Understanding Gene Involvement in Hepatocellular Carcinoma: Implications for Gene Therapy and Personalized Medicine

Figures & data

Figure 1 An illustration outlining the potential role of the MK signaling pathway in the acquired resistance to SOR by HCC cells. (A) The standard molecular mechanism of SOR when acting on HCC cells. (B) The overexpression of MK in HCC mechanistically opposes the therapeutic effects of SOR via upregulating STAT-3 and NF-kB and downregulating Caspase-3. The figure is reprinted from J Controlled Release, Volume 331, 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.335-349,¹⁰⁷ with permission from Elsevier (Copyright 2021, Elsevier).

Abbreviations: HCC, Hepatocellular carcinoma; ALK, Anaplastic lymphoma kinase; EGFR, Epidermal growth factor receptor; PI3K/AKT, Phosphatidyl inositol-3 kinase/protein kinase B; MAPKs, Mitogen-activated protein kinases; STAT-3, Signal transducer and activator of transcription 3; C-myc, MYC proto-oncogene; Bcl-2, B-cell lymphoma 2; VEGF, Vascular endothelial growth factor; NCID, Notch cytoplasmic intracellular domain; NF-kB, Nuclear factor kappa.

Figure 2 An outline for some of the potential strategies that could be applied in the gene therapy of HCC. The figure was created with BioRender.com, with a publication license.

Figure 3 An outline of the major challenges that are encountered in gene delivery to HCC. (1) The systemically administered vectors must escape from the host immunity and from the reticulo-endothelial system and possess a sufficient residence time in blood circulation in order to reach the tumor region. (2) The administered vectors must escape the phagocytosis promoted by the activated Kupffer cells in the tumor microenvironment. (3) The vectors must be small enough to extravasate from the narrowed fenestrations and to penetrate the stroma-rich tumor microenvironment to access HCC cells. (4) The vectors must be taken up efficiently and selectively by HCC cells, with a subsequent escape of the nucleic acid cargos from lysosomal degradation to exert their intracellular action. The figure is reprinted from Younis MA, Khalil IA, Harashima H. Gene Therapy for Hepatocellular Carcinoma: highlighting the Journey from Theory to Clinical Applications. Advanced Tharapeutics. 2020;3(11):2000087. © 2020 Wiley-VCH GmbH..⁹

Abbreviations: LSEC, liver sinusoidal endothelial cell; ASC, activated stellate cell; HCC, hepatocellular carcinoma cells.

Table 1 Examples of ncRNAs That Have Been Reported to Play Roles in the Progression/Suppression of HCC

Functional Classification	ncRNA name	Category	Mechanism of Action	References
Tumor promoter	miR-21	miRNA	Induced by HBV to activate STAT3	[139]
	miR-222		Silences PPP2R2A to activate AKT	[140]
	miR-151		Silences RhoGDIA to promote metastasis	[141]
	miR-429		Silences RBBP4 to activate T-ICs	[142]
	ANRIL	lncRNA	Silences KLF2 to resist apoptosis	[143]
	DBH-AS1		Activates MAPK signaling	[144]
	lnc-β-Catm		Stabilizes β-catenin to promote LCSCs	[145]
	linc01225		Stabilizes EGFR	[146]
Tumor suppressor	let-7	miRNA	Silences PBX3 to inhibit T-ICs	[147]
	miR-195		Silences VEGF to inhibit angiogenesis	[148]
	miR-199a-3p		Silences PAK4 to inhibit RAF–MEK–ERK	[149]
	miR-142-3p		Silences CD133 to inhibit LCSCs	[150]
	AOC4P	lncRNA	Degrades of vimentin to inhibit EMT	[151]
	FTX		Sequesters miR-374 to repress Wnt/β-catenin	[152]
	PTENP1		Sequesters miR-17, miR-19b, miR-20a to rescue PTEN	[153]
	MEG3		Activates p53-mediated transcriptional activity	[154]

Abbreviations: PPP2R2A, Protein phosphatase 2A subunit B; RhoGDIA, Rho GDP-dissociation inhibitor A; RBBP4, Rb binding protein 4; T-ICs, Tumor-initiating cells; KLF2, Kruppel-like factor 2; LCSCs, Liver cancer stem cells; PBX3, PBX Homeobox 3.

Figure 4 A graphical summary of a comprehensive strategy to achieve efficient drug and gene delivery to HCC using microfluidics and targeted lipid nanoparticles technologies. The figure is reprinted from Adv. Drug Delivery Rev, Volume 188, Nakamura T, Sato Y, Yamada Y, et al. Extrahepatic targeting of lipid nanoparticles in vivo with intracellular targeting for future nanomedicines. 114417,¹⁵⁶ with permission from Elsevier (Copyright 2022, Elsevier).

Abbreviations: LNP, lipid nanoparticle; PK, pharmacokinetics; siRNA, small interfering RNA; SOR, sorafenib; PEG, polyethylene glycol; ApoE, apolipoprotein E.

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 Controlled Release. 2021;331:335–349.

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