Hepatocellular Carcinoma Cell Proliferation Research Articles

ACYP2 functions as an innovative nano-therapeutic target to impede the progression of hepatocellular carcinoma by inhibiting the activity of TERT and the KCNN4/ERK pathway

An increasing body of evidence suggests that acylphosphatase-2 (ACYP2) polymorphisms are correlated with an increased susceptibility to a range of malignancies. Nevertheless, its potential functions, molecular mechanisms in hepatocellular carcinoma (HCC) and whether it can be act as a therapeutic target remain uninvestigated. Herein, ACYP2 was found to be lowly expressed in HCC and was negatively correlated with tumor size, tumor differentiation, microvascular invasion and the prognosis of HCC patients. Functional investigations revealed that overexpression of ACYP2 inhibited the proliferation and metastasis of HCC cells while promoting apoptosis; knockdown of ACYP2 had the exact opposite effect. Additionally, it was observed that ACYP2 was distributed in both the cytoplasm and nucleus of HCC cells. According to the mechanistic studies, the expression of potassium calcium-activated channel subfamily N member 4 (KCNN4) was negatively regulated by cytoplasmic ACYP2, resulting in the inhibition of K+ outflow and subsequent inactivation of the ERK pathway, which impeded the growth and metastasis of HCC. Furthermore, the activity of telomerase reverse transcriptase (TERT) was inhibited by nuclear ACYP2, leading to the reduction in length of telomeres and consequent reversal of HCC cell immortalization. Additionally, a novel targeted nanotherapy strategy was developed wherein the pcDNA-ACYP2 vector was encapsulated within polyetherimide nanoparticles (PEI/NPs), which were subsequently coated with HCC cell membranes (namely pcDNA/PEI/NPs@M). Safety and targeting characteristics abound for these nanocomposites, in both subcutaneous graft tumor models and orthotopic mouse models, they inhibited the progression of HCC by impeding TERT activity and the KCNN4/ERK pathway. In conclusion, our research identifies novel molecular mechanisms involving cytoplasmic and nuclear ACYP2 that inhibit the progression of HCC. Moreover, pcDNA/PEI/NPs@M represents a targeted therapeutic strategy for HCC that holds great promising.Graphical

TFCP2L1 drives stemness and enhances their resistance to Sorafenib treatment by modulating the NANOG/STAT3 pathway in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a prevalent and aggressive malignancy associated with high risks of recurrence and metastasis. Liver cancer stem cells (CSCs) are increasingly recognized as pivotal drivers of these processes. In our previous research, we demonstrated the involvement of TFCP2L1 in maintaining the pluripotency of embryonic stem cells. However, its relevance to liver CSCs remains unexplored. In this study, we report an inverse correlation between TFCP2L1 protein levels in HCC tissue and patient outcomes. The knockdown of TFCP2L1 significantly reduced HCC cell proliferation, invasion, metastasis, clonal formation, and sphere-forming capacity, while its overexpression enhanced these functions. In addition, experiments using a nude mouse model confirmed TFCP2L1’s essential role in liver CSCs’ function and tumorigenic potential. Mechanistically, we showed that TFCP2L1 promotes the stemness of CSCs by upregulating NANOG, which subsequently activates the JAK/STAT3 pathway, thereby contributing to HCC pathogenesis. Importantly, we identified a specific small molecule targeting TFCP2L1’s active domain, which, in combination with Sorafenib, sensitizes hepatoma cells to treatment. Together, these findings underscore TFCP2L1’s pathological significance in HCC progression, supporting its potential as a prognostic biomarker and therapeutic target in this disease.

