Progesterone and adipose Q receptor 5 (PAQR5), a membrane receptor characterized by seven transmembrane domains, has been indirectly implicated in pro-carcinogenic activities, though its specific role in hepatocellular carcinoma (HCC) remains to be defined.

This study aimed to elucidate the molecular mechanisms by which PAQR5 facilitates HCC progression and contributes to the immunosuppressive microenvironment through an integrative approach combining multi-omics analysis and experimental validation. Utilizing data from bulk, single-cell, and spatial transcriptomics cohorts, this study systematically assessed the expression patterns, immune landscape, and functional characteristics of PAQR5 across different levels of resolution in HCC.

PAQR5 expression was significantly upregulated in tumor tissues and correlated with poor clinical outcomes. Enrichment analysis revealed that PAQR5 activated the NF-κB signaling pathway in HCC. Single-cell transcriptomics identified PAQR5 as predominantly localized within malignant cell clusters, with significant association with NF-κB pathway activation. Spatial transcriptomics further corroborated the alignment of PAQR5 expression with tumor cell distribution. In vitro assays showed elevated PAQR5 levels in HCC cell lines, and silencing PAQR5 significantly suppressed cell proliferation, invasion, epithelial-mesenchymal transition (EMT), and prevented the formation of immunosuppressive microenvironment. In vivo studies demonstrated that targeting PAQR5 attenuated tumorigenic potential, disrupted the invasion-metastasis cascade and inhibited the tumor immune escape. Mechanistically, PAQR5 was found to activate NF-κB signaling by inducing ERK phosphorylation, thereby driving proliferation, invasion, EMT, and immune escape in HCC through the pathway.

GLUT2 (SLC2A2), a vital glucose transporter in liver, pancreas, and kidney tissues, regulates blood glucose levels and energy metabolism. Beyond its metabolic role, SLC2A2 contributes to cell differentiation and metabolic adaptation during embryogenesis and tissue regeneration. Despite its significance, the role of SLC2A2 in liver differentiation and hepatocellular carcinoma (HCC) remains underexplored. This study investigated SLC2A2's role in liver differentiation using in silico, in vitro, and in vivo approaches. Analysis of GEO datasets (GSE132606, GSE25417, GSE67848) and TCGA HCC data revealed that while SLC2A2 expression decreases with HCC progression, stemness-associated genes, including SOX2 and POU5F1, are upregulated. Zebrafish embryos injected with SLC2A2-targeting morpholino exhibited reduced expression of the liver differentiation marker fabp10a without significantly altering the hepatoblast marker hhex. In HepG2 cells, SLC2A2 knockdown increased stemness and IGF1R pathway markers, indicating a shift toward less differentiated states. These findings suggest that SLC2A2 supports liver differentiation by regulating glucose metabolism and suppressing pathways associated with stemness and malignancy. Targeting SLC2A2 may serve as a promising therapeutic strategy for liver-related diseases, particularly HCC, by addressing its dual role in differentiation and tumor progression. Further mechanistic studies are warranted to fully elucidate these processes.

Hepatocellular carcinoma (HCC) is a malignant tumour with high prevalence and mortality rate worldwide. Metabolic reprogramming of cancer cells may be a major factor in the process of this disease. Glucose transporter proteins (GLUTs) are members of the major facilitator superfamily of membrane transporters, playing a pivotal role in the metabolic reprogramming and tumour progression in HCC. This review discusses the advances in the study of GLUTs in HCC, including the expression patterns, functions and possibilities of GLUTs. In HCC, the expression levels of GLUTs are closely associated with tumour aggressiveness, metabolic reprogramming and prognosis. A series of inhibitors have been demonstrated efficacy in inhibiting HCC cell growth and glucose uptake in in vitro and in vivo models. These inhibitors offer a novel approach to HCC treatment by reducing the glucose metabolism of tumour cells, thereby impeding tumour growth, and concurrently enhancing the sensitivity to chemotherapeutic agents. This reminds us of the urgent need to elucidate GLUTs' roles in HCC and to determine the most effective ways to translate these findings into clinical practice.

The use of black soybean (Glycine max L.), an edible crop prevalent in Asia, has attracted attention for its hepatoprotective properties. Notably, the anthocyanin components in black soybean coats have shown potential in inhibiting tumor growth. Here, anthocyanins were extracted from black soybean coats using both microwave and water bath methods. The physicochemical characteristics of black soybean coat anthocyanins (BSCAs) and their biological activities were examined. The results from the MTT and EDU assays demonstrated a dose-dependent inhibitory effect of BSCAs on hepatocellular carcinoma HepG2 cells, while leaving normal cells unaffected. Flow cytometry and mitochondrial membrane potential assays revealed that BSCA treatment induces apoptosis in HepG2 cells. A network pharmacology approach was employed to explore the relationship between hepatocellular carcinoma and the active ingredients of BSCAs, identifying the JAK/STAT signaling pathway as a potential target. Molecular docking studies confirmed the interaction between BSCA components and JAK2/STAT3 targets. Subsequent Western blot and qPCR experiments validated that BSCAs promote apoptosis in HepG2 cells by modulating the JAK2/STAT3 signaling pathway.

Hepatocellular carcinoma (HCC) is a global health issue due to its late diagnosis and high recurrence rate. The early detection and diagnosis of HCC with specific and sensitive biomarkers and using novel treatment approaches to improve patient outcomes are essential. Glypican-3 (GPC-3) is a cell surface proteoglycan that is overexpressed in many tumors, including HCC. GPC-3 could be used as a specific biomarker for HCC early detection and could be a potential target for precise therapeutic strategies. Effective identification of GPC-3 could improve both diagnosis and targeted therapy of HCC. Moreover, targeted therapy using GPC-3 could result in a better treatment outcome. Recently, GPC3-targeted therapies have been used in different investigational therapeutic approaches like bi-specific/monoclonal antibodies, peptide vaccines, and CAR T cell therapies. This study aims to highlight the theranostic potential of GPC-3 as a novel biomarker for early detection and as a potential molecular target for HCC treatment as well.

Current embolic agents in transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) encounter instability and easy leakage, discounting TACE efficacy with residual HCC. Moreover, clinical TACE aggravates hypoxia and pro-metastatic microenvironments, rendering patients with HCC poor prognosis.

