Hepatocellular Carcinoma Proliferation Research Articles

CXCR7 promoted proliferation, migration and invasion in HCC Cells by inactivating Hippo-YAP signaling

BackgroundCXCR7 (ACKR3) has been well-supported as a promoter of growth and metastasis in hepatocellular carcinoma (HCC). Both CXCR7 and Hippo signaling play roles in organ development. We aimed to verify the involvement of Hippo-YAP signaling in CXCR7-regulated HCC proliferation, migration, and invasion.MethodsHCCLM3 cells were transfected with si-CXCR7, pcDNA-CXCR7, or related control RNA/empty vector. Cell proliferation was assessed using the Cell Counting Kit-8 (CCK-8), and mRNA and protein levels were measured via quantitative real-time PCR (qPCR) and Western blotting. Colony formation assays were conducted to evaluate proliferation capacity, and Transwell assays were used to assess invasion and migration. Transcriptome data from the TCGA-LIHC dataset were analyzed to investigate the potential effects of CXCR7 in HCC.Resultssi-CXCR7 inhibited cell proliferation in HCCLM3 cells, while pcDNA-CXCR7 promoted it. Migration and invasion were suppressed by si-CXCR7 but enhanced by pcDNA-CXCR7. Patients with higher CXCR7 expression in the TCGA-LIHC dataset had lower overall survival rates and increased gene transcription. The CXCR7-high expressing samples were characterized by the activation of several pathways, including PI3K-AKT signaling, calcium signaling, and the Hippo signaling pathway. si-CXCR7 reduced the relative protein levels of Gαq/11 and GαS while increasing phosphorylated LATS and phosphorylated YAP. Opposite trends in these proteins were observed with pcDNA-CXCR7. Finally, the inhibitory effects of si-CXCR7 on cell proliferation, migration, and invasion were reversed by the YAP inhibitor verteporfin.ConclusionWe suggest that CXCR7 promotes the growth and metastasis of HCC cells, at least in part, by inactivating the Hippo-YAP signaling pathway.

A deep learning model based on self-supervised learning for identifying subtypes of proliferative hepatocellular carcinoma from dynamic contrast-enhanced MRI

ObjectivesThis study employs dynamic contrast-enhanced MRI (DCE-MRI) to noninvasively predict the proliferative subtype of hepatocellular carcinoma (HCC). This subtype is marked by high tumor proliferation and aggressive clinical behavior. We developed a deep learning prediction model that employs a dynamic radiomics workflow and self-supervised learning (SSL). The model analyzes temporal and spatial patterns in DCE-MRI data to identify the proliferative subtype efficiently and accurately. Our goal is to improve diagnostic precision and guide personalized treatment planning.MethodsThis retrospective study included 381 HCC patiephonnts who underwent curative resection at two medical centers. The cohort was divided into the training (n = 220), internal (n = 93), and external (n = 68) test sets. A DL model was developed using DCE-MRI of the primary tumor. Class activation mapping was used to interpret HCC proliferation in HCC.ResultsThe pHCC-SSL model performed well in predicting HCC proliferation, with a training set AUC) of 1.00, an internal test set AUC of 0.91, and an external test set AUC of 0.94. Without SSL pre-training, the AUC for internal and external testing decreased to 0.81 and 0.80, respectively. The predictive performance of the derived model was superior to that of the current single-sequence model.ConclusionsThe pHCC-SSL model employs dynamic radiomics and a two-stage training approach to efficiently predict HCC proliferation from multi-sequence DCE-MRI, surpassing traditional single-stage models in accuracy and speed.Critical relevance statementOur study introduces the pHCC-SSL model, a self-supervised deep learning approach using DCE-MRI that enhances the diagnostic accuracy of HCC subtypes, significantly advancing clinical radiology by enabling personalized treatment strategies.Key PointsThe proposed model enables noninvasive identification of HCC with high proliferation and aggressive behavior.SSL improves lesion differentiation by reducing redundancy and enhancing feature diversity.Dynamic feature extraction captures vascular infiltration, aiding preoperative metastasis risk assessment.Graphical

CPDS Promotes Cell Apoptosis by Reducing the Translational Efficiency of BIRC3 mRNA in HCC.