STC2 knockdown inhibits cell proliferation and glycolysis in hepatocellular carcinoma through promoting autophagy by PI3K/Akt/mTOR pathway

BackgroundThe pathogenesis exploration and timely intervention of hepatocellular carcinoma (HCC) are crucial due to its global impact on human health. As a general tumor biomarker, stanniocalcin 2 (STC2), its role in HCC remains unclear. We aimed to analyze the effect and mechanism of STC2 on HCC. MethodsSTC2 expressions in HCC tissues and cell lines were measured. si-STC2 and oe-STC2 transfections were utilized to analyze how STC2 affected cell functions. Functional enrichment analysis of STC2 was performed by Gene Set Enrichment Analysis (GSEA). The regulatory mechanism of STC2 on HCC was investigated using 2-DG, 3-MA, IGF-1, Rap, and LY294002. The impact of STC2 on HCC progression in vivo was evaluated by the tumor formation experiment. ResultsHigher levels of STC2 expression were observed in HCC tissues and cell lines. Besides, STC2 knockdown reduced proliferation, migration, and invasion, while inducing cell apoptosis. Further analysis indicated a positive correlation between STC2 and glycolysis. STC2 knockdown inhibited glycolysis progression and down-regulated the expressions of PKM2, GLUT1, and HK2 in HCC cells. However, treatment with glycolysis inhibitor (2-DG) prevented oe-STC2 from promoting the growth of HCC cells. Additionally, STC2 knockdown up-regulated the levels of LC3II/LC3I and Beclin1 and reduced the phosphorylation of PI3K, AKT, and mTOR. Treatment with 3-MA, IGF-1, Rap, and LY294002 altered the function of STC2 on proliferation and glycolysis in HCC cells. Tumor formation experiment results revealed that STC2 knockdown inhibited HCC progression. ConclusionsSTC2 knockdown inhibited cell proliferation and glycolysis in HCC through the PI3K/Akt/mTOR pathway-mediated autophagy induction.

Overexpression of ZFP69B promotes hepatocellular carcinoma growth by upregulating the expression of TLX1 and TRAPPC9

BackgroundT-cell leukemia homeobox protein 1 (TLX1) has been revealed as a hub transcription factor in leukemia, while its function in hepatocellular carcinoma (HCC) has not been well described. Here, we investigated the regulation and function of TLX1 in HCC.MethodsTLX1 and its possible upstream and downstream molecules in HCC were identified using bioinformatics tools, which were then verified by RT-qPCR assay. CCK-8, wound healing, and Transwell invasion assays were performed to detect the effects of TLX1 knockdown on HCC cells. The interactions between TLX1 and trafficking protein particle complex subunit 9 (TRAPPC9) or Zinc finger protein 69 homolog B (ZFP69B) were further probed by ChIP and luciferase reporter assays. Rescue experiments were finally conducted in vitro and in vivo.ResultsTLX1 was highly expressed in HCC cells, and the knockdown of TLX1 led to reduced malignant biological behavior of HCC cells. TLX1 bound to the promoter region of TRAPPC9, thereby promoting TRAPPC9 expression. Overexpression of TRAPPC9 attenuated the effect of TLX1 reduction on suppressing malignant behavior of HCC cells. ZFP69B was also highly expressed in HCC cells and bound to the promoter region of TLX1 to induce TLX1 expression. Knockdown of ZFP69B inhibited the viability and mobility of HCC cells in vitro and tumor growth in vivo, and overexpression of TLX1 rescued this inhibition.ConclusionThese findings suggest that ZFP69B promotes the proliferation of HCC cells by directly upregulating the expression of TLX1 and the ensuing TRAPPC9.

Hepatic stellate cells promote hepatocellular carcinoma development by regulating histone lactylation: Novel insights from single-cell RNA sequencing and spatial transcriptomics analyses

This study evaluated the cellular heterogeneity and molecular mechanisms of hepatocellular carcinoma (HCC). Single cell RNA sequencing (scRNA-seq), transcriptomic data, histone lactylation-related genes were collected from public databases. Cell-cell interaction, trajectory, pathway, and spatial transcriptome analyses were executed. Differential expression and survival analyses were conducted. Western blot, Real-time reverse transcription PCR (qRT-PCR), and Cell Counting Kit 8 (CCK8) assay were used to detect the expression of αSMA, AKR1B10 and its target genes, and verify the roles of AKR1B10 in HCC cells. Hepatic stellate cell (HSC) subgroups strongly interacted with tumor cell subgroups, and their spatial distribution was heterogeneous. Two candidate prognostic genes (AKR1B10 and RMRP) were obtained. LONP1, NPIPB3, and ZSWIM6 were determined as AKR1B10 targets. Besides, the expression levels of AKR1B10 and αSMA were significantly increased in LX-2 + HepG2 and LX-2 + HuH7 groups compared to those in LX-2 group, respectively. sh-AKR1B10 significantly inhibited the HCC cell proliferation and change the expression of AKR1B10 target genes, Bcl-2, Bax, Pan Kla, and H3K18la at protein levels. Our findings unveil the pivotal role of HSCs in HCC pathogenesis through regulating histone lactylation.