Herein, we developed Zein-based embolic agents that harness water-insoluble but ethanol-soluble Zein to encompass doxorubicin (DOX)-loaded mesoporous hollow MnO2 (HMnO2). The conditions and capacity of HMnO2 to generate reactive oxygen species (ROS) were assayed. Mechanical examinations of Zein-HMnO2@DOX were performed to evaluate its potential as the embolic agent. In vitro experiments were carried out to evaluate the effect of Zein-HMnO2@DOX on HCC. The subcutaneous HCC mouse model and rabbit VX2 HCC model were established to investigate its anti-tumor and anti-metastasis efficacy and explore its potential anti-tumor mechanism.

The high adhesion and crosslinking of Zein with HMnO2@DOX impart Zein-HMnO2@DOX with strong mechanical strength to resist deformation and wash-off. Zein gelation and HMnO2 decomposition in response to water and acidic tumor microenvironment, respectively, enable continuous DOX release and Fenton-like reaction for reactive oxygen species (ROS) production and O2 release to execute ROS-enhanced TACE. Consequently, Zein-based embolic agents outperform clinically-used lipiodol to significantly inhibit orthotopic HCC growth. More significantly, O2 release down-regulates hypoxia inducible factor (HIF-1α), vascular endothelial growth factor (VEGF) and glucose transporter protein 1 (GLUT1), which thereby re-programmes TACE-aggravated hypoxic and pro-metastatic microenvironments to repress HCC metastasis towards lung. Mechanistic explorations uncover that such Zein-based TACE agents disrupt oxidative stress, angiogenesis and glycometabolism pathways to inhibit HCC progression.

This innovative work not only provides a new TACE agent for HCC, but also establishes a new strategy to ameliorate TACE-aggravated hypoxia and metastasis motivation against clinically-common HCC metastasis after TACE operation.

Excellent Young Science Fund for National Natural Science Foundation of China (82022033); National Natural Science Foundation of China (Grant No. 82373086, 82102761); Major scientific and technological innovation project of Wenzhou Science and Technology Bureau (Grant No. ZY2021009); Shanghai Young Top-Notch Talent.

Chronic infection with hepatitis C virus (HCV) has a long-term impact on hepatic consequences. A comprehensive evaluation of the global burden of HCV-related health outcomes can help to develop a global HCV prevention and treatment program.

We used the 2019 Global Burden of Disease (GBD) Study to comprehensively investigate burden and temporal trends in incidence, mortality and disability-adjusted life-years (DALYs) of HCV-related diseases, including liver cancer and cirrhosis and other liver diseases across 264 countries and territories from 2010 to 2019.

Globally, there were 152 225 incident cases, 141 811 deaths and approximately 2.9 million DALYs because of HCV-related liver cancer, and 551 668 incident cases, 395 022 deaths and about 12.2 million DALYs because of HCV-related cirrhosis in 2019. Worldwide, during the 2010-2019 period, liver cancer incidence declined, however, there was a 62% increase in cirrhosis incidence. In 2019, the Eastern Mediterranean was the region with the highest rates of incidence and mortality of both liver cancer and cirrhosis. Africa was the region with the fastest-growing trend of incidence of cirrhosis in the 2010-2019 period [annual percentage change (APC) = 2.09, 95% confidence interval (CI): 1.93-2.25], followed by the Western Pacific region (APC = 1.17, 95% CI: 1.09-1.22). Americas were the only region observing increased trends in liver cancer and cirrhosis mortality (APC = 0.70 and 0.12, respectively). We identified three patterns of temporal trends of mortality rates of liver cancer and cirrhosis in countries that reported HCV treatment rates.

Urgent measures are required for diagnosis, treatment and research on HCV-related cirrhosis at global, regional and country levels, particularly in Africa, the Western Pacific and the Eastern Mediterranean.

Hepatocellular carcinoma (HCC) ranks among the most prevalent malignant tumors, exhibiting a high incidence rate that presents a substantial threat to human health. The use of sorafenib and lenvatinib, commonly employed as single-agent targeted inhibitors, complicates the treatment process due to the absence of definitive targeting. Nevertheless, the advent of nanotechnology has injected new optimism into the domain of liver cancer therapy. Nanocarriers equipped with active targeting or passive targeting mechanisms have demonstrated the capability to deliver drugs to tumor cells with high efficiency. This approach not only facilitates precise delivery to the affected site but also enables targeted drug release, thereby enhancing therapeutic efficacy. As medical technology progresses, there is an increasing call for innovative treatment modalities, including novel chemotherapeutic agents, gene therapy, phototherapy, immunotherapy, and combinatorial treatments for HCC. These emerging therapies are anticipated to yield improved clinical outcomes for patients, while minimizing systemic toxicity and adverse effects. Consequently, the application of nanotechnology is poised to significantly improve HCC treatment. This review focused on targeted strategies for HCC and the application of nanotechnology in this area.

Circular RNA (circRNA) plays important role in hepatocellular carcinoma (HCC) progression. However, the role and mechanism of circETV6 in HCC progression remain unclear. The levels of circETV6, ETV6, miR-383-5p, and PTPRE were tested by quantitative reverse-transcription polymerase chain reaction. Cell functions were assessed using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, 5-ethynyl-2'-deoxyuridine assay, colony formation assay, wound healing assay, transwell assay, and flow cytometry. The protein levels of poptosis-related markers and PTPRE were determined by western blot analysis. RNA interaction was analyzed by dual-luciferase reporter assay and RNA pull-down assay. A xenograft model was established to assess circETV6 roles in vivo. CircETV6 was highly expressed in HCC tissues and cells. CircETV6 knockdown repressed HCC cell proliferation, migration, invasion, and cell cycle, while accelerated apoptosis. CircETV6 targeted miR-383-5p, and miR-383-5p inhibition reversed the regulation of circETV6 knockdown on HCC cell progression. CircETV6 promoted PTPRE level via targeting miR-383-5p. Overexpressed PTPRE abolished the inhibition effect of miR-383-5p on HCC cell progression. In addition, circETV6 knockdown slowed HCC tumor growth in vivo. CircETV6 might facilitate HCC progression via the miR-383-5p/PTPRE axis, providing a novel target for HCC treatment.

Late recurrence of hepatocellular carcinoma (HCC) following orthotopic liver transplant (OLT) is infrequently reported, and among cases, those isolated to the spine are rare. Prognoses are poor for this patient population, and no work has been undertaken to create uniform guidelines for management. Here, we report two cases of late recurrent HCC to the spine after OLT and favorable survival outcomes following intervention.