Hepatocellular carcinoma (HCC) is one of the primary liver tumors with high incidence and mortality. RNA G-quadruplexes (rG4) are nucleic acid structures involved in gene expression and genome duplication. rG4 exerts its function by interacting with rG4-binding proteins. The carboxypyridostatin (cPDS), a specific ligand of rG4, are widely studied in numerous tumors. However, the role of cPDS in HCC and its regulatory mechanisms are not yet fully understood. Our study aimed to discuss the regulatory mode of cPDS on Baculoviral IAP Repeat Containing 3 (BIRC3) expression and its impact on proliferation, apoptosis, and other biologic functions in HCC. We conducted colony formation, CCK8, Edu incorporation, scratch healing, and cell spheroid formation assays to analyze the function of cPDS on cell proliferation and migration. Additionally, we explored the role of cPDS in regulating BIRC3 expression by Western blot and qRT-PCR. Furthermore, we evaluated the impact of BIRC3 on cell proliferation and subcutaneous tumor formation in nude mice. Finally, we analyzed the regulatory mechanisms of cPDS on cell apoptosis by Western blot, qRT-PCR, flow cytometry, and Annexin V-FITC staining. Our results demonstrated that cPDS inhibited HCC cells proliferation and migration. Moreover, cPDS elevated the mRNA level while inhibiting the protein expression of BIRC3 in HCC cells. Overexpression of BIRC3 significantly enhanced the proliferation of HCC cells. In the nude mice model, BIRC3 significantly increased the tumor volume and weight. Mechanistically, cPDS promoted cell apoptosis via inhibiting BIRC3-mediated anti-apoptotic effect. Our findings revealed a critical role of rG4 ligand cPDS in HCC progression and indicate that cPDS may be used for HCC treatment considering its tumor inhibitory properties by regulating cell apoptosis.

VRK1 promotes epithelial-mesenchymal transition in hepatocellular carcinoma mediated by SNAI1 via phosphorylating CHD1L

Vaccinia-related kinase 1 (VRK1) is involved in numerous cellular processes, including DNA repair, cell cycle and cell proliferation. However, its roles and molecular mechanism underlying the progression of hepatocellular carcinoma (HCC) are yet largely unexplored. Here, we demonstrated that VRK1 expression is elevated in HCC tumor tissues, which is associated with high tumor stage and poor prognosis in HCC patients. In vitro and in vivo experiments manifested that VRK1 overexpression significantly promotes cell proliferation, colony formation, migration and tumor growth of HCC by inducing epithelial-mesenchymal transition (EMT) program. Mechanistically, immunoprecipitation combined with mass spectrometry analysis determined that VRK1 interacts with CHD1L, which mediates the phosphorylation of CHD1L at serine 122 site. RNA-seq revealed that one of the key downstream target genes of VRK1 is SNAI1, by which VRK1 promotes EMT process and HCC progression. Furthermore, VRK1 upregulates SNAI1 expression through phosphorylating CHD1L. In conclusion, these findings suggested that VRK1/CHD1L/SNAI1 axis acts as a cancer-driving pathway to promote the proliferation and EMT of HCC, indicating that targeting VRK1 may be an attractive therapeutic strategy of HCC.

MEX3A promotes cell proliferation by regulating the RORA/β-catenin pathway in hepatocellular carcinoma.