Elevated choline drives KLF5-dominated transcriptional reprogramming to facilitate liver cancer progression.

An increase in the total choline-containing compound content is a common characteristic of cancer cells, and aberrant choline metabolism in cancer is closely associated with malignant progression. However, the potential role of choline-induced global transcriptional changes in cancer cells remains unclear. In this study, we reveal that an elevated choline content facilitates hepatocellular carcinoma (HCC) cell proliferation by reprogramming Krüppel-like factor 5 (KLF5)-dominated core transcriptional regulatory circuitry (CRC). Mechanistically, choline administration leads to elevated S-adenosylmethionine (SAM) levels, inducing the formation of H3K4me1 within the super-enhancer (SE) region of KLF5 and activating its transcription. KLF5, as a key transcription factor (TF) of CRC established by choline, further transactivates downstream genes to facilitate HCC cell cycle progression. Additionally, KLF5 can increase the expression of choline kinase-α (CHKA) and CTP:phosphocholine cytidylyltransferase (CCT) resulting in a positive feedback loop to promote HCC cell proliferation. Notably, the histone deacetylase inhibitor (HDACi) vorinostat (SAHA) significantly suppressed KLF5 expression and liver tumor growth in mice, leading to a prolonged lifespan. In conclusion, these findings highlight the epigenetic regulatory mechanism of the SE-driven key regulatory factor KLF5 conducted by choline metabolism in HCC and suggest a potential therapeutic strategy for HCC patients with high choline content.

HN1-mediated activation of lipogenesis through Akt-SREBP signaling promotes hepatocellular carcinoma cell proliferation and metastasis.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide, with more than 800,000 deaths each year, and its 5-year survival rate is less than 12%. The role of the HN1 gene in HCC has remained elusive, despite its upregulation in various cancer types. In our investigation, we identified HN1's heightened expression in HCC tissues, which, upon overexpression, fosters cell proliferation, migration, and invasion, unveiling its role as an oncogene in HCC. In addition, silencing HN1 diminished the viability and metastasis of HCC cells, whereas HN1 overexpression stimulated their growth and invasion. Gene expression profiling revealed HN1 silencing downregulated 379 genes and upregulated 130 genes, and suppressive proteins associated with the lipogenic signaling pathway networks. Notably, suppressing HN1 markedly decreased the expression levels of SREBP1 and SREBP2, whereas elevating HN1 had the converse effect. This dual modulation of HN1 affected lipid formation, hindering it upon HN1 silencing and promoting it upon HN1 overexpression. Moreover, HN1 triggers the Akt pathway, fostering tumorigenesis via SREBP1-mediated lipogenesis and silencing HN1 effectively curbed HCC tumor growth in mouse xenograft models by deactivating SREBP-1, emphasizing the potential of HN1 as a therapeutic target, impacting both external and internal factors, it holds promise as an effective therapeutic strategy for HCC.