Convenient therapeutic protocols for hepatocellular carcinoma (HCC) are often ineffective due to late diagnosis and high tumor heterogeneity, leading to poor long-term outcomes. However, recently performed studies suggest that using nanostructures in liver cancer treatment may improve therapeutic effects. Inorganic nanoparticles represent a unique material that tend to accumulate in the liver when introduced in-vivo. Typically, this is a major drawback that prevents the therapeutic use of nanoparticles in medicine. However, in HCC tumours, this may be advantageous because nanoparticles may accumulate in the target organ, where the leaky vasculature of HCC causes their accumulation in tumour cells via the EPR effect. On the other hand, recent studies have shown that combining low- and high-LET radiation emitted from the same radionuclide, such as 161Tb, can increase the effectiveness of radionuclide therapy. Therefore, to improve the efficacy of radionuclide therapy for hepatocellular carcinoma, we suggest utilizing radioactive palladium nanoparticles in the form of 109Pd/109mAg in-vivo generator that simultaneously emits β- particles and Auger electrons.

Palladium nanoparticles with a size of 5 nm were synthesized using 109Pd produced through neutron irradiation of natural palladium or enriched 108Pd. Unlike the 109Pd-cyclam complex, where the daughter radionuclide diffuses away from the molecules, 109mAg remains within the nanoparticles after the decay of 109Pd. In vitro cell studies using radioactive 109Pd nanoparticles revealed that the nanoparticles accumulated inside cells, reaching around 50% total uptake. The 109Pd-PEG nanoparticles exhibited high cytotoxicity, even at low levels of radioactivity (6.25 MBq/mL), resulting in almost complete cell death at 25 MBq/mL. This cytotoxic effect was significantly greater than that of PdNPs labeled with β- (131I) and Auger electron emitters (125I). The metabolic viability of HCC cells was found to be correlated with cell DNA DSBs. Also, successful radioconjugate anticancer activity was observed in three-dimensional tumor spheroids, resulting in a significant treatment response.

The results indicate that nanoparticles labeled with 109Pd can be effectively used for combined β- - Auger electron-targeted radionuclide therapy of HCC. Due to the decay of both components (β- and Auger electrons), the 109Pd/109mAg in-vivo generator presents a unique potential in this field.

Liver cancer is the fourth leading cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being the most common type of primary liver cancer. APG-1252 is a small molecule inhibitor targeting Bcl-2 and Bcl-xl. However, its anti-tumor effects in HCC, alone or in combination with Cabozantinib, have not been extensively studied.

Approach: TCGA database analysis was used to analysis the gene expression levels of Bcl-2 and Bcl-xl in HCC tissues. Western blot was employed to detect the protein expression levels. And the inhibitory effects of APG-1252 and Cabozantinib on the proliferation of HCC cell lines was detected by CCK-8. The effect on the migration and invasion of HCC cells was verified by transwell assay. Huh7 xenograft model in nude mice was used to investigate the combination antitumor effect in vivo.

Our study demonstrated that APG-1252 monotherapy inhibited the proliferation and migration ability of HCC cells, and induced HCC cells apoptosis. The combination of APG-1252 and Cabozantinib showed significant synergistic antitumor effects. Furthermore, the in vivo experiment demonstrated that the combination therapy exerted a synergistic effect in delaying tumor growth, notably downregulating MEK/ERK phosphorylation levels. In terms of mechanism, Cabozantinib treatment caused an increase in the phosphorylation levels of CREB and Bcl-xl proteins, while the combination with APG-1252 mitigated this effect, thereby enhanced the antitumor effect of Cabozantinib.

Our findings suggest that APG-1252 in combination with Cabozantinib offers a more effective treatment strategy for HCC patients, warranting further clinical investigation.

Liver hepatocellular carcinoma (LIHC) is a significant global health issue with limited treatment options. In this study, single-cell RNA sequencing (scRNA-seq) data were used to explore the molecular mechanisms of LIHC development and identify potential targets for therapy. The expression of peroxisome proliferator-activated receptors (PPAR)-related genes was analysed in LIHC samples, and primary cell populations, including natural killer cells, T cells, B cells, myeloid cells, endothelial cells, fibroblasts and hepatocytes, were identified. Analysis of the differentially expressed genes (DEGs) between normal and tumour tissues revealed significant changes in gene expression in various cell populations. PPAR activity was evaluated using the 'AUCell' R software, which indicated higher scores in the normal versus the malignant hepatocytes. Furthermore, the DEGs showed significant enrichment of pathways related to lipid and glucose metabolism, cell development, differentiation and inflammation. A prognostic model was then constructed using 8 PPARs-related genes, including FABP5, LPL, ACAA1, PPARD, FABP4, PLIN1, HMGCS2 and CYP7A1, identified using least absolute shrinkage and selection operator-Cox regression analysis, and validated in the TCGA-LIHC, ICGI-LIRI and GSE14520 datasets. Patients with low-risk scores had better prognosis in all cohorts. Based on the expression of the eight model genes, two clusters of patients were identified by ConsensusCluster analysis. We also predicted small-molecule drugs targeting the model genes, and identified perfluorohexanesulfonic acid, triflumizole and perfluorononanoic acid as potential candidates. Finally, wound healing assay confirmed that PPARD can promote the migration of liver cancer cells. Overall, our study offers novel perspectives on the molecular mechanisms of LIHC and potential areas for therapeutic intervention, which may facilitate the development of more effective treatment regimens.

Hepatocellular carcinoma (HCC) is a prevalent and deadly form of cancer globally with typically unfavorable outcomes. Increasing research suggests that lactate serves as an important carbon contributor to cellular metabolism and holds a crucial part in the progression, sustenance, and treatment response of tumors. However, the contribution of lactate-related genes (LRGs) in HCC is still unclear. In this study, we analyzed TCGA datasets and screened 21 differentially expressed LRGs related to long-term survivals in HCC patients. Pan-cancer assays revealed that 21 LRGs expression exhibited a dysregulated level in man types of tumors and associated with clinical prognosis of tumor patients. The analysis of 21 LRGs successfully classified HCC samples into two molecular subtypes, and these two subtypes showed significant differences in clinical information, gene expression, and immune characteristics. Subsequently, based on the aforementioned 21 LRGs, a novel prognostic signature (DTYMK, IRAK1, POLRMT, MPV17, UQCRH, PDSS1, SLC16A3, SPP1 and LDHD) was generated by LASSO-Cox regression analysis. Survival assays demonstrated that the signature performed well in predicting the overall survival of patients with HCC. The results of Gene Set Variation Analysis indicated that the high GSVA scores were associated with poor prognosis. Moreover, we also investigated the correlation between GSVA scores and various signaling pathways in HCC. Among the nine prognostic genes, our attention focused on POLRMT which was highly expressed in HCC specimens based on TCGA datasets and several HCC cell lines. In addition, functional assays indicated that POLRMT distinctly promoted the proliferation, migration and energy metabolism of HCC cells via regulating Wnt/β-Catenin signaling. Overall, through the establishment of a novel prognostic signature, we have provided potential clinical value for assessing the prognosis of HCC patients. Furthermore, our study has identified the high expression of POLRMT in HCC and demonstrated its crucial role in HCC cell proliferation. These findings hold great importance in advancing our understanding of the pathophysiology of HCC, identifying new therapeutic targets, and improving patient survival rates.

