El-Serag Hashem B. Hepatocellular carcinoma. N Engl J Med. 2011;365:1118–27.

Article  CAS  PubMed  Google Scholar 

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.

Article  PubMed  Google Scholar 

Gauthier A, Ho M. Role of sorafenib in the treatment of advanced hepatocellular carcinoma: an update. Hepatol Res. 2013;43(2):147–54.

Article  CAS  PubMed  Google Scholar 

Wilson GS, Hu Z, Duan W, Tian A, Wang XM, McLeod D, et al. Efficacy of using cancer stem cell markers in isolating and characterizing liver cancer stem cells. Stem Cells Dev. 2013;22(19):2655–64.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6.

Article  PubMed  Google Scholar 

Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature. 2019;575(7782):299–309.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Xiao Y, Lin M, Jiang X, Ye J, Guo T, Shi Y, et al. The recent advances on liver cancer stem cells: biomarkers, separation, and therapy. Anal Cell Pathol. 2017;2017:5108653.

Article  Google Scholar 

Wang N, Wang S, Li MY, Hu BG, Liu LP, Yang SL, et al. Cancer stem cells in hepatocellular carcinoma: an overview and promising therapeutic strategies. Ther Adv Med Oncol. 2018;10:1758835918816287.

Article  PubMed  PubMed Central  Google Scholar 

Thorgeirsson SS. Stemness in Liver Cancer. Dig Dis. 2017;35(4):387–9.

Article  PubMed  Google Scholar 

Li Y, Chen G, Han Z, Cheng H, Qiao L, Li Y. IL-6/STAT3 signaling contributes to sorafenib resistance in Hepatocellular carcinoma through targeting cancer stem cells. Onco Targets Ther. 2020;13:9721–30.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cheng CC, Chao WT, Liao CC, Shih JH, Lai YS, Hsu YH, et al. The roles of angiogenesis and cancer stem cells in sorafenib drug resistance in Hepatocellular carcinoma. Onco Targets Ther. 2019;12:8217–27.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yamashita T, Wang XW. Cancer stem cells in the development of liver cancer. J Clin Invest. 2013;123(5):1911–8.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sun JH, Luo Q, Liu LL, Song GB. Liver cancer stem cell markers: progression and therapeutic implications. World J Gastroenterol. 2016;22(13):3547–57.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Biagioni A, Laurenzana A, Margheri F, Chilla A, Fibbi G, Del Rosso M. Delivery systems of CRISPR/Cas9-based cancer gene therapy. J Biol Eng. 2018;12:33.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wang L, Li F, Dang L, Liang C, Wang C, He B, et al. In Vivo delivery systems for therapeutic genome editing. Int J Mol Sci. 2016;17(5):626.

Article  PubMed  PubMed Central  Google Scholar 

Xu CL, Ruan MZC, Mahajan VB, Tsang SH. Viral delivery systems for CRISPR. Viruses. 2019;11(1):28.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lee Y, El Andaloussi S, Wood MJ. Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum Mol Genet. 2012;21(R1):R125–34.

Article  CAS  PubMed  Google Scholar 

van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19(4):213–28.

Article  PubMed  Google Scholar 

Jiang Z, Jiang X, Chen S, Lai Y, Wei X, Li B, et al. Anti-GPC3-CAR T cells suppress the growth of tumor cells in patient-derived xenografts of hepatocellular carcinoma. Front Immunol. 2016;7:690.

PubMed  Google Scholar 

Nakatsura T, Ofuji K, Saito K, Yoshikawa T. Critical analysis of the potential of targeting GPC3 in hepatocellular carcinoma. J Hepatocell Carcinoma. 2014. https://doi.org/10.2147/JHC.S48517.

Article  PubMed  PubMed Central  Google Scholar 

He C, Jaffar Ali D, Li Y, Zhu Y, Sun B, Xiao Z. Engineering of HN3 increases the tumor targeting specificity of exosomes and upgrade the anti-tumor effect of sorafenib on HuH-7 cells. PeerJ. 2020;8: e9524.

