Therapeutic Strategy For Hepatocellular Carcinoma Research Articles

Natural Product Auraptene Targets SLC7A11 for Degradation and Induces Hepatocellular Carcinoma Ferroptosis.

The natural product auraptene can influence tumor cell proliferation and invasion, but its effect on hepatocellular carcinoma (HCC) cells is unknown. Here, we report that auraptene can exert anti-tumor effects in HCC cells via inhibition of cell proliferation and ferroptosis induction. Auraptene treatment induces total ROS and lipid ROS production in HCC cells to initiate ferroptosis. The cell death or cell growth inhibition of HCC cells induced by auraptene can be eliminated by the ROS scavenger NAC or GSH and ferroptosis inhibitor ferrostatin-1 or Deferoxamine Mesylate (DFO). Mechanistically, the key ferroptosis defense protein SLC7A11 is targeted for ubiquitin-proteasomal degradation by auraptene, resulting in ferroptosis of HCC cells. Importantly, low doses of auraptene can sensitize HCC cells to ferroptosis induced by RSL3 and cystine deprivation. These findings demonstrate a critical mechanism by which auraptene exhibits anti-HCC effects via ferroptosis induction and provides a possible therapeutic strategy for HCC by using auraptene or in combination with other ferroptosis inducers.

AXL inhibition prevents RPA2/CHK1-mediated homologous recombination to increase PARP inhibitor sensitivity in hepatocellular carcinoma

Homologous recombination defects (HRD) render cells fail to repair DNA double-strand break (DSB), which causes synthetic lethality in these cells with punch by poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). Here, we reveal a receptor tyrosine kinase, AXL, whose inhibition leads to HRD in hepatocellular carcinoma (HCC) cells. AXL is upregulated in HCC tumors, which is positively correlated with low survival rates. AXL knockdown or AXL inhibition by bemcentinib reduces HR efficiency in HCC cells, and AXL plays its role in HR repair through its kinase activity. Furthermore, we find that AXL interacts with RPA2, enhancing the recruitment of RPA2 to DNA damage sites. Mechanistically, AXL promotes the tyrosinization of RPA2 at tyrosine 9, promoting the phosphorylation of CHK1, thereby strengthens the HR repair ability in HCC cells to resist DNA damage. In conclusion, our results reveal that AXL is a promising therapeutic biomarker for HCC patients, and present that targeting AXL-RPA2-CHK1 pathway together with PARP inhibitor will be effective therapeutic strategy in HCC.

Exploring potential therapeutic strategy for hepatocellular carcinoma and COVID-19 using bioinformatics analysis

BackgroundHepatocellular carcinoma (HCC) constitutes an important contributor to fatalities. Coronavirus disease 2019 (COVID-19) frequently presents with complications such as respiratory distress, systemic inflammatory responses, and damage to various organs. Several studies have investigated the relationship between COVID-19 and mortality in patients with liver cancer, but there are few research on the relationship between them. This study is to explore the correlation between the two diseases and drugs treating them.MethodsThe Gene Expression Omnibus (GEO) database provides gene datasets of COVID-19 patients and HCC patients. Through differential gene analysis and weighted gene co-expression network analysis, we determined 223 genes represented in HCC and COVID-19. We then used functional annotation, protein–protein interaction network construction, predictive model development and verification, prognostic value analysis, and miRNA–gene network construction. Besides, we created a drug–hub–gene network by predicting possible medications that interact with hub genes using the Drug–Gene Interaction Database (DGIdb). Ultimately, we applied immunohistochemistry to ascertain the hub genes expression.ResultsThis study revealed that eight core genes (RRM2, TPX2, DTL, CDT1, TYMS, CDCA5, CDC25C, and HJURP) co-existed in both HCC and COVID-19 and were differentially expressed in both HCC and normal tissues.CDC25C, RRM2, CDCA5, and HJURP had diagnostic value (AUC > 0.8) and prognostic value (adjusted P-value < 0.05). Genome enrichment analysis indicated that eight genes may function in liver cancer through engagement in the cell cycle, DNA replication, etc. In liver cancer samples, these genes were significantly and adversely associated with plasma cells while RRM2 was positively associated with neutrophil and NK cell activation and with dendritic cell resting. Using the miRNAnet database and DGIdb, 9 transcription factors, 7 miRNAs, and 51 drugs or molecular compounds were predicted to interact with the hub genes. Finally, RRM2 expression showed significant variation in clinical specimens, and analysis of the association of RRM2 with immunomodulators indicated that RRM2 was closely connected to MICB and CD276.ConclusionsOur study revealed several metabolic genes related to HCC and COVID-19. Moreover, potential drugs related to central genes were predicted. These findings may provide new ideas for treating COVID-19 and HCC.

