Therapeutic Target For Hepatocellular Carcinoma Research Articles

Recent progress in understanding mitokines as diagnostic and therapeutic targets in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent tumors worldwide and the leading contributor to cancer-related deaths. The progression and metastasis of HCC are closely associated with altered mitochondrial metabolism, including mitochondrial stress response. Mitokines, soluble proteins produced and secreted in response to mitochondrial stress, play an essential immunomodulatory role. Immunotherapy has emerged as a crucial treatment option for HCC. However, a positive response to therapy is typically dependent on the interaction of tumor cells with immune regulation within the tumor microenvironment. Therefore, exploring the specific immunomodulatory mechanisms of mitokines in HCC is essential for improving the efficacy of immunotherapy. This study provides a comprehensive overview of the association between HCC and the immune microenvironment and highlights recent progress in understanding the involvement of mitochondrial function in preserving liver function. In addition, a systematic review of mitokines-mediated immunomodulation in HCC is presented. Finally, the potential diagnostic and therapeutic roles of mitokines in HCC are prospected and summarized. Recent progress in mitokine research represents a new prospect for mitochondrial therapy. Considering the potential of mitokines to regulate immune function, investigating them as a relevant molecular target holds great promise for the diagnosis and treatment of HCC.

TAF1B depletion leads to apoptotic cell death by inducing nucleolar stress and activating p53-miR-101 circuit in hepatocellular carcinoma.

TAF1B (TATA Box Binding Protein (TBP)-Associated Factor) is an RNA polymerase regulating rDNA activity, stress response, and cell cycle. However, the function of TAF1B in the progression of hepatocellular carcinoma (HCC) is unknown. In this study, we intended to characterize the crucial role and molecular mechanisms of TAF1B in modulating nucleolar stress in HCC. We analyzed the differential expression and prognostic value of TAF1B in hepatocellular carcinoma based on The Cancer Genome Atlas (TCGA) database, tumor and paraneoplastic tissue samples from clinical hepatocellular carcinoma patients, and typical hepatocellular carcinoma. We detected cell proliferation and apoptosis by lentiviral knockdown of TAF1B expression levels in HepG2 and SMMC-7721 cells using clone formation, apoptosis, and Western blotting (WB) detection of apoptosis marker proteins. Simultaneously, we investigated the influence of TAF1B knockdown on the function of the pre-initiation complex (PIC) by WB, and co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP) assays verified the interaction between the complexes and the effect on rDNA activity. Immunofluorescence assays measured the expression of marker proteins of nucleolus stress, fluorescence in situ hybridization (FISH) assays checked the rDNA activity, and qRT-PCR assays tested the pre-rRNA levels. Regarding molecular mechanisms, we investigated the role of p53 and miR-101 in modulating nucleolar stress and apoptosis. Finally, the impact of TAF1B knockdown on tumor growth, apoptosis, and p53 expression was observed in xenograft tumors. We identified that TAF1B was highly expressed in hepatocellular carcinoma and associated with poor prognosis in HCC patients. TAF1B depletion modulated nucleolar stress and apoptosis in hepatocellular carcinoma cells through positive and negative feedback from p53-miR-101. RNA polymerase I transcription repression triggered post-transcriptional activation of miR-101 in a p53-dependent manner. In turn, miR-101 negatively feeds back through direct inhibition of the p53-mediated PARP pathway. These findings broaden our comprehension of the function of TAF1B-mediated nucleolar stress in hepatocellular carcinoma and may offer new biomarkers for exploring prospective therapeutic targets in HCC.

Stratifin Promotes Hepatocellular Carcinoma Progression by Modulating the Wnt/β-Catenin Pathway.

Abnormal stratifin (SFN) expression is closely related to the progression of several human cancers, but the potential roles of SFN in hepatocellular carcinoma (HCC) remain largely unknown. In this study, we found that SFN was upregulated in HCC cell lines and tissues and was positively associated with tumor size, poor differentiation, Tumor Node Metastasis (TNM) stage, and vascular invasion. In addition, high expression levels of SFN were associated with poor overall survival and disease-free survival. Biologically, downregulation of SFN suppressed tumor cell proliferation, epithelial-mesenchymal transition (EMT), invasion, and migration in vitro and tumor growth in vivo. However, overexpression of SFN promoted cell proliferation, EMT, invasion, and migration in vitro and tumor growth in vivo. Mechanistically, overexpression of SFN activated the Wnt/β-catenin pathway by promoting Glycogen synthase kinase-3 beta (GSK-3β) phosphorylation, decreasing β-catenin phosphorylation, promoting β-catenin transport into the nucleus, and enhancing the expression of c-Myc, whereas depletion of SFN inhibited the Wnt/β-catenin pathway. In addition, TOPFlash/FOPFlash reporter assays showed that overexpression or downregulation of SFN obviously increased or decreased, respectively, the activity of the Wnt/β-catenin pathway. Our results indicated that SFN plays an important role in HCC, possibly providing a prognostic factor and therapeutic target for HCC.