MEX3A is a member of the human homologous gene MEX-3 family. It has been shown to promote cell proliferation and migration in various cancers, indicating its potential clinical significance. However, the role of MEX3A in hepatocellular carcinoma (HCC) remains largely unexplored, with limited reports available in the literature. To investigate expression and clinical significance of MEX3A in HCC and explore its potential role in tumor progression. We analyzed MEX3A mRNA expression in HCC and adjacent tissues using data from The Cancer Genome Atlas (TCGA). The correlation between MEX3A expression and overall survival (OS) was evaluated. Immunohistochemistry was performed on HCC surgical specimens to validate MEX3A expression and its association with clinical parameters, including hepatitis B virus (HBV) positivity, tumor differentiation and tumor size. Additionally, MEX3A knockdown HCC cell lines were constructed to explore the biological functions of MEX3A. Cell proliferation was assessed using cell counting kit-8 and clone formation assays, while cell cycle progression was analyzed by flow cytometry. The effects of MEX3A on the Wnt/β-catenin signaling pathway were examined by western blotting and immunofluorescence. Cell migration was evaluated using scratch and Transwell assays. Finally, the role of the transcription factor RORA in mediating MEX3A effects was explored by silencing RORA and analyzing its impact on cell proliferation and protein expression. TCGA data analysis revealed that MEX3A mRNA expression was significantly higher in HCC tissues compared to adjacent tissues. Higher MEX3A expression was associated with poorer OS. These findings were validated in HCC surgical specimens. Immunohistochemistry confirmed elevated MEX3A expression in HCC tissues and showed positive correlations with Ki-67 and vimentin levels. MEX3A expression was closely related to HBV positivity, tumor differentiation and tumor size. Mechanistic studies demonstrated that MEX3A knockdown inhibited cell proliferation and cell cycle progression, as shown by reduced expression of β-catenin, c-Myc and cyclin D1. Additionally, MEX3A knockdown inhibited the nuclear entry of β-catenin, thereby suppressing the activation of downstream oncogenic pathways. MEX3A depletion significantly reduced the migratory ability of HCC cells, likely through downregulation of the epithelial-mesenchymal transition pathway. Transcription factor analysis identified RORA as a potential mediator of MEX3A effects. Silencing RORA antagonized the effects of MEX3A on cell proliferation and the expression of β-catenin, c-Myc and cyclin D1. MEX3A promotes cell proliferation in HCC by regulating the RORA/β-catenin pathway. Our findings suggest that MEX3A could serve as a prognostic marker and therapeutic target for HCC.

SF3B4 regulates proliferation and apoptosis in hepatocellular carcinoma via alternative splicing and interaction with TRIM28 and SETD5

BackgroundSF3B4 encodes a core subunit of the U2-type spliceosome and is implicated in abnormal cell growth and tumorigenesis. However, its role in regulating gene expression and alternative splicing in hepatocellular carcinoma (HCC) remains inadequately understood.MethodsSF3B4 expression was downregulated in HCC cells, followed by high-throughput transcriptome sequencing to capture the transcriptomic changes induced by SF3B4. This approach facilitated the identification of potential targets regulated by SF3B4 at both the transcriptional and alternative splicing levels in HCC cells. Additionally, SF3B4-binding RNAs in Huh7 cells were identified through iRIP-seq. The RNA-seq data were subsequently analyzed to elucidate the molecular mechanisms by which SF3B4 affects gene expression and alternative splicing in HCC.ResultsDownregulation of SF3B4 promoted apoptosis and inhibited cell proliferation. In the RNA-seq data, the number of regulated alternative splicing events (RASE) significantly outnumbered the differentially expressed genes (DEGs), consistent with SF3B4’s role as a splicing factor that regulates a wide array of pre-mRNA splicing events. Furthermore, a total of 252 common RNA targets bound by SF3B4 were identified. Correlation analysis with RNA-seq data suggested that SF3B4 may bind to TRIM28, potentially modulating its mRNA expression levels. Additionally, SF3B4 may influence pre-mRNA alternative splicing by interacting with SETD5.ConclusionSF3B4 contributes to HCC progression by directly binding mRNAs and interacting with proteins, thereby regulating gene expression and alternative splicing.

Identification of telomere maintenance-driven molecular subtypes in hepatocellular carcinoma: implications for prognosis and targeted therapy via KPNA2