USP26 as a hepatitis B virus-induced deubiquitinase primes hepatocellular carcinogenesis by epigenetic remodeling

Despite recent advances in systemic therapy for hepatocellular carcinoma (HCC), the prognosis of hepatitis B virus (HBV)-induced HCC patients remains poor. By screening a sgRNA library targeting human deubiquitinases, we find that ubiquitin-specific peptidase 26 (USP26) deficiency impairs HBV-positive HCC cell proliferation. Genetically engineered murine models with Usp26 knockout confirm that Usp26 drives HCC tumorigenesis. Mechanistically, we find that the HBV-encoded protein HBx binds to the promoter and induces the production of USP26, which is an X-linked gene exclusively expressed in the testis. HBx consequently promotes the association of USP26 with SIRT1 to synergistically stabilize SIRT1 by deubiquitination, which promotes cell proliferation and impedes cell apoptosis to accelerate HCC tumorigenesis. In patients with HBV-positive HCC, USP26 is robustly induced, and its levels correlate with SIRT1 levels and poor prognosis. Collectively, our study highlights a causative link between HBV infection, deubiquitinase induction and development of HCC, identifying a druggable target, USP26.

Thiostrepton as a Potential Therapeutic Agent for Hepatocellular Carcinoma.

Due to limited drug efficacy and drug resistance, it is urgent to explore effective anti-liver cancer drugs. Repurposing drugs is an efficient strategy, with advantages including reduced costs, shortened development cycles, and assured safety. In this study, we adopted a synergistic approach combining computational and experimental methods and identified the antibacterial drug thiostrepton (TST) as a candidate for an anti-liver cancer drug. Although the anti-tumor capabilities of TST have been reported, its role and underlying mechanisms in hepatocellular carcinoma (HCC) remain unclear. TST was found here to inhibit the proliferation of HCC cells effectively, arresting the cell cycle and inducing cell apoptosis, as well as suppressing the cell migration. Further, our findings revealed that TST induced mitochondrial impairment, which was demonstrated by destroyed mitochondrial structures, reduced mitochondria, and decreased mitochondrial membrane potential (MMP). TST caused the production of reactive oxygen species (ROS), and the mitochondrial impairment and proliferation inhibition of HCC cells were completely restored by the ROS scavenger N-acetyl-L-cysteine (NAC). Moreover, we discovered that TST induced mitophagy, and autophagy inhibition effectively promoted the anti-cancer effects of TST on HCC cells. In conclusion, our study suggests TST as a promising candidate for the treatment of liver cancers, and these findings provide theoretical support for the further development and potential application of TST in clinical liver cancer therapy.

Proteogenomic Identification and Analysis of KIF5B as a Prognostic Signature for Hepatocellular Carcinoma.

Metabolic disorders are significant risk factors for liver cancer, particularly Hepatocellular Carcinoma (HCC). However, the molecular genetic basis of metabolic reprogramming in the liver remains largely uncertain. This study aimed to investigate some novel prognostic biomarkers in HCC by using proteogenomic and transcriptomic analysis and explore the potential role of specific prognostic genes in HCC. Here, we have presented a proteogenomic analysis of 10 pairs of HCC. Protein co-expression and pathway analysis were performed to investigate the biological characteristics of HCC. Protein and mRNA expression profiles of multi-cohorts were integrated to detect novel prognostic protein markers of HCC. The carcinogenic roles of candidate prognostic markers were further evaluated by MTS assay, colony formation, monolayer wound healing assay, and xenograft models. A total of 2086 proteins with significantly different expressions were detected in HCC. Pathways related to oncogenic signaling and insulin-related metabolism have been found to be dysregulated and differentially regulated in HCC. We have identified the novel prognostic biomarkers, KIF5B, involved in liver metabolic reprogramming. The biomarkers were identified using multivariable COX regression analysis from two independent proteomic datasets (Fudan Cohort and our recruited cohort) and the TCGA mRNA database. Both the protein and mRNA up-regulation of KIF5B have been found to be associated with a poor clinical outcome in HCC. Insulin activated the protein expression of KIF5B in HCC. Knocking out KIF5B expression by sgRNA decreased the protein expression of FASN and SCD1 and the intracellular triglyceride concentration. Silencing KIF5B suppressed HCC cell proliferation and colony formation in vitro, as well as HCC growth in xenograft models. Our findings have suggested KIF5B protein to function as a novel prognostic biomarker in HCC. KIF5B expression has been found to activate the AKT/mTOR pathway and reprogram triglyceride metabolism, leading to HCC development. Targeting KIF5B may be an effective strategy in the clinical treatment of HCC.