Lnc-PLA2G4A-4 facilitates the progression of hepatocellular carcinoma by inducing versican expression via sponging miR-23b-3p

Aberrant expression of long non-coding RNAs (lncRNAs) is associated with progression of multiple human cancers including hepatocellular carcinoma (HCC). However, the role of lncRNAs in HCC is not been fully understood. Our study aimed to investigate the biological function and potential molecular mechanism of Lnc-PAL2G4A-4 in HCC. In the current study, we show that Lnc-PLA2G4A-4 was significantly up-regulated in HCC tissues and high Lnc-PLA2G4A-4 expression was remarkably associated with tumor size, microvascular invasion and poor prognosis of HCC patients. Functionally, Lnc-PLA2G4A-4 positively regulated cell proliferation, invasion and migration in vitro, and facilitated lung metastasis of HCC in vivo. Mechanistically, Lnc-PLA2G4A-4 functioned as a competing endogenous RNA (ceRNA) to bind to miR-23b-3p and subsequently facilitate miR-23b-3p's target gene versican (VCAN) expression in HCC cells. Over-expression of miR-23b-3p could reverse Lnc-PLA2G4A-4 induced cell phenotypes in HCC and suppress versican expression of by rescue analysis. Collectively, Lnc-PLA2G4A-4 promotes HCC progression by targeting the miR-23b-3p/versican axis, which may be a potential biomarker and therapeutic target for HCC.

Multiple Roles of LOXL2 in the Progression of Hepatocellular Carcinoma and Its Potential for Therapeutic Targeting.

LOXL2, a copper-dependent amine oxidase, has emerged as a promising therapeutic target in hepatocellular carcinoma (HCC). Increased LOXL2 expression in HCC has been linked with an aggressive phenotype and represents a poor prognostic factor. Here, we focus on the mechanisms through which LOXL2 orchestrates multiple oncogenic functions in HCC development. We performed a review of the current knowledge on the roles LOXL2 performs in the modulation of the HCC tumor microenvironment, formation of premetastatic niches, and epithelial-mesenchymal transition. We also highlighted the complex interplay between LOXL2 and hypoxia, angiogenesis, and vasculogenic mimicry in HCC. At the end of the review, we summarize the current LOXL2 inhibitors and discuss their potential in HCC precision treatment.

A spotlight on the interplay between Wnt/β-catenin signaling and circular RNAs in hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers due to multifocal development and distant metastasis resulting from late diagnosis. Consequently, new approaches to HCC diagnosis and treatment are required to reduce mortality rates. A large body of evidence suggests that non-coding RNAs (ncRNAs) are important in cancer initiation and progression. Cancer cells release many of these ncRNAs into the blood or urine, enabling their use as a diagnostic tool. Circular RNAs (CircRNAs) are as a members of the ncRNAs that regulate cancer cell expansion, migration, metastasis, and chemoresistance through different mechanisms such as the Wnt/β-catenin Signaling pathway. The Wnt/β-catenin pathway plays prominent roles in several biological processes including organogenesis, stem cell regeneration, and cell survival. Aberrant signaling of both pathways mentioned above could affect the progression and metastasis of many cancers, including HCC. Based on several studies investigated in the current review, circRNAs have an effect on HCC formation and progression by sponging miRNAs and RNA-binding proteins (RBPs) and regulating the Wnt/β-catenin signaling pathway. Therefore, circRNAs/miRNAs or RBPs/Wnt/β-catenin signaling pathway could be considered promising prognostic and therapeutic targets in HCC.

The expression of tuftelin 1 as a new theranostic marker in early diagnosis and as a therapeutic target in hepatocellular carcinoma.