Anlotinib potentiates anti-PD1 immunotherapy via transferrin receptor-dependent CD8+ T-cell infiltration in hepatocellular carcinoma.

The therapeutic potential of immune checkpoint blockade (ICB) extends across various cancers; however, its effectiveness in treating hepatocellular carcinoma (HCC) is frequently curtailed by both inherent and developed resistance. This research explored the effectiveness of integrating anlotinib (a broad-spectrum tyrosine kinase inhibitor) with programmed death-1 (PD-1) blockade and offers mechanistic insights into more effective strategies for treating HCC. Using patient-derived organotypic tissue spheroids and orthotopic HCC mouse models, we assessed the effectiveness of anlotinib combined with PD-1 blockade. The impact on the tumour immune microenvironment and underlying mechanisms were assessed using time-of-flight mass cytometry, RNA sequencing, and proteomics across cell lines, mouse models, and HCC patient samples. The combination of anlotinib with an anti-PD-1 antibody enhanced the immune response against HCC in preclinical models. Anlotinib remarkably suppressed the expression of transferrin receptor (TFRC) via the VEGFR2/AKT/HIF-1α signaling axis. CD8+ T-cell infiltration into the tumour microenvironment correlated with low expression of TFRC. Anlotinib additionally increased the levels of the chemokine CXCL14, crucial for attracting CD8+ T cells. CXCL14 emerged as a downstream effector of TFRC, exhibiting elevated expression following the silencing of TFRC. Importantly, low TFRC expression was also associated with a better prognosis, enhanced sensitivity to combination therapy, and a favourable response to anti-PD-1 therapy in patients with HCC. Our findings highlight anlotinib's potential to augment the efficacy of anti-PD-1 immunotherapy in HCC by targeting TFRC and enhancing CXCL14-mediated CD8+ T-cell infiltration. This study contributes to developing novel therapeutic strategies for HCC, emphasizing the role of precision medicine in oncology. Synergistic effects of anlotinib and anti-PD-1 immunotherapy demonstrated in HCC preclinical models. Anlotinib inhibits TFRC expression via the VEGFR2/AKT/HIF-1α pathway. CXCL14 upregulation via TFRC suppression boosts CD8+ T-cell recruitment. TFRC emerges as a potential biomarker for evaluating prognosis and predicting response to anti-PD-1-based therapies in advanced HCC patients.

Pregnane X receptor (PXR) deficiency promotes hepatocarcinogenesis via induction of Akr1c18 expression and prostaglandin F2α (PGF2α) levels

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, plays a critical role in the metabolism of endogenous and exogenous substances in the liver. Here, we investigate whether PXR plays a role in pathogenesis of HCC. We show that liver tumors were developed in diethylnitrosamine (DEN)-treated in PXR knockout (KO) mice. Hepatic levels of prostaglandin F2α (PGF2α) and aldo–keto reductase family 1 member C18 (Akr1c18), a prostaglandin synthase of catalyzing reduction of PGH2 to PGF2α, were significantly elevated in DEN-treated PXR KO mice. Hepatic mRNA levels of alpha fetoprotein (AFP), cyclin D1 (Ccnd1), fibroblast growth factor 21 (FGF21), and inflammatory cytokine interleukin 6 (IL-6) were significantly increased in DEN-treated PXR KO mice. Other members of Akr1c family, liver metabolizing enzymes including Cyp1a2, Cyp2b10 and Cyp3a11, and bile acid synthesis enzyme Cyp7a1 mRNA levels were significantly decreased in DEN-treated PXR KO mice. Our findings revealed that PXR deficiency promoted DEN-induced HCC in mice via induction of Akr1c18 expression and PGF2α levels and the increased PGF2α levels synthetized by Akr1c18 enhanced hepatocytes proliferation and induced inflammatory cytokine production, which accelerated liver tumor development after DEN treatment, suggesting that PXR deficiency may create a microenvironment that is more prone to DEN-induced liver tumors and targeting PXR and Akr1c18 to reduce PGF2α biosynthesis may be a potential and novel therapeutic strategy for HCC.