Retraction Note: Ruthana date extract inhibited proliferation of human hepatocellular carcinoma (HepG2) cells by modulation of BAX gene.

Retraction Note: Ruthana date extract inhibited proliferation of human hepatocellular carcinoma (HepG2) cells by modulation of BAX gene.

Schistosoma japonicumsja-let-7 Inhibits the Growth of Hepatocellular Carcinoma Cells via Cross-Species Regulation of Col1α2.

Liver fibrosis, a critical precursor to hepatocellular carcinoma (HCC), results from chronic liver injury and significantly contributes to HCC progression. Schistosomiasis, a neglected tropical disease, is known to cause liver fibrosis; however, this process can be modulated by schistosome-derived miRNAs. Previous studies from our laboratory have demonstrated that Schistosoma japonicum extracellular vesicles (EVs) deliver sja-let-7 to hepatic stellate cells, leading to the inhibition of Col1α2 expression and alleviation of liver fibrosis. Given the well-documented antifibrotic and antiproliferative properties of the let-7 miRNA family, this study aims to preliminarily investigate the effects of the sja-let-7/Col1α2 axis on BALB/c mice and HCC cell line SNU387, providing a basis for the potential application of parasite-derived molecules in HCC therapy. In the present study, schistosome-induced fibrosis datasets were analyzed to identify the role of Col1α2 in extracellular matrix organization. Pan-cancer analysis revealed that Col1α2 is upregulated in various cancers, including HCC, with significant associations with immune cell infiltration and clinical parameters, highlighting its diagnostic importance. Functional assays demonstrated that transfection with sja-let-7 mimics significantly reduced Col1α2 expression, inhibited HCC cell proliferation, migration, and colony formation. These findings suggest that sja-let-7, by targeting Col1α2, has the potential to serve as a therapeutic agent in HCC treatment. This study indicates the pivotal role of Col1α2 in liver fibrosis and HCC, and the promising therapeutic application of helminth-derived miRNAs.

Exploring the mechanism of genistein in treating hepatocellular carcinoma through network pharmacology and molecular docking

Abstract Objectives Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, with treatment options limited and outcomes often poor, especially in advanced stages. This study explores the therapeutic potential of genistein, a soybean-derived isoflavone, on HCC using network pharmacology to uncover its multi-targeted anti-cancer mechanisms. Methods Potential targets of genistein were predicted using databases such as Super-PRED, PharmMapper, and SwissTargetPrediction. Abnormally expressed genes in HCC tissues were analyzed from TCGA and GEO datasets, with genes linked to the prognosis of HCC patients selected as potential therapeutic targets. GO and KEGG pathway enrichment analyses were conducted for both genistein’s targets and the HCC-related gene set. Key targets were identified through network analysis using Cytoscape software. Molecular docking was performed with Autodock to assess the binding affinity between genistein and these key targets. The therapeutic effects of genistein on HCC were validated through animal experiments and cell line studies. Results This study identified 343 potential targets for genistein in treating hepatocellular carcinoma (HCC). Analyses revealed enrichment in cell cycle regulation pathways through GO and KEGG assessments. Transcriptomic data from HCC datasets unveiled 184 potential therapeutic targets, emphasizing cell cycle regulation. Notably, 12 proteins were identified as targets of both genistein and HCC treatment. Molecular docking studies demonstrated genistein’s strong binding affinity with CDC25C and MELK. In vitro and in vivo validations affirmed genistein’s role in inhibiting HCC proliferation by inducing G2/M phase arrest. This study elucidates genistein’s multi-target mechanism in suppressing HCC cell proliferation, supporting its potential clinical application in HCC treatment. Conclusions This study demonstrates that genistein effectively suppresses the malignant growth of HCC by interfering with the transition from the G2 to M phase, revealing a multifaceted mechanism of action.