BackgroundTelomere maintenance (TM) plays a pivotal role in regulating the pathogenesis of hepatocellular carcinoma (HCC) and is crucial for defining the clinical characteristics of patients. Despite previous publications highlighting the correlation between individual TM-related genes and HCC, comprehensive exploration and systematic analysis of these genes are still lacking.MethodsThrough the analysis of transcriptome data, we identified two distinct clusters (termed telomere maintenance-associated clusters, or TCs) that exhibited marked heterogeneity in clinical traits and the tumor microenvironment. Following this, we conducted an exhaustive screening process to select 15 prognostic genes related to telomere maintenance and developed corresponding TM scores for these genes. Additionally, we rigorously validated the expression and oncogenic functions of karyopherin subunit alpha 2 (KPNA2) in both HCC tissues and cell lines.ResultsTC1 demonstrated a significant correlation with cellular differentiation and the fatty acid metabolism pathway, while also predicting a low tumor mutation burden (TMB) alongside favorable prognostic outcomes. In contrast, TC2 was intricately linked to TM, cell cycle regulation, and DNA repair. When examining the relationship between TMB and overall survival rates. Notably, substantial heterogeneity was observed among the various TCs. Furthermore, KPNA2 exhibited upregulation and has the potential to enhance HCC proliferation and migration.ConclusionIn summary, through the integration of bioinformatics and functional experimentation, we have delineated two distinct molecular classifications predicated on their association with TM-related genes in HCC. This groundbreaking discovery holds the potential to introduce innovative concepts and novel biomarkers into clinical practice.

Low-intensity pulsed ultrasound affects proliferation and migration of human hepatocellular carcinoma cells

PurposeLow-intensity pulsed ultrasound (LIPUS) is an effective ancillary treatment modality for various malignancies. However, the mechanisms underlying the role of LIPUS in cancer treatment have not been fully elucidated. We investigated the effects and underlying mechanism of LIPUS on the proliferation, apoptosis, migration, and invasion of hepatocellular carcinoma (HCC) cells.MethodsThe HCC cell lines SMMC7721 and HCCLM3 were exposed to 1 MHz LIPUS at intensities of 0.5, 1.0, 1.5 W/cm2 for 60 s. Cell morphology, viability, apoptosis, colony formation, migration, and invasion were assessed. Intracellular reactive oxygen species (ROS) levels and mitochondrial membrane potential were evaluated using a ROS assay kit and a JC-1 staining kit. Western blotting was performed to quantify changes in matrix metallopeptidases and epithelial-mesenchymal transition-related proteins. Orthotopic Hep3B-Luc tumor-bearing mice were treated with LIPUS at 1.5 W/cm2 or 0 W/cm2 and growth trend was measured.ResultsThe results showed that different intensities of ultrasound affected cellular activity, inhibited cell proliferation and cloning, facilitated intracellular cytoskeletal protein reorganization, and induced cell apoptosis, particularly at the intensity of 1.5 W/cm2, through the ROS/mitochondria pathway. LIPUS enhanced SMCC7721 and HCCLM3 cell migration and invasion in a dose-dependent manner by regulating matrix metallopeptidases and epithelial-mesenchymal transition-related proteins. In vivo experiments confirmed the inhibitory effect of LIPUS at 1.5 W/cm2 on tumor growth.ConclusionsAlthough LIPUS induced cell apoptosis and inhibited cell proliferation, it also promoted the invasion and metastasis of HCC cells under certain conditions, which was related to the regulation of matrix metallopeptidases and epithelial-mesenchymal transition-related proteins.

PET imaging of hepatocellular carcinoma with [124I]IV-14

BackgroundCurrently, positron emission tomography (PET) plays no clear role in clinical imaging and management of hepatocellular carcinoma (HCC). New radiotracers for new target(s) are needed for PET imaging of HCC. Uridine-cytidine kinase 2 (UCK2) is a rate-limiting enzyme of the pyrimidine salvage synthesis pathway to phosphorylate uridine and cytidine. Studies have demonstrated that UCK2 is overexpressed in many types of solid cancers including HCC and is associated with the poor prognosis and proliferation of HCC. This study reported PET imaging using a UCK2-specific radiotracer with a clinically relevant anima model of spontaneously occurring HCC in the woodchucks.MethodsThis study used 3′-(E)-(2-iodovinyl) uridine (IV-14), which is derived from a UCK2-selective antitumor agent 3′-(Ethynyl)uridine (EUrd), a cytotoxic ribonucleoside analogs of uridine. By radiolabeling IV-14 with Iodine-124 (124I), a UCK2-specific radiotracer [124I]IV-14 was obtained for PET imaging of UCK2. A naturally occurring woodchuck model of HCC following chronic viral hepatitis infection was used for PET imaging. Potassium iodide (KI) was tested in one of the three animals to block possible uptake of free 124I from de-iodination of [124I]IV-14.ResultsWe confirmed that UCK2 expression is higher in the woodchuck model of HCC than in the surrounding hepatic tissue, similar to human UCK2 that is highly expressed in human HCC. PET imaging with [124I]IV-14 showed a strong uptake in woodchuck HCC with low background uptake at one-hour post-injection. De-iodination did not seem to be an issue for PET imaging.ConclusionOur results demonstrate that UCK2 is a viable target for imaging HCC and has the potential for targeted endoradiotherapy of HCC.