Currently, many challenges are associated with hepatocellular carcinoma (HCC) as the failure of early diagnosis, and the lack of effective therapy. This study aimed to investigate the possible role of tuftelin 1 (TUFT 1) in the early diagnosis of HCC and evaluate the potential contribution of the TUFT 1/Ca+2 /phosphinositol 3 kinase (PI3K) pathway in dantrolene sodium (Dan) therapeutic outcomes. The study was performed on two sets of rats, the staging (30 rats) and treatment sets (80 rats). HCC was induced by a single dose of diethylnitrosamine (DENA). The hepatic content of TUFT 1 protein was assayed via western blot and immunohistochemistry (IHC), while PI3K, vascular endothelial growth factor (VEGF), Cyclin D1, and matrix-metalloproteinase-9 (MMP-9) contents were assessed using enzyme-linked immunosorbent assay. Hepatic and serum calcium were measured colorimetrically. Furthermore, the nuclear proliferation marker, (Ki-67), (Kiel [Ki] where the antibody was produced in the University Department of Pathology and the original clone number is 67)-expression was assessed by IHC. TUFT 1/Ca+2 /PI3K signaling pathway was progressively activated in the 3 studied stages of HCC with subsequent upregulation of angiogenesis, cell cycle, and metastasis. More interestingly, Dan led to TUFT 1/Ca+2 /PI3K pathway disruption by diminution of the hepatic contents of TUFT 1, calcium, PI3K, VEGF, Cyclin D1, and MMP-9 in a dose-dependent pattern. TUFT 1 can serve as a theranostic biomarker in HCC. Moreover, Dan exerted an antineoplastic effect against HCC via the interruption of TUFT 1/Ca+2 /PI3K pathway.

Vasorin promotes proliferation and migration via STAT3 signaling and acts as a promising therapeutic target of hepatocellular carcinoma

Abnormal expression of Vasorin (VASN) is related to many types of cancer, but the signaling pathway and mechanism of how VASN contributes to the carcinogenesis of hepatocellular carcinoma (HCC) are poorly understood. Here, we found that VASN was up-regulated in serum/serum exosome and tissues of HCC patients. The expression of VASN in serum improve the detection rate of HCC in alpha-fetoprotein-negative HCC patients. Immunohistochemistry revealed that VASN was highly expressed in HCC tissues and associated with different stages of HCC. Noticeably, when serum VASN combined with α-fetoprotein, the area under the curve (AUC), sensitivity, and specificity of HCC patients compared with healthy patients reached 0.918 (95% CI: 0.869–0.967, P < 0.001), 90.91%, and 90.20%, respectively. VASN knockout HCC cells were obtained by CRISPR/Cas9 and a VASN-specific monoclonal antibody was prepared by hybridoma technology. Knockout of VASN or the addition of VASN-specific monoclonal antibody suppressed the proliferation and migration of HCC. Mechanistically, VASN promote the proliferation and migration of HCC by regulating the phosphorylation of STAT3 and the expression of downstream genes CCND1 and MMP2. In conclusion, our findings suggest that VASN plays a crucial role in the activation of STAT3 signaling pathway in HCC, which is a promising target for the diagnosis and therapy of HCC.

Bone Morphogenetic Protein 13 Has Protumorigenic Effects on Hepatocellular Carcinoma Cells In Vitro.

Activated hepatic stellate cells (HSCs) play a key role in hepatic fibrosis and, thus, build the "soil" for hepatocarcinogenesis. Furthermore, HSCs are known to promote the progression of hepatocellular carcinoma (HCC), but the molecular mechanisms are only incompletely understood. Recently, we newly described the expression of bone morphogenetic protein 13 (BMP13) by HSCs in fibrotic liver tissue. In addition, BMP13 has mostly been studied in the context of cartilage and bone repair, but not in liver disease or cancer. Thus, we aimed to analyze the expression and function of BMP13 in HCC. Expression analyses revealed high BMP13-expression in activated human HSCs, but not in human HCC-cell-lines. Furthermore, analysis of human HCC tissues showed a significant correlation between BMP13 and α-smooth muscle actin (α-SMA), and immunofluorescence staining confirmed the co-localization of BMP13 and α-SMA, indicating activated HSCs as the cellular source of BMP13 in HCC. Stimulation of HCC cells with recombinant BMP13 increased the expression of the inhibitors of differentiation 1 (ID1) and 2 (ID2), which are known targets of BMP-signaling and cell-cycle promotors. In line with this, BMP13-stimulation caused an induced SMAD 1/5/9 and extracellular signal-regulated kinase (ERK) phosphorylation, as well as reduced expression of cyclin-dependent kinase inhibitors 1A (CDKN1A) and 2A (CDKN2A). Furthermore, stimulation with recombinant BMP13 led to increased proliferation and colony size formation of HCC cells in clonogenicity assays. The protumorigenic effects of BMP13 on HCC cells were almost completely abrogated by the small molecule dorsomorphin 1 (DMH1), which selectively blocks the intracellular kinase domain of ALK2 and ALK3, indicating that BMP13 acts via these BMP type I receptors on HCC cells. In summary, this study newly identifies stroma-derived BMP13 as a potential new tumor promotor in HCC and indicates this secreted growth-factor as a possible novel therapeutic target in HCC.