Since the inception of the interferon-free direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV) infection, guidelines as to who should receive this potentially curative treatment have evolved. Treatment with DAAs is now considered for all patients except for those considered moribund.

To determine the DAA treatment rate for patients with HCV-related hepatocellular carcinoma (HCC).

This was a retrospective study from January 2015 to March 2021 of a national sample of privately insured patients with HCV-related HCC using Optum's Clinformatics® Data Mart (CDM) Database - a large, de-identified, adjudicated claims database.

We identified 3922 patients with HCV-related HCC: 922 (23.5%) received DAA. Compared to untreated patients, DAA-treated patients were younger (65.2 ± 7.5 vs. 66.4 ± 7.5 years, p < 0.001), more frequently saw a gastroenterology/infectious disease (GI/ID) physician (41.2% vs. 34.2%), and had decompensated cirrhosis (56% vs. 53%, p = 0.001). In multivariable analysis, younger age (HR: 0.98, 95% CI: 0.97-0.99, p < 0.001), GI/ID care (HR: 3.06, 95% CI: 2.13-4.51, p < 0.001), and having cirrhosis (compensated: HR: 1.60, 95% CI: 1.18-2.21, p = 0.003; decompensated: HR: 1.45, 95% CI: 1.07-1.98, p = 0.02) were associated with receiving DAA treatment, but not sex, race, or ethnicity. DAA-treated patients had significantly higher 5-year survival than untreated patients (47.2% vs. 35.2%, p < 0.001). Following adjustment for age, sex, race/ethnicity, Charlson Comorbidity Index, and HCC treatment, receiving DAA treatment was associated with lower mortality (aHR: 0.61, 95% CI: 0.53-0.69, p < 0.001).

DAA treatment remains underutilised in insured patients with HCV-related HCC; fewer than one in four patients received treatment. Seeing a specialist and having decompensated cirrhosis were predictors for DAA treatment; additional efforts are needed to increase awareness of HCV treatment.

Hepatocellular carcinoma (HCC) is a highly lethal malignant neoplasm, and the involvement of bone morphogenetic protein 9 (BMP9) has been implicated in the pathogenesis of liver diseases and HCC. Our goal was to investigate the role of BMP9 signaling in regulating N6-methyladenosine (m6A) methylation and cell cycle progression, and evaluate the therapeutic potential of BMP receptor inhibitors for HCC treatment. We observed that elevated levels of BMP9 expression in tumor tissues or serum samples from HCC patients were associated with a poorer prognosis. Through in vitro experiments utilizing the m6A dot blotting assay, we ascertained that BMP9 reduced the global RNA m6A methylation level in Huh7 and Hep3B cells, thereby facilitating their cell cycle progression. This effect was mediated by an increase in the expression of the inhibitor of DNA-binding protein 1 (ID1). Additionally, using methylated RNA immunoprecipitation qPCR(MeRIP-qPCR), we showed that the BMP9-ID1 pathway promoted CyclinD1 expression by decreasing the m6A methylation level in the 5' UTR of mRNA. This occurred through the upregulation of the fat mass and obesity-associated protein (FTO) in Huh7 and Hep3B cells. In our in vivo mouse xenograft models, we demonstrated that blocking the BMP receptor with LDN-212854 effectively suppressed HCC growth and induced global RNA m6A methylation. Overall, our findings indicate that the BMP9-ID1 pathway promotes HCC cell proliferation by down-regulating the m6A methylation level in the 5' UTR of CyclinD1 mRNA. Targeting the BMP9-ID1 pathway holds promise as a potential therapeutic strategy for treating HCC.

Cancer imposes a substantial burden and its incidence is persistently increasing in recent years. Cancer treatment has been difficult due to its inherently complex nature. The tumor microenvironment (TME) includes a complex interplay of cellular and noncellular constituents surrounding neoplastic cells, intricately contributing to the tumor initiation and progression. This critical aspect of tumors involves a complex interplay among cancer, stromal, and inflammatory cells, forming an inflammatory TME that promotes tumorigenesis across all stages. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is implicated in modulating various critical processes linked to tumor pathogenesis, including but not limited to the regulation of tumor cell proliferation, invasion, migration, and survival. Furthermore, TRAF6 prominently contributes to various immune and inflammatory pathways. The TRAF6-mediated activation of nuclear factor (NF)-κB in immune cells governs the production of proinflammatory cytokines. These cytokines sustain inflammation and stimulate tumor growth by activating NF-κB in tumor cells. In this review, we discuss various types of tumors, including gastrointestinal cancers, urogenital cancers, breast cancer, lung cancer, head and neck squamous cell carcinoma, uterine fibroids, and glioma. Employing a rigorous and systematic approach, we comprehensively evaluate the functional repertoire and potential roles of TRAF6 in various cancer types, thus highlighting TRAF6 as a compelling and emerging therapeutic target worthy of further investigation and development.

The liver cancer has microenvironmental features such as low pH, M2 tumor-associated macrophage enrichment, low oxygen, rich blood supply and susceptibility to hematotropic metastasis, high chemokine expression, enzyme overexpression, high redox level, and strong immunosuppression, which not only promotes the progression of the disease, but also seriously affects the clinical effectiveness of traditional therapeutic approaches. However, nanotechnology, due to its unique advantages of size effect and functionalized modifiability, can be utilized to develop various responsive nano-drug delivery system (NDDS) by using these characteristic signals of the liver cancer microenvironment as a source of stimulation, which in turn can realize the intelligent release of the drug under the specific microenvironment, and significantly increase the concentration of the drug at the target site. Therefore, researchers have designed a series of stimuli-responsive NDDS based on the characteristics of the liver cancer microenvironment, such as hypoxia, weak acidity, and abnormal expression of proteases, and they have been widely investigated for improving anti-tumor therapeutic efficacy and reducing the related side effects. This paper provides a review of the current application and progress of NDDS developed based on the response and regulation of the microenvironment in the treatment of liver cancer, compares the effects of the microenvironment and the NDDS, and provides a reference for building more advanced NDDS.