Deletion of Tfap2a in hepatocytes and macrophages promotes the progression of hepatocellular carcinoma by regulating SREBP1/FASN/ACC pathway and anti-inflammatory effect of IL10

The transcription factor AP-2α plays a crucial role in the control of tumor development and progression, and suppresses the proliferation and migration of hepatocellular carcinoma (HCC). However, the detailed function and mechanisms of AP-2α in the pathogenesis of HCC are still elusive. In the current study, we investigated the role of AP-2α regulation in liver injury-mediated HCC development. Downregulation of Tfap2a expression was found in the livers of DEN/CCl4-induced fibrosis and HCC mouse model. Hepatocyte (Alb-Cre), hepatic stellate cell (HSC) (Lrat-Cre) and macrophage (LysM-Cre) specific Tfap2a knockout mice were generated, respectively. Conditional knockout of Tfap2a was able to promote hepatic steatosis in Tfap2aΔHep and Tfap2aΔMΦ mice, but not in Tfap2aΔHSC mice fed with normal chow. Tfap2aΔHep and Tfap2aΔMΦ mice treated with DEN/CCl4 for 6 months increased tumor burden compared to Tfap2a flox controls. Tfap2a-deleted macrophages or hepatocytes could enhance lipid droplet (LD) accumulation in hepatocytes. Mechanistically, AP-2α binds to the promoter regions of SREBP1/ACC/FASN and inhibits hepatic lipid de novo synthesis. Deletion of Tfap2a in macrophages enhances polarization of M1 macrophages with increased iNOS expression but decreased CD206 expression, which resulted in increased pro-inflammatory cytokines and decreased anti-inflammatory factors, especially the hepatoprotective factor IL-10. The m6A modification writer WTAP could reduce the mRNA stability of AP-2α in a reader YTHDC1-dependent manner, whereas knockdown of WTAP or YTHDC1 enhances AP-2α expression and decreases lipid accumulation in HCC cells. Clinically, AP-2α expression negatively correlates with the expression of FASN, WTAP, YTHDC1 and the development of liver disease. Taken together, hepatocyte- or macrophage-specific deletion of Tfap2a promotes hepatic steatosis, fibrosis, and the development of HCC. These results suggest that AP-2α has been identified as a novel therapeutic target in fibrosis and inflammation-related HCC, exerting anti-lipogenesis, anti-inflammatory, and anti-tumor multi-roles.

Effects of FABP5 Expression on Clinicopathological and Survival Characteristics in Digestive System Malignancies: A Systematic Review and Meta-Analysis.

Digestive system malignancies are a major global health burden, and the role of fatty acid binding protein 5 (FABP5) in these tumors remains controversial. This meta-analysis aimed to evaluate the correlation between FABP5 expression and clinicopathological features, as well as survival outcomes in digestive system malignancies. Data from 11 studies (1207 patients) retrieved from PubMed, Embase, Cochrane Library, CNKI, and WanFang were analyzed. FABP5 overexpression was associated with poorer overall survival (OS), larger tumor size, advanced UICC stage, and increased risk of vascular invasion and lymph node metastasis. Notably, FABP5 overexpression is particularly associated with poorer OS in the subgroup of digestive tract malignancies and larger tumor sizes in the subgroup of Chinese patients. Cellular experiments demonstrated that FABP5 overexpression enhances proliferation, migration, and invasion in hepatocellular carcinoma (Huh7) and gastric cancer (HGC-27) cell lines, while FABP5 knockdown reduces these effects. Mechanistically, FABP5 may drive tumor progression through PPARβ/δ signaling, epithelial-mesenchymal transition induction, angiogenesis regulation, and potential effects on fatty acid metabolism and hypoxia-related pathways. FABP5 overexpression correlates with adverse clinicopathological features and prognosis in digestive system malignancies, suggesting its potential as a biomarker for these tumors. Further research is warranted.