Lipid Nanoparticles as a Platform for miRNA and siRNA Delivery in Hepatocellular Carcinoma.

Liver cancer is the sixth most common cancer and the fourth leading cause of death worldwide. Hepatocellular carcinoma (HCC) comprises 75-80% of liver cancer cases. Therapeutic strategies for HCC are available and have been shown to prolong survival but not treat HCC. Gene expression and regulation are responsible for the pathogenesis and progression of HCC. Altering these genetic networks can impact cellular behaviors and in turn cure HCC. Single-stranded and double-stranded non-coding ribonucleic acid known as microRNA and small interfering RNA, respectively have been investigated as possible therapeutic options. Currently, efficient delivery systems that ensure cell-specific targeting and efficient transfection into tumor cells are still under investigation. Viral vectors have been studied extensively, but immunogenicity hinders their use as delivery systems. Non-viral vectors which include inorganic, lipid, or polymeric nanoparticles are promising delivery systems. However, there are a lot of challenges during the formulation of such systems to ensure efficient and specific delivery. In vitro and in vivo studies have investigated different LNPs to deliver miRNA or siRNA. In this review, we highlight the role of LNPs as a delivery system for miRNA and siRNA in HCC in addition to the latest results achieved using this approach.

Antiproliferative Activity of N-Acylhydrazone Derivative on Hepatocellular Carcinoma Cells Involves Transcriptional Regulation of Genes Required for G2/M Transition.

Liver cancer is the second leading cause of cancer-related death in males. It is estimated that approximately one million deaths will occur by 2030 due to hepatic cancer. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer subtype and is commonly diagnosed at an advanced stage. The drug arsenal used in systemic therapy for HCC is very limited. Multikinase inhibitors sorafenib (Nexavar®) and lenvatinib (Lenvima®) have been used as first-line drugs with modest therapeutic effects. In this scenario, it is imperative to search for new therapeutic strategies for HCC. Herein, the antiproliferative activity of N-acylhydrazone derivatives was evaluated on HCC cells (HepG2 and Hep3B), which were chemically planned on the ALL-993 scaffold, a potent inhibitor of vascular endothelial growth factor 2 (VEGFR2). The substances efficiently reduced the viability of HCC cells, and the LASSBio-2052 derivative was the most effective. Further, we demonstrated that LASSBio-2052 treatment induced FOXM1 downregulation, which compromises the transcriptional activation of genes required for G2/M transition, such as AURKA and AURKB, PLK1, and CDK1. In addition, LASSBio-2052 significantly reduced CCNB1 and CCND1 expression in HCC cells. Our findings indicate that LASSBio-2052 is a promising prototype for further in vivo studies.

Increased expression of long non-coding RNA FIRRE promotes hepatocellular carcinoma by HuR-CyclinD1 axis signaling

There is a critical need to understand the disease processes and identify improved therapeutic strategies for hepatocellular carcinoma (HCC). The long noncoding RNAs (lncRNAs) display diverse effects on biological regulations. The aim of this study was to identify a lncRNA as a potential biomarker of HCC and investigate the mechanisms by which the lncRNA promotes HCC progression using human cell lines and in vivo. Using RNA-Seq analysis, we found that lncRNA FIRRE was significantly upregulated in hepatitis C virus (HCV) associated liver tissue and identified that lncRNA FIRRE is significantly upregulated in HCV associated HCC compared to adjacent non-tumor liver tissue. Further, we observed that FIRRE is significantly upregulated in HCC specimens with other etiologies, suggesting this lncRNA has a potential to serve as an additional biomarker for HCC. Overexpression of FIRRE in hepatocytes induced cell proliferation, colony formation, and xenograft tumor formation as compared to vector transfected control cells. Using RNA pull-down proteomics, we identified HuR as an interacting partner of FIRRE. We further showed that the FIRRE-HuR axis regulates cyclin D1 expression. Our mechanistic investigation uncovered that FIRRE is associated with an RNA binding protein HuR for enhancing hepatocyte growth. Together, these findings provide molecular insights into the role of FIRRE in HCC progression.