Chromatin-associated OGT promotes the malignant progression of hepatocellular carcinoma by activating ZNF263.

Reversible and dynamic O-GlcNAcylation regulates vast networks of highly coordinated cellular and nuclear processes. Although dysregulation of the sole enzyme O-GlcNAc transferase (OGT) was shown to be associated with the progression of hepatocellular carcinoma (HCC), the mechanisms by which OGT controls the cis-regulatory elements in the genome and performs transcriptional functions remain unclear. Here, we demonstrate that elevated OGT levels enhance HCC proliferation and metastasis, in vitro and in vivo, by orchestrating the transcription of numerous regulators of malignancy. Diverse transcriptional regulators are recruited by OGT in HCC cells undergoing malignant progression, which shapes genome-wide OGT chromatin cis-element occupation. Furthermore, an unrecognized cooperation between ZNF263 and OGT is crucial for activating downstream transcription in HCC cells. We reveal that O-GlcNAcylation of Ser662 is responsible for the chromatin association of ZNF263 at candidate gene promoters and the OGT-facilitated HCC malignant phenotypes. Our data establish the importance of aberrant OGT activity and ZNF263 O-GlcNAcylation in the malignant progression of HCC and support the investigation of OGT as a therapeutic target for HCC.

Circ_0091579 Knockdown Inhibited HCC Proliferation and Glutamine Metabolism Through miR-1270/YAP1 Axis.

A growing number of studies have indicated that circRNAs play an important role in the progression of malignant tumors, including hepatocellular carcinoma (HCC). In this study, we designed to explore the abnormal expression of hsa_circ_0091579 (circ_0091579) and its role in the pathogenesis of HCC. In this study, the mRNA levels of circ_0091579, miR-1270, and Yes-associated protein (YAP1) were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). RNase R and Actinomycin D were used to test the stability of circ_0091579. Cell Counting Kit-8 (CCK-8) was used to measure cell viability. Tubule formation assay was used to determine the effect of HCC cells on the number of tubes. Cell apoptosis was detected by flow cytometry. Western blot was used for the protein levels. Transwell and wound healing tests were used to measure the abilities of invasion and migration. The effect of circ_0091579 knockdown on tumor growth was verified in vivo by xenograft tumor assay and Immunohistochemistry (IHC) analysis. Dual-luciferase reporter or RIP assay was used to detect the relationship between miR-1270 and circ_0091579 or YAP1. Glutamine metabolism was determined by ELISA and western blot assays. In the present study, we found that circ_0091579 was upregulated in HCC tissues and cells. Inhibited circ_0091579 expression significantly suppressed proliferation and promoted apoptosis of HCC cells. Moreover, circ_0091579 knockdown inhibited tumor growth in vivo. Bioinformatic prediction and luciferase assay showed that circ_0091579 acted as a molecular sponge for miR-1270 and YAP1 was a target gene of miR-1270. MiR-1270 silencing could reverse the inhibitory effect of circ_0091579 knockdown on HCC progression, and YAP1 overexpression also could reverse the suppressive effect of circ_0091579 silencing on HCC progression. Meanwhile, miR-1270 inhibitor could invert the negative regulation effect of circ_0091579 silencing on YAP1 expression. Circ_0091579 promoted HCC progression by regulating the miR-1270/YAP1 axis, and our study might offer novel biomarkers and therapeutic targets for HCC.

Fibulin-2 Facilitates Malignant Progression of Hepatocellular Carcinoma.