MicroRNA-6069 ASO inhibits the growth of hepatocellular carcinoma by PLEKHO1.

MicroRNA-6069 ASO inhibits the growth of hepatocellular carcinoma by PLEKHO1.

NUB1 reduction promotes PCNA-mediated tumor growth by disturbing the PCNA polyubiquitination/NEDDylation in hepatocellular carcinoma cells

Negative regulator of ubiquitin-like protein 1 (NUB1), an inhibitor of neural precursor cells expressed developmentally downregulated 8 (NEDD8), is implicated in tumor growth. However, the expression of NUB1 in hepatocellular carcinoma (HCC) and its effects on HCC growth remain unclear. In this study, our findings revealed reduced NUB1 protein expression in HCC tissues and cells, leading to increased proliferating cell nuclear antigen (PCNA) protein stability through upregulating NEDD8 to promote HCC cell growth. Mechanistically, NUB1 reduction upregulated NEDD8 to promote PCNA NEDDylation at lysine 164 (Lys164), in turn, antagonized PCNA K48-linked polyubiquitination, thereby increasing the stability of PCNA in HCC cells. Finally, the results of the in vitro and in vivo experiments revealed that the NEDDylation inhibitor TAS4464 could inhibit PCNA NEDDylation to decrease PCNA protein expression, thereby suppressing HCC cell growth. Collectively, our results identified NUB1 as a negative regulator of HCC proliferation and confirmed that PCNA NEDDylation promotes PCNA protein stability by antagonizing PCNA polyubiquitination. This study provides a new perspective on the specific mechanism of HCC growth. It expands our understanding of the role of NEDDylation in the regulation of substrate proteins and their functions.

AEBP1 inhibition reduces cell growth and PI3K/AKT pathway while less regulates cell mobility in hepatocellular carcinoma

BackgroundAdipocyte enhancer-binding protein 1 (AEBP1) regulates collagen fibrosis, extracellular matrix, and important oncogene pathways, but its regulation on hepatocellular carcinoma (HCC) is not known. This study aimed to investigate the effect of AEBP1 knockdown on HCC cell proliferation, apoptosis, migration, invasion and PI3K/AKT pathway.MethodsMHCC-97 H and Huh7 cell lines were applied. Negative control or AEBP1 siRNA (siAEBP1) were transfected into cells, and cells without transfection were set as blank control. Quantitative polymerase chain reaction (qPCR), western blot, Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2’-deoxyuridine (EdU) staining, Terminal-deoxynucleotidyl Transferase Mediated Nick End Labeling (TUNEL) staining, Transwell invasion, and cell scratch assays were performed.ResultsAEBP1 mRNA and protein expressions were lower after siAEBP1 transfection in MHCC-97 H and Huh7 cells. OD value of CCK-8 and EdU positive cell percentage were decreased, while TUNEL reflected cell apoptosis rate was increased, after siAEBP1 transfection in MHCC-97 H and Huh7 cells. However, invasive cell number and cell migration rate were only reduced after siAEBP1 transfection in Huh7 cells but not in MHCC-97 H cells. Expressions of p-PI3K/PI3K and p-AKT/AKT were downregulated after siAEBP1 transfection in MHCC-97 H and Huh7 cells. Subsequent rescue experiment revealed that th activation of PI3K/AKT pathway by 740Y-P attenuated the effect of siAEBP1 transfection in MHCC-97 H and Huh7 cells.ConclusionAEBP1 exhibits the potency to be a target for HCC treatment, reflected by its regulation on HCC proliferation, apoptosis and PI3K/AKT pathway, but its effect on HCC invasion and migration seems limited.