Article  PubMed  PubMed Central  Google Scholar 

Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature. 2012;487(7408):505–9.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Moritz A, Li Y, Guo A, Villen J, Wang Y, MacNeill J, et al. Akt-RSK-S6 kinase signaling networks activated by oncogenic receptor tyrosine kinases. Sci Signal. 2010;3(136):ra64.

Article  PubMed  PubMed Central  Google Scholar 

Zhang H, Wang Q, Liu J, Cao H. Inhibition of the PI3K/Akt signaling pathway reverses sorafenib-derived chemo-resistance in hepatocellular carcinoma. Oncol Lett. 2018;15(6):9377–84.

PubMed  PubMed Central  Google Scholar 

Zhang N, Wei P, Gong A, Chiu WT, Lee HT, Colman H, et al. FoxM1 promotes beta-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis. Cancer Cell. 2011;20(4):427–42.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kopanja D, Pandey A, Kiefer M, Wang Z, Chandan N, Carr JR, et al. Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features. J Hepatol. 2015;63(2):429–36.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7(1):1535750.

Article  PubMed  PubMed Central  Google Scholar 

Xin HW, Ambe CM, Hari DM, Wiegand GW, Miller TC, Chen JQ, et al. Label-retaining liver cancer cells are relatively resistant to sorafenib. Gut. 2013;62(12):1777–86.

Article  CAS  PubMed  Google Scholar 

Zhu Z, Hao X, Yan M, Yao M, Ge C, Gu J, et al. Cancer stem/progenitor cells are highly enriched in CD133+CD44+ population in hepatocellular carcinoma. Int J Cancer. 2010;126(9):2067–78.

CAS  PubMed  Google Scholar 

Yamashita T, Honda M, Nakamoto Y, Baba M, Nio K, Hara Y, et al. Discrete nature of EpCAM+ and CD90+ cancer stem cells in human hepatocellular carcinoma. Hepatology. 2013;57(4):1484–97.

Article  CAS  PubMed  Google Scholar 

He C, Jaffar Ali D, Xu H, Kumaravel S, Si K, Li Y, et al. Epithelial cell -derived microvesicles: A safe delivery platform of CRISPR/Cas9 conferring synergistic anti-tumor effect with sorafenib. Exp Cell Res. 2020;392(2): 112040.

Article  CAS  PubMed  Google Scholar 

Kim SM, Yang Y, Oh SJ, Hong Y, Seo M, Jang M. Cancer-derived exosomes as a delivery platform of CRISPR/Cas9 confer cancer cell tropism-dependent targeting. J Control Release. 2017;266:8–16.

Article  CAS  PubMed  Google Scholar 

Scott M, Wilhelm CC, Tang LiYa, Wilkie Dean, McNabola Angela, Rong Hong, Chen Charles, Zhang Xiaomei, Vincent Patrick, McHugh Mark, Cao Yichen, Shujath Jaleel, Gawlak Susan, Eveleigh Deepa, Rowley Bruce, Liu Li, Adnane Lila, Lynch Mark, Auclair Daniel, Taylor Ian, Gedrich Rich, Voznesensky Andrei, Riedl Bernd, Post Leonard E, Bollag Gideon, Trail Pamela A. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF MEK ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–109.

Article  Google Scholar 

Chang YS, Adnane J, Trail PA, Levy J, Henderson A, Xue D, et al. Sorafenib (BAY 43–9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol. 2007;59(5):561–74.

Article  CAS  PubMed  Google Scholar 

Chen F, Zhu HH, Zhou LF, Wu SS, Wang J, Chen Z. IQGAP1 is overexpressed in hepatocellular carcinoma and promotes cell proliferation by Akt activation. Exp Mol Med. 2010;42(7):477–83.

Article  CAS  PubMed  PubMed Central  Google Scholar 

de Sousa EMF, Vermeulen L. Wnt signaling in cancer stem cell biology. Cancers. 2016;8(7):60.

Article  Google Scholar