Identification of biomarkers to assist in the clinical management of hepatocellular carcinoma represents an urgent requirement. Fibulin-2 is known to contribute to the development and progression of various cancer types. This research investigated the role of fibulin-2 in hepatocellular carcinoma and explored the possible mechanisms. The expression of fibulin-2 in hepatocellular carcinoma was measured by bioinformatic analysis and confirmed by western blot and immunohistochemical staining in cell lines or patients' samples. The clinicopathologic features of hepatocellular carcinoma patients was analyzed. Cell viability assays were used to explore the role of fibulin-2 on proliferation in hepatocellular carcinoma. Western blot was conducted to uncover changes of protein expression of Ras-MEK-ERK1/2 pathway when Fibulin-2 was overexpressed or silenced. Flow cytometry analyses were used to determine the roles of fibulin-2 in the function of apoptosis and cell cycle. Subcutaneous xenograft mouse models showed the tumor growth pattern after fibulin-2 silence in vivo. We reported the upregulation of fibulin-2 in most hepatocellular carcinoma tissues and cells lines. Fibulin-2 promoted the proliferation of hepatocellular carcinoma cells in vitro by regulating Ras-MEK-ERK1/2 signaling pathway, whereas knockdown of fibulin-2 incurred the opposite effect on proliferation. Consistently, knockdown of fibulin-2 resulted in increased apoptosis and induced growth arrest during the G0/G1 phase transition. In vivo xenograft assessment confirmed that knockdown of fibulin-2 inhibited hepatocellular carcinoma tumor growth. Fibulin-2 exhibited tumor promotor activities in malignant progression of hepatocellular carcinoma. The results of the study highlighted the potential of fibulin-2 to be utilized as a promising biomarker and therapeutic target for hepatocellular carcinoma.

AATF inhibition exerts antiangiogenic effects against human hepatocellular carcinoma.

Angiogenesis is a key factor in the growth and metastasis of hepatic tumors and thus a potential therapeutic target in hepatocellular carcinoma (HCC). In this study, we aim to identify the key role of apoptosis antagonizing transcription factor (AATF) in tumor angiogenesis and its underlying mechanisms in HCC. HCC tissues were analyzed for AATF expression by qRT-PCR and immunohistochemistry. Stable clones of control and AATF knockdown (KD) were established in human HCC cells. The effect of AATF inhibition on the angiogenic processes was determined by proliferation, invasion, migration, chick chorioallantoic membrane (CAM) assay, zymography, and immunoblotting techniques. We identified high levels of AATF in human HCC tissues compared to adjacent normal liver tissues, and the expression was found to be correlated with the stages and tumor grades of HCC. Inhibiting AATF in QGY-7703 cells resulted in higher levels of pigment epithelium-derived factor (PEDF) than controls due to decreased matric metalloproteinase activity. Conditioned media from AATF KD cells inhibited the proliferation, migration, and invasion of human umbilical vein endothelial cells as well as the vascularization of the chick chorioallantoic membrane. Furthermore, the VEGF-mediated downstream signaling pathway responsible for endothelial cell survival and vascular permeability, cell proliferation, and migration favoring angiogenesis was suppressed by AATF inhibition. Notably, PEDF inhibition effectively reversed the anti-angiogenic effect of AATF KD. Our study reports the first evidence that the therapeutic strategy based on the inhibition of AATF to disrupt tumor angiogenesis may serve as a promising approach for HCC treatment.

Pien-Tze-Huang prevents hepatocellular carcinoma by inducing ferroptosis via inhibiting SLC7A11-GSH-GPX4 axis

BackgroundMalignant transformation from hepatic fibrosis to carcinogenesis may be a therapeutic target for hepatocellular carcinoma (HCC). The aim of this study was to evaluate anti-cancer efficacy of Pien-Tze-Huang (PZH), and to investigate the underlying mechanisms by integrating transcriptional regulatory network analysis and experimental validation.MethodsA diethylnitrosamine (DEN)-induced HCC model in rats was established and used to evaluate the anti-cancer efficacy of PZH. After detecting a transcriptomic profiling, the “disease-related gene–drug effective target” interaction network was constructed, and the candidate targets of PZH against malignant transformation from hepatic fibrosis to HCC were identified and verified in vitro.ResultsPZH effectively alleviated the pathological changes of hepatic fibrosis and cirrhosis, and inhibited tumor formation and growth in DEN-induced HCC rats. Additionally, the administration of PZH reduced the levels of various hepatic function-related serological indicators significantly. Mechanically, a ferroptosis-related SLC7A11-GSH-GPX4 axis might be one of potential targets of PZH against malignant transformation from hepatic fibrosis to HCC. Especially, high SLC7A11 expression may be associated with poor prognosis of HCC patients. Experimentally, the administration of PZH markedly increased the trivalent iron and ferrous ion, suppressed the expression levels of SLC7A11 and GPX4 proteins, and reduced the GSH/GSSG ratio in the liver tissues of DEN-induced HCC rats.ConclusionsOur data offer an evidence that PZH may effectively improve the hepatic fibrosis microenvironment and prevent the occurrence of HCC through promoting ferroptosis in tumor cells via inhibiting the SLC7A11-GSH-GPX4 axis, implying that PZH may be a potential candidate drug for prevention and treatment of HCC at an early stage.