CSF3R-AS promotes hepatocellular carcinoma progression and sorafenib resistance through the CSF3R/JAK2/STAT3 positive feedback loop

Antisense circular RNA is a special type of circular RNA that is derived from the antisense complementary strand of parental mRNA. However, the function of antisense circRNA in hepatocellular carcinoma (HCC) is still unclear. Here, we reported that CSF3R-AS was upregulated in HCC and correlated with a poor prognosis. CSF3R-AS promoted the proliferation, angiogenesis, and metastasis of HCC, and inhibited apoptosis. Mechanistically, CSF3R-AS has a 180-base complementary pairing sequence with its parental mRNA CSF3R, which can directly bind to CSF3R and recruit RBMS3 to stabilize its parental mRNA, and finally activate JAK2/STAT3 signaling pathway. Interestingly, STAT3 can act as a transcription factor of CSF3R-AS, which means that there is a CSF3R-AS/CSF3R/JAK2/STAT3 positive feedback loop in HCC. Finally, the CSF3R-AS/CSF3R/JAK2/STAT3 positive feedback loop was also activated in HCC sorafenib-resistant cells, and blocking this loop was expected to improve the sensitivity of HCC to sorafenib. These findings suggested that the CSF3R-AS/CSF3R/JAK2/STAT3 positive feedback loop could promote HCC progression and sorafenib resistance. Blocking this loop is expected to provide new research directions and therapy targets for HCC.

Migrasome-related ITGA5 for predicting prognosis, immune infiltration and drug sensitivity of hepatocellular carcinoma.

To clarify the biological functions and prognostic significance of migrasome-related integrin subunit alpha 5 (ITGA5) in hepatocellular carcinoma (HCC). We used The Cancer Genome Atlas datasets and RNA-seq data from nine sets of paired HCC and adjacent normal tissues to identify key migrasome-related genes through a comprehensive analysis and weighted correlation network analysis. We then confirmed their roles in HCC through analyses of gene mutations, methylation, and immune cell infiltration, as well as molecular docking, molecular dynamics, and cell experiments. A comprehensive analysis of migrasome-related genes showed that ITGA5 was a critical gene related to HCC, and it is highly expressed in HCC tissues, which is related to poor prognosis. Further enrichment analysis revealed that ITGA5 is involved in many pathways related to tumor occurrence and metastasis, such as the PI3K-AKT pathway. In addition, ITGA5 was found to be expressed in multiple types of immune cells and was closely associated with immune infiltration. Drug sensitivity, molecular docking, and molecular dynamics analyses indicated that ITGA5 may enhance the sensitivity of HCC to drug TGX221. Finally, cell phenotype experiments confirmed that ITGA5 knockdown suppressed the proliferation, migration, and invasion of HCC cells, and while overexpression exacerbated malignant phenotypes. Our analyses showed that ITGA5 is a key migrasome-related gene involved in the proliferation and metastasis of HCC that has promise as a therapeutic target and candidate prognostic indicator.

Circular RNA hsa_circ_0006421 inhibits hepatocellular carcinoma by acting as a ceRNA targeting miR-134-5p/CELF2 pathway

Background: Hepatocellular carcinoma (HCC), ranking as the sixth most prevalent malignancy globally, exhibits substantial clinical burden. Emerging evidence underscores the critical involvement of circular RNAs (circRNAs) in the pathogenesis of various malignancies. While hsa_circ_0006421 has been implicated in gastric cancer progression, its functional significance in HCC remains unexplored. This study investigates the mechanistic role of hsa_circ_0006421 in HCC pathogenesis. Methods: Differentially expressed circRNAs in HCC tissues were identified through integrated bioinformatics analysis of the GSE97332 dataset and high-throughput sequencing of clinical specimens. Functional characterization of hsa_circ_0006421 was performed using in vitro cellular models (HepG2, MHCC97H) and xenograft experiments. Molecular interactions were validated via qRT-PCR, Western blot, and dual-luciferase reporter assays. Results: Clinical analyses revealed significant downregulation of hsa_circ_0006421 in HCC tissues, particularly in patients with cirrhosis history. Functional studies demonstrated that hsa_circ_0006421 overexpression suppressed HCC proliferation, migration, and invasion. Mechanistically, hsa_circ_0006421 functioned as a competitive endogenous RNA by sequestering miR-134-5p, thereby alleviating its inhibitory effect on CELF2 expression. A negative regulatory relationship between miR-134-5p and CELF2 was established, with hsa_circ_0006421 restoration significantly upregulating CELF2 protein levels in HCC cells. Conclusion: Our findings elucidate a novel hsa_circ_0006421/miR-134-5p/CELF2 regulatory axis that suppresses HCC progression, providing potential therapeutic targets for HCC management.