Tumour-derived exosomes (TDEs) play an important role in tumourigenesis and progression by regulating components in the tumour microenvironment (TME), however, the role of TDE-related immune genes in hepatocellular carcinoma is not fully known. We systematically analysed TDE genes from ExoCarta and immune genes from Immport,Machine learning ultimately identified eight TDE-related prognostic immune genes and used them as the basis for constructing a risk model, which was constructed to better predict patients with hepatocellular carcinoma (HCC) compared with published prognostic models. There were significant differences between the high and low risk groups in terms of biological functioning. Low-risk group were more sensitive to immunotherapy, the sensitivity to oxaliplatin and cisplatin differed between the high- and low-risk groups, and knockout of the core gene RAC1 limited the malignant biological behaviour of hepatocellular carcinoma cells. In conclusion, TIRGs are effective in predicting the prognosis of patients with hepatocellular carcinoma and provide a new perspective on immunotherapy and chemotherapy for patients.

Immune checkpoint inhibitors (ICIs) have emerged as effective therapeutics for multiple cancers. Nevertheless, as immunotherapeutic approaches are being extensively utilized, substantial hurdles have arisen for clinicians. These include countering ICIs resistance and ensuring precise efficacy assessments of these drugs, especially in the context of hepatocellular carcinoma (HCC). This review attempts to offer a holistic overview of the latest insights into the ICIs resistance mechanisms in HCC, the molecular underpinnings, and immune response. The intent is to inspire the development of efficacious combination strategies. This review also examines the unconventional response patterns, namely pseudoprogression (PsP) and hyperprogression (HPD). The prompt and rigorous evaluation of these treatment efficacies has emerged as a crucial imperative. Multiple clinical, radiological, and biomarker tests have been advanced to meticulously assess tumor response. Despite progress, precise mechanisms of action and predictive biomarkers remain elusive. This necessitates further investigation through prospective cohort studies in the impending future.

Primary hepatocellular carcinoma (HCC) is a malignancy with high morbidity and mortality. KH domain-containing, RNA-binding signal transduction-associated protein 3 (KHDRBS3) is an RNA-binding protein that is aberrantly expressed in multiple tumors; however, its expression and biological function in HCC have not been reported.

KHDRBS3 knockdown and overexpression were performed using the lentiviral vector system to investigate the effects of KHDRBS3 on cell proliferation, apoptosis, chemoresistance, and glycolysis. Murine xenograft tumor models were constructed to study the role of KHDRBS3 on tumor growth in vivo. Furthermore, RNA-Pull Down and RNA immunoprecipitation were utilized to explore the interaction between KHDRBS3 and 14-3-3ζ, a phosphopeptide-binding molecule encoded by YWHAZ.

KHDRBS3 was highly expressed in human HCC tissues and predicted the poor prognosis of patients with HCC. Knockdown of KHDRBS3 exhibited a carcinostatic effect in HCC and impeded proliferation and tumor growth, reduced glycolysis, enhanced cell sensitivity to doxorubicin, and induced apoptosis. On the contrary, forced expression of KHDRBS3 expedited the malignant biological behaviors of HCC cells. The expression of KHDRBS3 was positively correlated with the expression of 14-3-3ζ. RNA immunoprecipitation and RNA pull-down assays demonstrated that KHDRBS3 bound to YWHAZ. We further confirmed that 14-3-3ζ silencing significantly reversed the promotion of proliferation and glycolysis and the inhibition of apoptosis caused by KHDRBS3 overexpression.

Our findings suggest that KHDRBS3 promotes glycolysis and malignant progression of HCC through upregulating 14-3-3ζ expression, providing a possible target for HCC therapy.

This article aimed to examine the effect of metformin use on improving outcomes after liver-directed therapy in patients with HCC and identify future directions with the adjuvant use of and potential therapeutic agents that operate on similar mechanistic pathways. Databases were queried to identify pertinent articles on metformin's use as an anti-cancer agent in HCC. Eleven studies were included, with five pre-clinical and six clinical studies. The mean overall survival (OS) and progression-free survival were both higher in the locoregional therapy (LRT) + metformin-treated groups. The outcome variables, including local tumor recurrence rate, reduction in HCC tumor growth and size, tumor growth, proliferation, migration and invasion of HCC cells, HCC cell apoptosis, DNA damage, and cell cycle arrest, showed favorable outcomes in the LRT + metformin-treated groups compared with LRT alone. This systemic review provides a strong signal that metformin use can improve the tumor response after locoregional therapy. Well-controlled prospective trials will be needed to elucidate the potential antitumor effects of metformin and other mTOR inhibitors.

Currently, there are no recognized biomarkers for predicting the immunotherapy response and prognosis of hepatocellular carcinoma (HCC). This study aimed to establish an immune-related gene prognostic index (IRGPI) for HCC, and to investigate the clinical, immune, molecular, and microenvironmental characteristics of the IRGPI subgroups, as well as their impact on the effectiveness of immune checkpoint inhibitors (ICIs) therapy and patients' prognosis.

We analyzed the LIHC dataset (n = 424) from the The Cancer Genome Atlas (TCGA) database and the GSE10140 dataset (n = 84) from the Gene Expression Omnibus (GEO) database using weighted gene co-expression network analysis (WGCNA) and univariate/multivariate Cox regression analysis to identify immune-related hub genes with prognostic significance. Subsequently, The IRGPI was then established with these special genes obtained, and the molecular, immune, and clinicopathological characteristics of the IRGPI subgroups, along with their predictive role in ICIs treatment and HCC prognosis, were investigated.

The IRGPI was composed of nine genes, namely CHGA, GAL, CCR3, MMP7, STC1, UCN, OXT, SOCS2, and GCG. The IRGPI-high group exhibited a worse prognosis in both the TCGA and GEO databases compared to the IRGPI-low group. The IRGPI-high group was primarily associated with adaptive immune response and cell-cell interaction pathways and exhibited a higher frequency of gene mutations (such as TP53 and CTNNB1), higher expression of PD-L1 and CTLA4, a higher proportion of macrophages M0 and follicular helper T cells, and a higher APC_co_inhibition and T_cell_co-inhibition immune score. Furthermore, the IRGPI-high group was associated with worse immune subtypes, clinicopathological characteristics, immunotherapy response, and clinical prognosis.

IRGPI is a biomarker with significant potential for predicting the immunotherapy response and prognosis of HCC patients, and is closely related to the immunosuppressive microenvironment and poorer clinicopathological characteristics.