SAT-239 - Neutrophil degranulation and ageing as potential therapeutic targets in hepatocellular carcinoma?

SAT-239 - Neutrophil degranulation and ageing as potential therapeutic targets in hepatocellular carcinoma?

Increased expression of autophagy-related gene 5 indicates poor prognosis in patients with Hepatocellular carcinoma.

As an critical component of the autophagic machinery, autophagy-related gene 5 (ATG5) is essential for autophagosome formation. Autophagy participates in various malignant tumor transformation and progression, but the role of ATG5 involved in hepatocellular carcinoma (HCC) remains to be illustrated. The expression of ATG5 was evaluated in 89 pairs of liver tumor and adjacent normal tissues. The correlation between ATG5 expression and clinicopathological characteristics or prognosis were evaluated. Moreover, clinical special analysis was conducted in the young patients group and the old patients group respectively, and nomograms estimating overall survival and disease-free survival were investigated. Our study demonstrated that the ATG5 level was increased in tumor specimens than adjacent normal tissues. Upregulated ATG5 level had positive association with serum α-fetoprotein (AFP). Moreover, cases with higher ATG5 level had poorer disease-free survival (DFS) and overall survival (OS) than those with lower ATG5 level. Multivariate analysis showed that overexpression of ATG5 predicts poor OS and DFS. Further analysis indicated that cases with higher ATG5 level had poorer OS and DFS in the young patients and solitary tumor number subgroup. The nomogram models suggested that it had a coherence between nomogram prediction and actual situation. Together these findings revealed that ATG5 promotes progression of HCC, making it a potentially biomarker in diagnosis and therapeutic target of hepatocellular carcinoma. This article is protected by copyright. All rights reserved.

BAIAP2L2 is a novel prognostic biomarker related to migration and invasion of HCC and associated with cuprotosis

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and its pathophysiological mechanisms remain unknown. IRSp53 family members, such as BAIAP2L1, participate in the progression of multiple tumors. However, the role of BAIAP2L2 in HCC remains unclear. This study comprehensively analyzed the potential role of BAIAP2L2 in HCC using bioinformatic techniques. The expression of BAIAP2L2 in HCC was analyzed using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), International Cancer Genome Consortium (ICGC), and Human Protein Atlas (HPA) databases and in vitro experiments. In addition, the prognostic value of BAIAP2L2 in HCC was analyzed using the TCGA database. TCGA and GEO database were used to analyze the role of BAIAP2L2 in immune features. We also explored the function of BAIAP2L2 in methylation and cuprotosis. The CellMiner database was used to analyze the relationship between BAIAP2L2 expression and drug sensitivity. Our study revealed that BAIAP2L2 is overexpressed in HCC and promotes the migration and invasion of HCC cells. BAIAP2L2 may affect the prognosis of HCC by regulating immunity, methylation, and cuprotosis. BAIAP2L2 is a novel HCC prognostic gene involved in immune infiltration associated with cuprotosis and may be a potential prognosis and therapeutic target for HCC.

An integrative analysis reveals the prognostic value and potential functions of PSMD11 in hepatocellular carcinoma.