MiR-424-5p suppresses tumor growth and progression by directly targeting CHEK1 and activating cell cycle pathway in Hepatocellular Carcinoma

ObjectivesThe aim of this study is to elucidate the functional mechanism of the miRNA-424-5p/CHEK1 pathway in hepatocellular carcinoma (HCC), thereby offering novel insights for the development of targeted therapeutic strategies for HCC. MethodsWe employed a combination of bioinformatics analysis and data from the GEO to construct a regulatory network between miRNA and mRNA. Real-time quantitative polymerase chain reaction (RT-qPCR) was utilized to assess the expression levels of miR-424-5p and CHEK1. Protein expression of CHEK1 was determined using Western blot analysis. The targeting relationship between miR-424-5p and CHEK1 was validated through a dual-luciferase reporter assay. Furthermore, the effects of miR-424-5p on HCC cell proliferation, migration, and invasion were evaluated using the Cell Counting Kit-8 assay, wound healing assay, and Transwell invasion assay, respectively. Apoptosis of HCC cells was measured by flow cytometry. ResultsBioinformatics analysis revealed that miR-424-5p was significantly downregulated, while CHEK1 was upregulated respectively in GEO dataset. Furthermore, this inverse expression pattern was observed in both HCC tissues and cell lines. Specifically, downregulation of miR-424-5p was found to promote the proliferation, migration, and invasion of HCC cells, while also inhibiting their apoptosis. The dual-luciferase reporter assay confirmed a direct targeting relationship between miR-424-5p and CHEK1. Inhibition of miR-424-5p was shown to counteract the suppressive effects on HCC cell proliferation, migration, and invasion that result from CHEK1 silencing. Additionally, experimental verification indicated that the activation of the cell cycle pathway is implicated in the oncogenic function of miR-424-5p/CHEK1 in HCC. ConclusionsThe present study demonstrates that miR-424-5p exerts a suppressive effect on HCC cell proliferation, migration, and invasion by downregulating the expression of CHEK1. This finding may offer a theoretical foundation for improving the prognosis and developing novel therapeutic strategies for HCC patients.

Cancer-associated fibroblasts-derived exosomal ZNF250 promotes the proliferation, migration, invasion, and immune escape of hepatocellular carcinoma cells by transcriptionally activating PD-L1.

Hepatocellular carcinoma (HCC) is a lethal form of liver cancer, and the tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), plays a critical role in its progression. This study aimed to elucidate the mechanism by which CAF-derived exosomes regulate the development of HCC. The study employed quantitative real-time polymerase chain reaction for mRNA expression analysis and western blot analysis for protein expression detection. Chromatin immunoprecipitation assay and dual-luciferase reporter assay were performed to investigate the relationship between zinc finger protein 250 (ZNF250) and programmed cell death 1 ligand 1 (PD-L1). Transmission electron microscopy and western blot analysis were used to characterize the isolated exosomes. The transferability of CAF-derived exosomes and normal fibroblasts (NFs)-derived exosomes into HCC cells was analyzed using a green fluorescent labeling dye PKH67. Cell proliferation was assessed via a 5-Ethynyl-2'-deoxyuridine assay, while Transwell assays were conducted to evaluate cell migration and invasion. Flow cytometry was performed to measure cell apoptosis, while enzyme-linked immunosorbent assays were used to assess the levels of tumor necrosis factor-α and perforin. Finally, a xenograft mouse model was constructed to examine the effects of exosomes derived from ZNF250-deficient CAFs on the tumor properties of HCC cells. The study revealed increased expression of ZNF250 in HCC tissues and cells, with ZNF250 transcriptionally activating PD-L1 in HCC cells. ZNF250 expression was associated with HbsAg, clinical stage and tumor size of HCC patients. CAF-derived exosomal ZNF250 can regulate PD-L1 expression in HCC cells. Furthermore, exosomes derived from ZNF250-deficient CAFs inhibited the proliferation, migration, invasion, and immune escape of HCC cells by downregulating PD-L1 expression. Moreover, CAF-derived exosomal ZNF250 promoted tumor formation in vivo. These findings provide insights into the role of CAF-derived exosomes in the suppression of HCC development, highlighting the significance of ZNF250 and PD-L1 regulation in tumor progression.