Chemokine CCL21 determines immunotherapy response in hepatocellular carcinoma by affecting neutrophil polarization

BackgroundThe efficacy of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) is poor and great heterogeneity among individuals. Chemokines are highly correlated with tumor immune response. Here, we aimed to identify an effective chemokine for predicting the efficacy of immunotherapy in HCC.MethodsChemokine C‐C motif ligand 21 (CCL21) was screened by transcriptomic analysis in tumor tissues from HCC patients with different responses to ICIs. The least absolute shrinkage and selection operator (LASSO) regression analysis was conducted to construct a predictive nomogram. Neutrophils in vitro and HCC subcutaneous tumor model in vivo were applied to explore the role of CCL21 on the tumor microenvironment (TME) of HCC.ResultsTranscriptome analysis showed that CCL21 level was much higher in HCC patients with response to immunotherapy. The predictive nomogram was constructed and validated as a classifier. CCL21 could inhibit N2 neutrophil polarization by suppressing the activation of nuclear factor kappa B (NF-κB) pathway. In addition, CCL21 enhanced the therapeutic efficacy of ICIs.ConclusionCCL21 may serve as a predictive biomarker for immunotherapy response in HCC patients. High levels of CCL21 in TME inhibit immunosuppressive polarization of neutrophils. CCL21 in combination with ICIs may offer a novel therapeutic strategy for HCC.

Current Trends on the Involvement of Zinc, Copper, and Selenium in the Process of Hepatocarcinogenesis.

Numerous nutritional factors increase the risk of hepatocellular carcinoma (HCC) development. The dysregulation of zinc, copper, and selenium homeostasis is associated with the occurrence of HCC. The impairment of the homeostasis of these essential trace elements results in oxidative stress, DNA damage, cell cycle progression, and angiogenesis, finally leading to hepatocarcinogenesis. These essential trace elements can affect the microenvironment in HCC. The carrier proteins for zinc and copper and selenium-containing enzymes play important roles in the prevention or progression of HCC. These trace elements enhance or alleviate the chemosensitivity of anticancer agents in patients with HCC. The zinc, copper, or selenium may affect the homeostasis of other trace elements with each other. Novel types of cell death including ferropotosis and cupropotosis are also associated with hepatocarcinogenesis. Therapeutic strategies for HCC that target these carrier proteins for zinc and copper or selenium-containing enzymes have been developed in in vitro and in vivo studies. The use of zinc-, copper- or selenium-nanoparticles has been considered as novel therapeutic agents for HCC. These results indicate that zinc, copper, and selenium may become promising therapeutic targets in patients with HCC. The clinical application of these agents is an urgent unmet requirement. This review article highlights the correlation between the dysregulation of the homeostasis of these essential trace elements and the development of HCC and summarizes the current trends on the roles of these essential trace elements in the pathogenesis of hepatocarcinogenesis.

OTUB1 accelerates hepatocellular carcinoma by stabilizing RACK1 via its non-canonical ubiquitination

BackgroundDysregulated ubiquitination modification occupies a pivotal role in hepatocellular carcinoma (HCC) tumorigenesis and progression. The ubiquitin aldehyde binding 1 (OTUB1) was aberrantly upregulated and exhibited the pro-tumorigenic function in HCC. However, the underlying mechanisms and responsible targets of OTUB1 remain unclear.MethodsFirst, bioinformatics analysis, western blot and immunohistochemistry staining were applied to analyze OTUB1 expression in HCC specimens. Then, immunoprecipitation assay-tandem mass spectrometry (MS) combined with the gene set enrichment analysis (GSEA) was used to explore the downstream target of OTUB1. Co-immunoprecipitation and ubiquitination assays were used to identify the mechanisms involved. Finally, we explored the regulatory effect of MAZ on OTUB1 through ChIP-qPCR and dual-luciferase reporter assay.ResultsOTUB1 was broadly elevated in HCC tissues and promoted the proliferation and metastasis of HCC in vitro and in vivo. The receptor for activated C kinase 1 (RACK1) performed as a functional partner of OTUB1 and its hyperactivation was associated with aggressive development and other malignant features in HCC by activating oncogenes transcription. Mechanistically, OTUB1 directly bound to RACK1 at its C-terminal domain and decreased the K48-linked ubiquitination of RACK1 through its non-canonical suppression of ubiquitination activity, which stabilized RACK1 protein levels in HCC cells. Therefore, OTUB1 significantly increased multiple oncogenes expression and activated PI3K/AKT and FAK/ERK signaling in a RACK1-dependent manner in HCC. Moreover, the transcription factor MAZ upregulated OTUB1 expression through identifying a putative response element of OTUB1 promoter area.ConclusionsOur findings might provide a new therapeutic strategy for HCC by modifying the MAZ-OTUB1-RACK1 axis.

