 promotes prostate cancer proliferation by promoting G1/S transition. Onco Targets Ther. 2016;9:787–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Xue C, Zhong Z, Ye S, Wang Y, Ye Q. Association between the overexpression of PBOV1 and the prognosis of patients with hepatocellular carcinoma. Oncol Lett. 2018;16(3):3401–7.

    PubMed  PubMed Central  Google Scholar 

  90. Romano PR, McCallus DE, Pachuk CJ. RNA interference-mediated prevention and therapy for hepatocellular carcinoma. Oncogene. 2006;25(27):3857–65.

    Article  CAS  PubMed  Google Scholar 

  91. Doan CC, Le LT, Hoang SN, Do SM, Le DV. Simultaneous silencing of VEGF and KSP by siRNA cocktail inhibits proliferation and induces apoptosis of hepatocellular carcinoma Hep3B cells. Biol Res. 2014;47(1):70. Published 2014 Dec 15. https://doi.org/10.1186/0717-6287-47-70.

  92. Ye Z, Wu W-R, Qin Y-F, Hu J, Liu C, Seeberger PH, Yin J. An integrated therapeutic delivery system for enhanced treatment of hepatocellular carcinoma. Adv Funct Mater. 2018;28(18):1706600. https://doi.org/10.1002/adfm.201706600.

  93. Lin Y, Wei X, Jian Z, Zhang X. METTL3 expression is associated with glycolysis metabolism and sensitivity to glycolytic stress in hepatocellular carcinoma. Cancer Med. 2020;9(8):2859–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhou L, Yang C, Zhang N, Zhang X, Zhao T, Yu J. Silencing METTL3 inhibits the proliferation and invasion of osteosarcoma by regulating ATAD2. Biomed Pharmacother. 2020;125: 109964.

    Article  CAS  PubMed  Google Scholar 

  95. Zhu X, Shi D, Cao K, Ru D, Ren J, Rao Z, Chen Y, You Q, Dai C, Liu L, et al. Sphingosine kinase 2 cooperating with Fyn promotes kidney fibroblast activation and fibrosis via STAT3 and AKT. Biochim Biophys Acta Mol Basis Dis. 2018;1864(11):3824–36.

    Article  CAS  PubMed  Google Scholar 

  96. Liu W, Ning J, Li C, Hu J, Meng Q, Lu H, Cai L. Overexpression of Sphk2 is associated with gefitinib resistance in non-small cell lung cancer. Tumour Biol. 2016;37(5):6331–6.

    Article  CAS  PubMed  Google Scholar 

  97. Scarabel L, Perrone F, Garziera M, Farra R, Grassi M, Musiani F, Russo Spena C, Salis B, De Stefano L, Toffoli G, et al. Strategies to optimize siRNA delivery to hepatocellular carcinoma cells. Expert Opin Drug Deliv. 2017;14(6):797–810.

    Article  CAS  PubMed  Google Scholar 

  98. Younis MA, Khalil IA, Abd Elwakil MM, Harashima H. A Multifunctional lipid-based nanodevice for the highly specific codelivery of sorafenib and midkine siRNA to hepatic cancer cells. Mol Pharm. 2019;16(9):4031–44.

    Article  CAS  PubMed  Google Scholar 

  99. Kanasty R, Dorkin JR, Vegas A, Anderson D. Delivery materials for siRNA therapeutics. Nat Mater. 2013;12(11):967–77.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Biopharmaceutical, Shanghai Ocean University, Shanghai, 201306, China

    Feng Chen, Wang Zhang, Xinran Gao, Hui Yuan & Kehai Liu

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  1. Feng Chen
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  2. Wang Zhang
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  3. Xinran Gao
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  4. Hui Yuan
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  5. Kehai Liu
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FC collected relevant information and wrote the whole manuscript. KHL established review idea and gave key comments. WZ, XRG, and HY collected data.

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Correspondence to Kehai Liu.

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Chen, F., Zhang, W., Gao, X. et al. The Role of Small Interfering RNAs in Hepatocellular Carcinoma. J Gastrointest Canc 55, 26–40 (2024). https://doi.org/10.1007/s12029-023-00911-w

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