Exploring the interplay between bisphenol A exposure, the immune microenvironment and hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) remains a formidable challenge in oncology, with its pathogenesis and progression influenced by myriad factors. Among them, the pervasive organic synthetic compound, bisphenol A (BPA), previously linked with various adverse health effects, has been speculated to play a role. This study endeavors to elucidate the complex interplay between BPA, the immune microenvironment of HCC, and the broader molecular landscape of this malignancy. A comprehensive analysis was undertaken using data procured from both The Cancer Genome Atlas and the Comparative Toxicogenomics Database. Rigorous differential expression analyses were executed, supplemented by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. In addition, single-sample gene set enrichment analysis, gene set enrichment analysis and gene set variation analysis were employed to reveal potential molecular links and insights. Immune infiltration patterns were delineated, and a series of in vitro experiments on HCC cells were conducted to directly assess the impact of BPA exposure. Our findings unveiled a diverse array of active immune cells and functions within HCC. Distinct correlations emerged between high-immune-related scores, established markers of the tumor microenvironment and the expression of immune checkpoint genes. A significant discovery was the identification of key genes simultaneously associated with immune-related pathways and BPA exposure. Leveraging these genes, a prognostic model was crafted, offering predictive insights into HCC patient outcomes. Intriguingly, in vitro studies suggested that BPA exposure could promote proliferation in HCC cells. This research underscores the multifaceted nature of HCC's immune microenvironment and sheds light on BPA's potential modulatory effects therein. The constructed prognostic model, if validated further, could serve as a robust tool for risk stratification in HCC, potentially guiding therapeutic strategies. Furthermore, the implications of the findings for immunotherapy are profound, suggesting new avenues for enhancing treatment efficacy. As the battle against HCC continues, understanding of environmental modulators like BPA becomes increasingly pivotal.

Ginsenoside Rh1 regulates the immune microenvironment of hepatocellular carcinoma via the glucocorticoid receptor

ObjectiveGinsenoside Rh1 (G-Rh1) has been confirmed to inhibit the growth of breast cancer and colon cancer, but its therapeutic effect on hepatocellular carcinoma (HCC) is unclear. This study investigates the therapeutic effect of G-Rh1 on HCC as well as the underlying mechanism. MethodsBioinformatics methods were used to analyze glucocorticoid receptor (GR) expression and the tumor microenvironment in HCC tissues from HCC patients. The effect of G-Rh1 on HCC cells was investigated in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. The therapeutic effect of G-Rh1 was investigated in vivo using subcutaneous transplantation models in C57BL/6J and nude mice. Additionally, the proportion of infiltrating immune cells in tumors was analyzed using flow cytometry, the GR and major histocompatibility complex class-I (MHC-I) expression of HCC cells after G-Rh1 treatment was analyzed using Western blotting, and G-Rh1-treated Hepa1-6 cells were cocultured with bone marrow-derived dendritic cells and B3Z T cells to further analyze the ability of G-Rh1 to induce dendritic cell (DC) maturation and CD8+ T cell activation. ResultsGR expression was upregulated in HCC tissues, and high GR expression was associated with a worsened immune microenvironment. In vitro studies showed that G-Rh1 had no significant effect on the proliferation of HCC cells, while in vivo studies showed that G-Rh1 exerted antitumor effects in C57BL/6J mice but not in nude mice. Further research revealed that G-Rh1 ameliorated the immunosuppressive tumor microenvironment, thereby enhancing the antitumor effects of lenvatinib by increasing the infiltration of CD8+ T cells, mature DCs, and MHC-I-positive cells. MHC-I was upregulated by G-Rh1 via GR suppression. Moreover, overexpression of GR abolished the G-Rh1-mediated promotion of MHC-I expression in Huh7 cells, as well as the maturation of DCs and the activation of CD8+ T cells. ConclusionG-Rh1 can regulate the immune microenvironment of HCC by targeting GR, thus increasing the antitumor effect of lenvatinib.Please cite this article as: Wang XH, Fu YL, Xu YN, Zhang PC, Zheng TX, Ling CQ, Feng YL. Ginsenoside Rh1 regulates the immune microenvironment of hepatocellular carcinoma via the glucocorticoid receptor. J Integr Med. 2024; Epub ahead of print.