Mitochondria-targeted carrier-free nanoparticles based on dihydroartemisinin against hepatocellular carcinoma

Hepatocellular carcinoma is a common and fatal malignancy for which there is no effective systemic therapeutic strategy. Dihydroartemisinin (DHA), a derivative of artemisinin, has been shown to exert anti-tumor effects through the production of reactive oxygen species (ROS) and resultant mitochondrial damage. However, clinical translation is limited by several drawbacks, such as insolubility, instability and low bioavailability. Here, based on a nanomedicine-based delivery strategy, we fabricated mitochondria-targeted carrier-free nanoparticles coupling DHA and triphenylphosphonium (TPP), aiming to improve bioavailability and mitochondrial targeting. DHA-TPP nanoparticles can be passively delivered to the tumor site by enhanced penetration and retention and then internalized. Flow cytometry and Western blot analysis showed that DHA-TPP nanoparticles increased intracellular ROS, which increased mitochondrial stress and in turn upregulated the downstream Bcl-2 pathway, leading to apoptosis. In vivo experiments showed that DHA-TPP nanoparticles exhibited anti-tumor effects in a mouse model of hepatocellular carcinoma. These findings suggest carrier-free DHA-TPP nanoparticles as a potential therapeutic strategy for hepatocellular carcinoma.

Network medicine analysis for dissecting the therapeutic mechanism of consensus TCM formulae in treating hepatocellular carcinoma with different TCM syndromes.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Traditional Chinese Medicine (TCM) is widely utilized as an adjunct therapy, improving patient survival and quality of life. TCM categorizes HCC into five distinct syndromes, each treated with specific herbal formulae. However, the molecular mechanisms underlying these treatments remain unclear. We employed a network medicine approach to explore the therapeutic mechanisms of TCM in HCC. By constructing a protein-protein interaction (PPI) network, we integrated genes associated with TCM syndromes and their corresponding herbal formulae. This allowed for a quantitative analysis of the topological and functional relationships between TCM syndromes, HCC, and the specific formulae used for treatment. Our findings revealed that genes related to the five TCM syndromes were closely associated with HCC-related genes within the PPI network. The gene sets corresponding to the five TCM formulae exhibited significant proximity to HCC and its related syndromes, suggesting the efficacy of TCM syndrome differentiation and treatment. Additionally, through a random walk algorithm applied to a heterogeneous network, we prioritized active herbal ingredients, with results confirmed by literature. The identification of these key compounds underscores the potential of network medicine to unravel the complex pharmacological actions of TCM. This study provides a molecular basis for TCM's therapeutic strategies in HCC and highlights specific herbal ingredients as potential leads for drug development and precision medicine.

Exploiting gender-based biomarkers and drug targets: advancing personalized therapeutic strategies in hepatocellular carcinoma.

This review systematically examines gender differences in hepatocellular carcinoma (HCC), identifying the influence of sex hormones, genetic variance, and environmental factors on the disease's epidemiology and treatment outcomes. Recognizing the liver as a sexually dimorphic organ, we highlight how gender-specific risk factors, such as alcohol consumption and obesity, contribute differently to hepatocarcinogenesis in men and women. We explore molecular mechanisms, including the differential expression of androgen and estrogen receptors, which mediate diverse pathways in tumor biology such as cell proliferation, apoptosis, and DNA repair. Our analysis underscores the critical need for gender-specific research in liver cancer, from molecular studies to clinical trials, to improve diagnostic accuracy and therapeutic effectiveness. By incorporating a gender perspective into all facets of liver cancer research, we advocate for a more precise and personalized approach to cancer treatment that acknowledges gender as a significant factor in both the progression of HCC and its response to treatment. This review aims to foster a deeper understanding of the biological and molecular bases of gender differences in HCC and to promote the development of tailored interventions that enhance outcomes for all patients.