EOGT knockdown promotes ferroptosis and inhibits hepatocellular carcinoma proliferation by regulating SLC7A11 via HEY1.

EOGT knockdown promotes ferroptosis and inhibits hepatocellular carcinoma proliferation by regulating SLC7A11 via HEY1.

SLC3A2-Mediated Lysine Uptake by Cancer Cells Restricts T cell Activity in Hepatocellular Carcinoma.

Abnormal amino acid metabolism supports cancer cell proliferation, invasion, and immune evasion in hepatocellular carcinoma (HCC). Previous research exploring amino acid metabolism in HCC has primarily focused on how metabolic reprogramming impacts tumor cells. Here, we focused on the role of amino acid metabolism dysregulation in the crosstalk between HCC and T cells. HCC cells disrupted lysine uptake in T cells, leading to impaired T cell immunity. Lysine deprivation decreased STAT3 levels in T cells, inhibiting T cell proliferation and effector function and ultimately promoting tumor progression. Mechanistically, HCC cells outcompeted T cells for lysine by expressing high levels of the lysine transporter SLC3A2. Clinically, elevated SLC3A2 expression correlated with poor survival and was linked to dysregulated T cell functional gene signatures in HCC patients. Furthermore, the multikinase inhibitor lenvatinib induced a c-Myc-SLC3A2 regulatory axis that limited the efficacy of lenvatinib treatment. Lysine supplementation enhanced tumor sensitivity to combined treatment with lenvatinib and anti-PD-1 immunotherapy. These findings suggest that lysine supplementation is a potential therapeutic strategy for treating HCC and enhancing the sensitivity of HCC to tyrosine kinase inhibitors and immune checkpoint blockade.

Migrasome Marker Epidermal Growth Factor Domain-Specific O-GlcNAc Transferase: Pan-Cancer Angiogenesis Biomarker and the Potential Role of circ_0058189/miR-130a-3p/EOGT Axis in Hepatocellular Carcinoma Progression and Sorafenib Resistance

Background: The EGF domain-specific O-GlcNAc transferase (EOGT), a migrasome marker, plays emerging roles in cancer biology through O-GlcNAcylation modifications, yet its pan-cancer functions and therapeutic implications remain underexplored. This study aimed to systematically characterize EOGT’s oncogenic mechanisms across malignancies, with particular focus on hepatocellular carcinoma (HCC) progression and sorafenib resistance. Methods: Multi-omics analysis integrated TCGA/GTEx data from 33 cancer types with spatial/single-cell transcriptomics and 10 HCC cohorts. Functional validation employed Huh7 cell models with EOGT modulation, RNA sequencing, and ceRNA network construction. Drug sensitivity analysis leveraged GDSC/CTRP/PRISM databases, while immune microenvironment assessment utilized ESTIMATE/TIMER algorithms. Results: EOGT showed cancer-specific dysregulation, marked by significant upregulation in HCC correlating with advanced stages and poor survival. Pan-cancer analysis revealed EOGT’s association with genomic instability, tumor stemness, and angiogenesis. Experimental validation demonstrated EOGT’s promotion of HCC proliferation and migration. A novel exosomal circ_0058189/miR-130a-3p/EOGT axis was identified, showing that circ_0058189 was upregulated in HCC tissues, plasma samples and exosomes of sorafenib-resistant cells. Conclusion: This study establishes EOGT as a pan-cancer angiogenesis biomarker, while elucidating its role in therapeutic resistance via exosomal circRNA-mediated regulation, providing mechanistic insights for targeted intervention strategies.