Being the sixth most diagnosed cancer and the fourth leading cause of cancer-related deaths worldwide, liver cancer is considered as a serious disease with a high prevalence and poor prognosis. Current anticancer drugs for liver cancer have drawbacks, such as limited efficacy in later stages of the disease, toxicity to healthy cells, and the potential for drug resistance. There is ample evidence that coumarin-based compounds are potent anticancer agents, with numerous analogues currently being investigated in preclinical and clinical studies. The current study aimed to explore the antitumor potency of a new class of 8-methoxycoumarin-3-carboxamides against liver cancer. Toward this aim, we have designed, synthesized, and characterized a new set of N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamide analogues. The assessment of antitumor activity revealed that the synthesized class of compounds possesses substantial cytotoxicity toward Hep-G2 cells when compared to staurosporine, without significant impact on normal cells. Out of the synthesized compounds, compound 7 demonstrated the most potent cytotoxic effect against Hep-G2 cells with an IC50 of 0.75 µM, which was more potent than the drug staurosporine (IC50 = 8.37 µM). The investigation into the mechanism behind the antiproliferative activity of compound 7 revealed that it interferes with DNA replication and induces DNA damage, leading to cell cycle arrest as demonstrated by a significant decrease in the percentage of cells in the G1 and G2/M phases, along with an increase in the percentage of cells in the S phase. Flow cytometric analysis further revealed that compound 7 has the ability to trigger programmed cell death by inducing necrosis and apoptosis in HepG-2 cells. Further explorations into the mechanism of action demonstrated that compound 7 displays a potent dual-inhibitory activity toward cytochrome P450 and vascular endothelial growth factor receptor-2 (VEGFR-2) proteins, as compared to sorafenib drug. Further, detailed computational studies revealed that compound 7 displays a considerable binding affinity toward the binding cavity of VEGFR2 and CYP450 proteins. Taken together, our findings indicate that the newly synthesized class of compounds, particularly compound 7, could serve as a promising scaffold for the development of highly effective anticancer agents against liver cancer.

MicroRNAs are small, noncoding molecules of about twenty-two nucleotides with crucial roles in both healthy and pathological cells. Their expression depends not only on genetic factors, but also on epigenetic mechanisms like genomic imprinting and inactivation of X chromosome in females that influence in a sex-dependent manner onset, progression, and response to therapy of different diseases like cancer. There is evidence of a correlation between miRNAs, sex, and cancer both in solid tumors and in hematological malignancies; as an example, in lymphomas, with a prevalence rate higher in men than women, miR-142 is "silenced" because of its hypermethylation by DNA methyltransferase-1 and it is blocked in its normal activity of regulating the migration of the cell. This condition corresponds in clinical practice with a more aggressive tumor. In addition, cancer treatment can have advantages from the evaluation of miRNAs expression; in fact, therapy with estrogens in hepatocellular carcinoma determines an upregulation of the oncosuppressors miR-26a, miR-92, and miR-122 and, consequently, apoptosis. The aim of this review is to present an exhaustive collection of scientific data about the possible role of sex differences on the expression of miRNAs and the mechanisms through which miRNAs influence cancerogenesis, autophagy, and apoptosis of cells from diverse types of tumors.

Atezolizumab plus bevacizumab was approved in 2020 as a first-line treatment for advanced hepatocellular carcinoma (HCC). The purpose of this study was to assess the curative effect and tolerability of the combination treatment in advanced HCC.

Web of Science, PubMed and Embase were retrieved for qualified literatures on the treatment of advanced HCC with atezolizumab plus bevacizumab until September 1, 2022. The outcomes included pooled overall response (OR), complete response (CR), partial response (PR), median overall survival (mOS), median progression-free survival (mPFS), and adverse events (AEs).

Twenty-three studies, comprising 3168 patients, were enrolled. The pooled OR, CR, and PR rates of the long-term (more than six weeks) therapy response based on Response Evaluation Criteria in Solid Tumors (RECIST) were 26%, 2%, and 23%, respectively. The pooled OR, CR, and PR rates of the short-term (six weeks) therapeutic response evaluated with RECIST were 13%, 0%, and 15%, respectively. The pooled mOS and mPFS were 14.7 months and 6.66 months, respectively. During the treatment, 83% and 30% of patients experienced any grade AEs and grade 3 and above AEs, respectively.

Atezolizumab in combination with bevacizumab showed good efficacy and tolerability in the treatment of advanced HCC. Compared with short-term, non-first-line, and low-dose therapy, atezolizumab plus bevacizumab in long-term, first-line, and standard-dose treatment for advanced HCC showed a better tumor response rate.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and its clinical treatment remains challenging. The development of new treatment regimens is important for effective HCC treatment. Phosphoinositide 3-kinase (PI3K) is a lipid kinase that plays an important role in cell growth and metabolism and is overexpressed in nearly 50% of patients with HCC. Studies have shown that PI-3065, a small-molecule inhibitor of phosphatidylinositol 3-kinase delta, significantly inhibits solid breast cancer. However, its antitumor effects against HCC and the underlying mechanisms remain unclear. In the present study, we found that PI-3065 dose- and time-dependently reduced HCC cell viability and induced apoptosis while posing no obvious apoptotic toxicity in normal liver cells. Further mechanistic analysis showed that PI-3065 induced apoptosis mainly by inhibiting survivin protein expression, decreasing mitochondrial membrane potential, and promoting cytochrome C release. Simultaneously, PI-3065 markedly suppressed the colony formation, migration, and epithelial-mesenchymal transition abilities of HCC cells. Furthermore, transplantation of nude mice with HCC tumors showed that PI-3065 inhibits HCC tumor growth in vivo by targeting survivin. In summary, PI-3065 specifically inhibited survivin expression and exerted anti-HCC activity in vivo and in vitro, suggesting that it may serve as an effective antitumor drug for HCC treatment, which warrants further study.

This study aimed to determine the impact of co-infection of Clonorchis sinensis (CS) and hepatitis B virus (HBV) on the prognosis of patients with hepatocellular carcinoma (HCC) following hepatectomy.

The clinicopathological information of 946 patients with HCC following hepatectomy was retrospectively analyzed. The patients were divided into four groups depending on whether they had CS infection and/or HBV infection: double-negative group (infected with neither CS nor HBV), simple CS group (infected with only CS), simple HBV group (infected with only HBV), and double-positive group (co-infected with CS and HBV). Kaplan-Meier curves were used to evaluate the overall survival (OS) and recurrence-free survival (RFS), while log-rank tests were used to compare survival rates. Further, Cox regression was used to perform both univariate and multivariate survival analyses to identify variables linked to the prognosis of HCC.