The global burden of hepatocellular carcinoma (HCC) as a preeminent etiology of cancer-related mortalities sheds light on the imperative necessity for a more profound comprehension of its fundamental biological mechanisms. In this context, the precise function of the 26S proteasome non-ATPase regulatory subunit 11 (PSMD11) in HCC remains equivocal. To address this vital knowledge gap, we interrogated the cancer genome atlas, genotype-tissue expression, International cancer genome consortium, gene expression omnibus, the cancer cell line encyclopedia, and tumor immune single-cell hub databases to evaluate the expression pattern of PSMD11, further confirmed by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) in LO2, MHCC-97H, HepG2, and SMMC7721 cell lines. Additionally, we meticulously assessed the clinical significance and prognostic value of PSMD11, while also exploring its potential molecular mechanisms in HCC. Our findings demonstrated that PSMD11 was highly expressed in HCC tissues, correlating with pathologic stage and histologic grade, thereby conferring a poor prognosis. Mechanistically, PSMD11 appears to exert its tumorigenic effects through the modulation of tumor metabolism-related pathways. Impressively, low PSMD11 expression was associated with increased immune effector cell infiltration, heightened responsiveness to molecular targeted drugs such as dasatinib, erlotinib, gefitinib, and imatinib, as well as reduced somatic mutation rate. Additionally, we demonstrated that PSMD11 might modulate HCC development through intricate interactions with cuproptosis-related genes ATP7A, DLAT, and PDHA1. Our comprehensive analyses collectively suggest that PSMD11 represents a promising therapeutic target in HCC.

Effects of Scutellaria strigillosa Hemsl. extract on HepG2 cell proliferation and apoptosis through binding to aspartate β-hydroxylase

This study aims to examine the impacts of Scutellaria strigillosa Hemsl. (SSH) on the proliferation, apoptosis of human hepatoma cell HepG2 and screen the bioactive components. We found that SSH extract inhibited HepG2 proliferation, arrested cell division prior to S phase. Additionally, SSH extract exposure induced apoptosis, and increased the proportions of late apoptotic cells. Specifically, we focus on the inhibitory effect of SSH extract on aspartate β-hydroxylase, a key therapeutic target of hepatocellular carcinoma closely related with the proliferation and apoptosis of HepG2. We found SSH extract with notable inhibitory activity against aspartate β-hydroxylase, elucidated the main bioactive constituents by HPLC-Q-TOF/MS and Molecular docking analysis. In conclusion, these results provided the antiproliferative and proapoptotic effects of SSH on HepG2 cell, elucidated the main bioactive constituents based on aspartate β-hydroxylase inhibition. These data revealed the potential value of SSH and its bioactive components for the prevention and treatment of liver cancer for the first time.

EHHADH is a key gene in fatty acid metabolism pathways in hepatocellular carcinoma: a transcriptomic analysis

To explore the driving gene of hepatocellular carcinoma (HCC) occurrence and progression and its potential as new therapeutic target of HCC. The transcriptome and genomic data of 858 HCC tissues and 493 adjacent tissues were obtained from TCGA, GEO, and ICGC databases. Gene Set Enrichment Analysis (GSEA) identified EHHADH (encoding enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase) as the hub gene in the significantly enriched differential pathways in HCC. The downregulation of EHHADH expression at the transcriptome level was found to correlate with TP53 mutation based on analysis of the TCGA- HCC dataset, and the mechanism by which TP53 mutation caused EHHADH downregulation was explored through correlation analysis. Analysis of the data from the Metascape database suggested that EHHADH was strongly correlated with the ferroptosis signaling pathway in HCC progression, and to verify this result, immunohistochemical staining was used to examine EHHADH expression in 30 HCC tissues and paired adjacent tissues. All the 3 HCC datasets showed signficnatly lowered EHHADH expression in HCC tissues as compared with the adjacent tissues (P < 0.05) with a close correlation with the degree of hepatocyte de-differentiation (P < 0.01). The somatic landscape of HCC cohort in TCGA dataset showed that HCC patients had the highest genomic TP53 mutation rate. The transcriptomic level of PPARGC1A, the upstream gene of EHHADH, was significantly downregulated in HCC patients with TP53 mutation as compared with those without the mutation (P < 0.05), and was significantly correlated with EHHADH expression level. GO and KEGG enrichment analyses showed that EHHADH expression was significantly correlated with abnormal fatty acid metabolism in HCC. The immunohistochemical results showd that the expression level of EHHADH in HCC tissues was down-regulated, and its expression level was related to the degree of hepatocytes de-differentiation and the process of ferroptosis. TP53 mutations may induce abnormal expression of PPARGC1A to cause downregulation of EHHADH expression in HCC. The low expression of EHHADH is closely associated with aggravation of de-differentiation and ferroptosis escape in HCC tissues, suggesting the potential of EHHADH as a therapeutic target for HCC.