Rosehip Phytochemicals: A Computational Approach for Inhibiting Protein Kinase C Delta in Hepatocellular Carcinoma Treatment

Hepatocellular carcinoma is a primary liver cancer that is responsible for a significant number of cancer-related deaths worldwide. The development and progression of hepatocellular carcinoma is a complex process that involves various signalling pathways and molecular mechanisms. One such pathway is the protein kinase C delta pathway, which has been shown to play a critical role in the development and progression of hepatocellular carcinoma. Diagnosis of hepatocellular carcinoma employs different techniques including use of imaging tools and biomarkers such as alpha-fetoprotein, des-gamma-carboxyprothrombin, Glypican-3, and protein kinase C delta. protein kinase C delta is a member of the protein kinase C family of serine/threonine kinases that regulates various cellular processes, including cell proliferation and differentiation. Inhibition of protein kinase C delta has been proposed as a potential therapeutic strategy for hepatocellular carcinoma. Several protein kinase C delta inhibitors have been developed and tested in preclinical studies, and some have shown promising results in inhibiting hepatocellular carcinoma cell proliferation and inducing apoptosis. Rosehip of various Rosa species are rich in biologically active compound which possess therapeutic properties such as anti-inflammatory, anti-cancerous and hepato-protectant. This study employs various bioinformatic tools to assess molecular, biological, and pharmacological activity of phytochemicals present in rosehip against protein kinase C delta. In order to choose hit compounds, a number of factors are taken into account, including biological activity, binding affinity (docking score), pharmacokinetics, physiochemical characteristics, physicochemical properties, ADME/t properties, and biological activity. Six compounds (quercetin, luteolin, p-coumaric acid, gallic acid, ferulic acid, and caffeine) out of 14 docked compounds matched the requirements. These six phytochemicals might be studied in vitro and in vivo to determine their effectiveness and efficiency.

The Curative and Preventative Effects of Traditional Chinese Medicine on Ferroptosis of Hepatocellular Carcinoma

Primary hepatocellular carcinoma (HCC), a leading variant of primary liver cancer, holds significant global prevalence with strong implications for morbidity, mortality, and prognosis. Prevention and treatment paradigms are perpetually evolving in response to this malignancy. Ferroptosis, an iron and reactive oxygen species (ROS) dependant mode of cellular death, is catalyzed by an overabundance of lipid peroxidation, subsequently causing plasma membrane rupture. There is a unique interest in the relationship of ferroptosis with HCC development and progression, as compared to the interplay of apoptosis, autophagy, and necroptosis. Recent discoveries underscore the implications of ferroptosis in HCC evolution. Moreover, Traditional Chinese Medicine (TCM) and its respective active components display anti-HCC properties, a mechanism thought to be primarily attributed to the induction of ferroptosis in HCC cells. In support of preventive and therapeutic strategies for HCC, this manuscript provides a comprehensive review of the role of ferroptosis in HCC, its regulatory network, and the cutting-edge research focused on the treatment of HCC via ferroptosis modulation using TCM.

Genomic and immune landscape in hepatocellular carcinoma: Implications for personalized therapeutics.

Hepatocellular carcinoma (HCC) is a globally prevalent malignancy, marked by genetic heterogeneity and intricate tumor microenvironment interactions. In this study, we undertook a detailed single-cell analysis of six active HCC patients, highlighting strong correlations between gene expression levels and cellular characteristics. UMAP clustering revealed seven distinct cell categories with associated gene expressions. A divergence was observed in tumor cells into high and low cuproptosis groups, each associated with distinct pathways: oxidative stress for the high cuproptosis group and inflammatory and angiogenesis pathways for the low group. CellChat analysis on the TCGA-LIHC cohort displayed unique intercellular interactions among hepatocytes, T cells, and other cells, with pathways like COLLAGEN and VEGF being pivotal. Functional enrichment analyses exposed pathways enriched between cuproptosis groups, with KEGG emphasizing diseases like Parkinson's. COX survival analysis identified key prognostic genes, revealing distinct survival rates between risk groups in TCGA and GSE14520 cohorts. Mutation data highlighted missense mutations, with TTN, TP53, and CTNNB1 being the most mutated in HCC. Immune infiltration analysis via CIBERSORTx indicated differences between risk groups in NK cells, neutrophils, and other cells. Our drug sensitivity investigation showed significant correlations between model genes and drug responsiveness, emphasizing the importance of patient risk stratification for therapeutic approaches. Further, ATP6V1G1 was recognized in its role in apoptosis and migration in HCC cells. In conclusion, our findings illuminate the complexities of HCC progression, potential predictive genetic markers for drug response, and the pivotal role of ATP6V1G1, suggesting avenues for targeted therapeutic strategies in HCC.