The median overall survival (OS) and recurrence-free survival (RFS) in the double-positive, simple CS, simple HBV, and double-negative groups were 27 months and 9 months, 20 months and 7 months, 44 months and 12 months, and 42 months and 17 months, respectively. The double-positive group's 1-year, 3-year, and 5-year OS and RFS rates were 79.2% and 46.9%, 62.6% and 28.4%, 47.8%, and 12.2%, respectively. The simple CS group's 1-year, 3-year, and 5-year OS and RFS rates were 86.3% and 41.5%, 56.5% and 27.7%, 50.2%, and 18.5%, respectively. The simple HBV group's 1-year, 3-year, and 5-year OS and RFS rates were 89.8% and 56.0%, 72.5% and 30.5%, 63.8%, and 19.9%, respectively. The double-negative group's 1-year, 3-year, and 5-year OS and RFS rates were 91.5% and 62.3%, 76.1% and 32.9%, 64.0%, and 22.4%, respectively. Further, according to a Cox multivariate analysis, tumor size (> 5cm), Edmonson grade (III-IV), BCLC-C stage, and tumor satellite focus were independent risk factors for RFS and OS in patients with HCC.

Patients with HCC and Clonorchis sinensis infection experience a poor prognosis after hepatectomy, regardless of whether they are co-infected with HBV.

Hepatocellular carcinoma (HCC) is a global health burden with poor prognosis. Anoikis, a novel programmed cell death, has a close interaction with metastasis and progression of cancer. In this study, we aimed to construct a novel bioinformatics model for evaluating the prognosis of HCC based on anoikis-related gene signatures as well as exploring the potential mechanisms.

We downloaded the RNA expression profiles and clinical data of liver hepatocellular carcinoma from TCGA database, ICGC database and GEO database. DEG analysis was performed using TCGA and verified in the GEO database. The anoikis-related risk score was developed via univariate Cox regression, LASSO Cox regression and multivariate Cox regression, which was then used to categorize patients into high- and low-risk groups. Then GO and KEGG enrichment analyses were performed to investigate the function between the two groups. CIBERSORT was used for determining the fractions of 22 immune cell types, while the ssGSEA analyses was used to estimate the differential immune cell infiltrations and related pathways. The "pRRophetic" R package was applied to predict the sensitivity of administering chemotherapeutic and targeted drugs.

A total of 49 anoikis-related DEGs in HCC were detected and 3 genes (EZH2, KIF18A and NQO1) were selected out to build a prognostic model. Furthermore, GO and KEGG functional enrichment analyses indicated that the difference in overall survival between risk groups was closely related to cell cycle pathway. Notably, further analyses found the frequency of tumor mutations, immune infiltration level and expression of immune checkpoints were significantly different between the two risk groups, and the results of the immunotherapy cohort showed that patients in the high-risk group have a better immune response. Additionally, the high-risk group was found to have higher sensitivity to 5-fluorouracil, doxorubicin and gemcitabine.

The novel signature of 3 anoikis-related genes (EZH2, KIF18A and NQO1) can predict the prognosis of patients with HCC, and provide a revealing insight into personalized treatments in HCC.

Liver cancer is the sixth common cancer and forth cause of cancer-related death worldwide. Based on usually advanced stages of hepatocellular carcinoma (HCC) at the time of diagnosis, therapeutic options are limited and, in many cases, not effective, and typically result in the tumor recurrence with a poor prognosis. Radioimmunotherapy (RIT) offers a selective internal radiation therapy approach using beta or alpha emitting radionuclides conjugated with tumor-specific monoclonal antibodies (mAbs), or specific selective peptides. When compared to chemotherapy or radiotherapy, radiolabeled mAbs against cancer-associated antigens could provide a high therapeutic and exclusive radiation dose for cancerous cells while decreasing the exposure-induced side effects to healthy tissues. The recent advances in cancer immunotherapy, such as blockade of immune-checkpoint inhibitors (ICIs), has changed the landscape of cancer therapy, and the efficacy of different classes of immunotherapy has been tested in many clinical trials. Taking into account the use of ICIs in the liver tumor microenvironment, combined therapies with different approaches may enhance the outcome in the future clinical studies. With the development of novel immunotherapy treatment options in the recent years, there has been a great deal of information about combining the diverse treatment modalities to boost the effectiveness of immunomodulatory drugs. In this opinion review, we will discuss the recent advancements in RIT. The current status of immunotherapy and internal radiotherapy will be updated, and we will propose novel approaches for the combination of both techniques. Potential target antigens for radioimmunotherapy in Hepatocellular carcinoma (HCC). HCC radioimmunotherapy target antigens are the most specific and commonly accessible antigens on the surface of HCC cells. CTLA-4 ligand and receptor, TAMs, PD-1/PD-L, TIM-3, specific IEXs/TEXs, ROBO1, and cluster of differentiation antigens CD105, CD147 could all be used in HCC radioimmunotherapy. Abbreviations: TAMs, tumor-associated macrophages; CTLA-4, cytotoxic T-lymphocyte associated antigen-4; PD-1, Programmed cell death protein 1; PD-L, programmed death-ligand1; TIM-3, T-cell immunoglobulin (Ig) and mucin-domain containing protein-3; IEXs, immune cell-derived exosomes; TEXs, tumor-derived exosomes.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and the third leading cause of cancer-related deaths worldwide. HCC is characterized by insidious onset, and most patients are diagnosed at an advanced stage with a poor prognosis. Identification of biomarkers for HCC onset and progression is imperative to development of effective diagnostic and therapeutic strategies. CD147 is a glycoprotein that is involved in tumor cell invasion, metastasis and angiogenesis through multiple mechanisms. In this review, we describe the molecular structure of CD147 and its role in regulating HCC invasion, metastasis and angiogenesis. We highlight its potential as a diagnostic and therapeutic target for HCC.

Hepatocellular carcinoma (HCC) has poor prognosis and high mortality among gastrointestinal tumors because of its insidious onset and strong invasiveness. However, there was little understanding of their pathogenesis. The purpose of this study was to use bioinformatics analysis to identify genes associated with the immune microenvironment in HBV-related HCC and to develop new therapeutic targets to prevent and treat cancer.

RNA-seq data of HBV-related HCC cases were downloaded from TCGA-LIHC database. ESTIMATE and Deseq2 algorithms were used to screen out differentially expressed genes (DEGs). WGCNA was used to construct gene coexpression networks. In key modules, functional enrichment analysis was performed. Protein-protein interaction (PPI) was used to screen hub genes, and survival analysis was conducted to assess their prognostic significance. Following, we search for key genes differentially expressed between cancerous and paracancerous tissues in GSE136247 and GSE121248 datasets. Reveal the potential links between key genes in immune infiltration by using TIMER. Finally, in TCGA-LIHC database, integration of key genes with clinical data were used to further validate their correlation with prognosis.