ZDHHC20 Activates AKT Signaling Pathway to Promote Cell Proliferation in Hepatocellular Carcinoma.

Liver cancer is the sixth most common cancer worldwide, and hepatocellular carcinoma (HCC) presents one of the most challenging global health issues. ZDHHC20, a member of the ZDHHC palmitoyltransferase (ZDHHC-PAT) family, is involved in a reversible lipid modification known as palmitoylation, which contributes to the occurrence and progression of various tumors. However, the specific mechanisms underlying the involvement of ZDHHC20 in this process are unclear. The effects of both ZDHHC20 knockdown and overexpression on hepatocellular carcinoma cell proliferation were evaluated using PCR, Western blotting, CCK-8 assay, colony formation assay, cell cycle analysis, apoptosis analysis, and EDU assay. The TCGA-LIHC dataset was analyzed bioinformatically, and the phosphorylation level of PI3K and AKT in SK-Hep1 and Huh7 cells was assessed using Western blotting. Nude mouse subcutaneous xenograft experiments were conducted to evaluate the effects of different treatment conditions on mouse tumor growth. ZDHHC20 knockdown inhibited cell proliferation and promoted apoptosis, while overexpression of ZDHHC20 promoted cell proliferation and inhibited apoptosis. Knockdown of ZDHHC20 also decreased phosphorylation of PI3K and AKT in HCC, whereas overexpression of ZDHHC20 increased phosphorylation of PI3K and AKT. The PI3K-AKT pathway inhibitors, LY294002 and MK2206, effectively inhibited the promotional effects of ZDHHC20 on the proliferation and growth of HCC. High expression of ZDHHC20 promotes the proliferation and tumor growth of HCC by activating the PI3K-AKT signaling pathway. The PI3K inhibitor LY294002 and the AKT inhibitor MK2206 inhibit the promotional effects of ZDHHC20 on the proliferation of HCC and the growth of tumors.

Expression Characteristics, Immune Signature, and Prognostic Value of the SOCS Family Identified by Multiomics Integrative Analysis in Liver Cancer.

Hepatocellular carcinoma (HCC) is a prevalent malignancy with a high mortality rate worldwide. Suppressor of cytokine signaling (SOCS) family members play important roles in the proliferation, metabolism, and immunity of HCC cells by regulating cytokines and growth factors. However, it remains uncertain whether the level of SOCS family members can affect the prognosis of HCC patients. This study aimed to comprehensively assess the role and mechanisms of SOCS family members in the development of HCC and to guide clinical selection. We investigated the expression levels of SOCS family genes in HCC patients and their associations with various clinicopathological characteristics. We also utilized a public database to analyze the changes in the expression, potential functions, transcription factors, and immune invasion of SOCS family members. Additionally, we examined the prognostic value of the SOC family for HCC and its correlation with the SOC family and ferroptosis-related genes. This study revealed that the expression of SOCS2-7, and CISH was downregulated in HCC. The SOCS4, SOCS5, and SOCS7 genes were associated with the clinicopathological features of HCC patients. SOCS family genes are mainly related to the PIK3R3, GHR, and TNS4 pathways. Additionally, this study revealed that STAT3, PPAR-gamma 2, and IRF-2 are important transcription factors that regulate SOCS family members. The expression levels of SOCS family members are closely related to immune infiltration in liver cancer. The study also indicated that SOCS2 and SOCS4 are risk-related genes for predicting the prognosis of patients with liver cancer. Finally, this study suggested that the SOCS2 gene may be involved in the development and progression of HCC. Our study enhances the current understanding of SOCS gene function in liver cancer and can help clinicians select appropriate drugs and predict the prognosis of HCC patients.

Regulation of KIF23 by miR-107 controls replicative tumor cell fitness in mouse and human hepatocellular carcinoma

Regulation of KIF23 by miR-107 controls replicative tumor cell fitness in mouse and human hepatocellular carcinoma