Downregulation of Rab23 inhibits hepatocellular carcinoma by repressing SHH signaling pathway.

Hepatocellular carcinoma (HCC) is the sixth most common malignant tumors and the third leading cause of cancer-related death worldwide. As an oncogene, Rab23 has been shown to be significantly related to the growth and migration of hepatocellular carcinoma in both in vitro and in vivo studies, but its underlying mechanism remains obscure. In the present study, we examined the effect of inhibiting Rab23 expression on the pathological progression of HCC. The correlation between liver Rab23 gene expression and survival probability in human HCC patients was analyzed using the TCGA database and CPTAC database. Rab23 knockdown hepatocellular carcinoma cell line was generated through lentiviral transduction, then we established a nude HCC xenograft model by subcutaneously implanting the transfected cells. The analysis of gene and protein expression was carried out using Western blot or RT-qPCR, respectively. Flow cytometry analysis was used to detect the level of apoptosis. The expression levels of key proteins involved in the Sonic Hedgehog (SHH) signaling pathway were assessed. The results showed that HCC patients with low levels of hepatic Rab23 mRNA and protein had a better survival tendency than those with higher levels of Rab23. Cell proliferations were reduced and apoptosis levels were increased after Knocking down Rab23 in HCC cell lines. Furthermore, in vivo studies have demonstrated that suppression of the Rab23 gene results in decreased tumor size, proliferation rate, and reduced levels of SHH-related proteins Smoothened and GLI-1. The above results suggest that Rab23 is involved in the pathological progression of HCC as an important regulator of the SHH signaling pathway, which also provides an important research basis for new therapeutic strategies for HCC.

Induction of ferroptosis by artesunate nanoparticles is an effective therapeutic strategy for hepatocellular carcinoma

Artesunate (ART) has great value in the field of tumor therapy. Interestingly, in this study, we found that ART could obviously induce ferroptosis in hepatocellular carcinoma (HCC) cells, but its low water solubility and bioavailability limited its application potential. Hence, we synthesized ART-loaded mesoporous silica nanoparticles (MSNs) conjugated with folic acid (FA) (MSN-ART-FA) with tumor-targeting performance and assessed their characteristics. We evaluated the ability of MSN-ART and MSN-ART-FA to induce ferroptosis of hepatoma cells via testing levels of reactive oxygen species (ROS), Fe2+, malondialdehyde (MDA) and glutathione (GSH), observation of mitochondrial morphology, as well as the expression of key proteins in ferroptosis. The results showed that prepared MSN-ART and MSN-ART-FA could remarkedly improve the bioavailability of ART to enhance ferroptosis, thereby inhibiting cell proliferation, migration and invasion in vitro. Besides, MSN-ART-FA group displayed slower tumor growth and smaller tumor volumes than MSN-ART group in HepG2 xenograft mouse model. It provided a potential therapeutic option for HCC and expanded the horizon for the clinical treatment of other cancers.Graphical

A novel bispecific antibody as an immunotherapeutic agent in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains one of the most common and highly fatal malignancies in humans worldwide with increasing prevalence and limited therapeutic options. For many decades, many researchers have attempted to find effective curative methods for HCC and great strides have been made. GPC3 is overexpressed in HCC, but not in normal liver, making it a rational immunotherapeutic target for HCC. GC33, a humanized mAb directed against GPC3, is a safe and well-tolerated therapy choice for patients with HCC, which tested in a phase I trial in advanced HCC patients. Phase II trials of GC33 to evaluate its efficacy and safety in advanced or metastatic HCC, showed no significant differences in overall survival and progression-free survival compared with the placebo. Retrospective analysis indicates that high drug exposure and high CD16 expression may contribute to the clinical efficacy of GC33. Chugai Pharmaceutical has restarted its Phase I trial of GC33, continuing to explore its clinical value targeting GPC3 in solid tumors. To enhance the antitumor potency of GC33, we designed a GPC3/CD16A bispecific antibody (QDEB). In this study, we obtained QDEB at high purity and assessed its effectiveness in the therapy of HCC compared with GC33. In vitro cytotoxicity assays and in vivo experiments demonstrated that QDEB could enhance anti-tumor efficacy compared with GC33. CD16A activation and increased cytokines release were associated with higher anti-tumor activity. In conclusion, this bispecific antibody may possibly help develop new therapeutic strategies for HCC and develop new treatment options in the future.