In the cohort of HBV-related HCC patients, immune/stromal/ESTIMATE scores were not significantly associated with patient prognosis. After bioinformatics analysis, screening out five key genes was significantly related to the prognosis of HBV-related HCC. Downregulation of SLAMF1 and TRAF3IP3 suggested poor prognosis and was related to a variety of immune cell infiltration. Furthermore, compared with adjacent nontumor tissues, TRAF3IP3 and SLAMF1 were highly expressed in tumor tissues and were linked to tumor recurrences.

In conclusion, SLAMF1 and TRAF3IP3 were identified with higher expression in tumor tissues and associated with tumor recurrence. It will be a new research direction of tumor progress and treatment.

Liver cancer is one of the most common malignant tumors worldwide, it is ranked sixth in incidence and fourth in mortality. According to the distinct origin of malignant tumor cells, liver cancer is mainly divided into hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Since most cases are diagnosed at an advanced stage, the prognosis of liver cancer is poor. Tumor growth depends on the dynamic interaction of various cellular components in the tumor microenvironment (TME). As the most abundant components of tumor stroma, cancer-associated fibroblasts (CAFs) have been involved in the progression of liver cancer. The interplay between CAFs and tumor cells, immune cells, or vascular endothelial cells in the TME through direct cell-to-cell contact or indirect paracrine interaction, affects the initiation and development of tumors. Additionally, CAFs are not a homogeneous cell population in liver cancer. Recently, single-cell sequencing technology has been used to help better understand the diversity of CAFs in liver cancer. In this review, we mainly update the knowledge of CAFs both in HCC and CCA, including their cell origins, chemoresistance, tumor stemness induction, tumor immune microenvironment formation, and the role of tumor cells on CAFs. Understanding the context-dependent role of different CAFs subsets provides new strategies for precise liver cancer treatment.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and therapeutic options for advanced HCC are limited. Here, we observe that intestinal dysbiosis affects antitumor immune surveillance and drives liver disease progression towards cancer. Dysbiotic microbiota, as seen in Nlrp6-/- mice, induces a Toll-like receptor 4 dependent expansion of hepatic monocytic myeloid-derived suppressor cells (mMDSC) and suppression of T-cell abundance. This phenotype is transmissible via fecal microbiota transfer and reversible upon antibiotic treatment, pointing to the high plasticity of the tumor microenvironment. While loss of Akkermansia muciniphila correlates with mMDSC abundance, its reintroduction restores intestinal barrier function and strongly reduces liver inflammation and fibrosis. Cirrhosis patients display increased bacterial abundance in hepatic tissue, which induces pronounced transcriptional changes, including activation of fibro-inflammatory pathways as well as circuits mediating cancer immunosuppression. This study demonstrates that gut microbiota closely shapes the hepatic inflammatory microenvironment opening approaches for cancer prevention and therapy.

Hepatocellular carcinoma (HCC) arises from hepatocytes and accounts for 90% of primary liver cancer. According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2020, globally HCC is the sixth most common cancer and the third most common cause of cancer-related deaths. Reasons for HCC prognosis remaining dismal are that HCC is asymptomatic in its early stages, leading to late diagnosis, and it is markedly resistant to conventional chemo- and radiotherapy. Liver transplantation is the treatment of choice in early stages, while surgical resection, radiofrequency ablation (RFA) and trans arterial chemoembolization (TACE) are Food and Drug Administration (FDA)-approved treatments for advanced HCC. Additional first line therapy for advanced HCC includes broad-spectrum tyrosine kinase inhibitors (TKIs), such as sorafenib and lenvatinib, as well as a combination of immunotherapy and anti-angiogenesis therapy, namely atezolizumab and bevacizumab. However, these strategies provide nominal extension in the survival curve, cause broad spectrum toxic side effects, and patients eventually develop therapy resistance. Some common mutations in HCC, such as in telomerase reverse transcriptase (TERT), catenin beta 1 (CTNNB1) and tumor protein p53 (TP53) genes, are still considered to be undruggable. In this context, identification of appropriate gene targets and specific gene delivery approaches create the potential of gene- and immune-based therapies for the safe and effective treatment of HCC. This review elaborates on the current status of HCC treatment by focusing on potential gene targets and advanced techniques, such as oncolytic viral vectors, nanoparticles, chimeric antigen receptor (CAR)-T cells, immunotherapy, and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9), and describes future prospects in HCC treatment.

Hepatocellular carcinoma (HCC) is an aggressive cancer that typically develops in the setting of underlying cirrhosis of the liver. HCC commonly presents in advanced stages and if eligible orthotopic liver transplantation (OLT) and surgical resection/ablation remain as the only curative options. Prior to 2007, no systemic therapy was available that demonstrated an improvement in survival. Underlying cirrhosis and poor synthetic hepatic function provides a major challenge into effective systemic options contributing to the poor success of cytotoxic chemotherapy in HCC. The first drug to achieve clinical success was sorafenib despite the underwhelming overall survival of 3 months. Since then, other targeted therapies have shown modest benefit as well. Most recently, immunotherapy advances have come to the forefront in the management of HCC and combination therapy with immunotherapy and monoclonal antibodies have now surpassed sorafenib as first line treatment. This article will review the various approved and emerging therapies that have had a significant clinical impact and highlight the future directions and ongoing research that will hopefully translate into better outcomes in the treatment approach of advanced HCC.

Hepatocellular carcinoma (HCC) is a complex, life threatening and most common neoplasm in the world. HCC tumors are genetically and phenotypically heterogeneous and involve various molecular mechanisms and stimulation of several signaling pathways such as Vascular Endothelial Growth Factor, Epidermal Growth Factor Receptors (EGFR), Insulin growth factor, Ras/extracellular signal-stimulated kinase, mammalian goal of rapamycin (mTOR), c-mesenchymal-epithelial transition factor-1 (c-Met), Hedgehog, Wnt and apoptotic signaling. Lately, in patient's multi-kinase cascade blockers such as sorafenib, selumetinib and regorafenib have increased survival rate of progressive HCC. This development presents a step forward towards the therapy of liver cancer infection and attests that molecular systemic rehabilitations can be useful in HCC treatment. The development of these systemic therapeutic agents has further expanded the research area for surplus molecular mediators to auxiliary increase cure rate of patients. This article reviews the complete consideration of focus on cascades, current enduring clinical tests by means of HCC therapeutic mediators, and imminent prospects in the cure of HCC.