Signaling Pathway In Hepatocellular Carcinoma Research Articles

Integrating anoikis and ErbB signaling insights with machine learning and single-cell analysis for predicting prognosis and immune-targeted therapy outcomes in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) poses a significant global health challenge due to its poor prognosis and limited therapeutic modalities. Anoikis and ErbB signaling pathways are pivotal in cancer cell proliferation and metastasis, but their relevance in HCC remains insufficiently explored. This study evaluates the prognostic significance of anoikis and ErbB signaling pathways in HCC by utilizing data from The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC), three additional independent validation cohorts, and an in-house cohort. Advanced bioinformatics analyses and 167 machine learning models based on leave-one-out cross-validation (LOOCV) were used to predict HCC prognosis and assess outcomes of immune-targeted therapies. Additionally, key biological processes of the anoikis and ErbB signaling pathways in HCC were further investigated. The single sample Gene Set Enrichment Analysis revealed a strong correlation between upregulated ErbB signaling in high anoikis-expressing tumors and poor clinical outcomes. The development of the Anoikis-ErbB Related Signature (AERS) using the LASSO + RSF model demonstrated robust predictive capabilities, as validated across multiple patient cohorts, and proved effective in predicting responses to immune-targeted therapies. Further investigation highlighted activated NOTCH signaling pathways and decreased macrophage infiltration was associated with resistance to sorafenib and immune checkpoint inhibitors, as evidenced by bulk and single-cell RNA sequencing (scRNA-seq). AERS provides a novel tool for clinical prognosis and paves the way for immune-targeted therapeutic approaches, underscoring the potential of integrated molecular profiling in enhancing treatment strategies for HCC.

AIBP promotes cell proliferation and migration through the ERK1/2-MAPK signaling pathway in hepatocellular carcinoma.

As a highly aggressive cancer, hepatocellular carcinoma (HCC) is often found at an advanced stage and has a poor prognosis. Therefore, in addition to the surgical treatment of HCC, the drug therapy for HCC is still under continuous exploration. The primary apolipoprotein of high-density lipoproteins (HDLs) is apolipoprotein A-I binding protein (AIBP), which has a significant impact on cholesterol metabolism, angiogenesis, and a wide range of inflammatory disorders, including cancer. The AIBP function in HCC is, however, yet unknown. This study aims to reveal the underlying mechanisms of AIBP influencing HCC proliferation and migration through mitogen-activated protein kinase (MAPK) pathways. AIBP expression and its clinical prognostic association were investigated using The Cancer Genome Atlas (TCGA) data. The AIBP expression was studied in human HCC tissues using immunohistochemistry (IHC) and western blotting. Colony formation assays (CFAs) and cell counting kit-8 (CCK-8) were used to determine in vitro cell proliferation. Cell migration and invasion were evaluated using wound-healing and transwell assays. A xenograft tumor model was employed to investigate HCC cell proliferation in nude mice. Tissues from HCC patients had much increased AIBP expression compared to nearby normal tissues. The prognosis for patients was bleak when AIBP expression was high. When AIBP was overexpressed in SMMC-7721 cells, the cells may become more proliferative, migrative, and invasive. In contrast, the HCC-LM3 cells' ability to proliferate, migrate, and invade was drastically decreased once AIBP was knocked down in vitro. Furthermore, in vivo research showed that AIBP overexpression may enhance cell proliferation in HCC. Finally, we discovered that AIBP could control the MAPK signaling pathway-involved genes expression, including P-MEK, MEK, c-Myc, P-ERK1/2, and ERK1/2, and that GDC-0994, a specific ERK1/2 inhibitor, could suppress the AIBP overexpression induced cell migration and proliferation abilities. These findings demonstrated that the ERK/MAPK signaling pathway might be stimulated by AIBP in HCC tissues, leading to increased cell invasion, migration, and proliferation. It was hypothesized that AIBP might act as a useful prognostic and diagnostic marker for HCC.

Does rAj-Tspin, a novel peptide from A. japonicus, exert antihepatocellular carcinoma effects via the ITGB1/ZYX/FAK/AKT signaling pathway?

rAj-Tspin, a soluble recombinant peptide from Apostichopus japonicus, can inhibit the integrin β1 (ITGB1)/FAK/AKT signaling pathway in hepatocellular carcinoma (HCC) via cell epithelial–mesenchymal transition (EMT) and apoptosis. Zyxin (ZYX) is a focal adhesion protein that is considered a novel mediator of EMT and apoptosis. However, the inhibitory mechanisms of rAj-Tspin in HCC and whether it is related to ZYX are unclear. We examined the antitumor effect of rAj-Tspin on the Huh7 human HCC cell line and on a nude mouse model generated via subcutaneous injection or orthotopic intrahepatic transplantation of Huh7 cells. Our results revealed that rAj-Tspin strikingly reduced the viability and promoted the apoptosis of Huh7 cells and inhibited HCC tumor growth in nude mice. rAj-Tspin inhibited ITGB1 and ZYX protein expression in vivo and in vitro in a dose-dependent manner. Mechanistically, the FAK/AKT signaling pathway and the proliferation and invasion of HCC cells were suppressed upon ITGB1 and ZYX knockdown. Moreover, the effect of ITGB1 overexpression on the growth of HCC cells was inhibited by rAj-Tspin. In contrast, the promoting effect of ITGB1 overexpression could be inhibited by ZYX knockdown. ZYX knockdown had no effect on ITGB1 expression. These findings suggest that ZYX is required for the indispensable role of ITGB1 in rAj-Tspin‐alleviated HCC and provide an important therapeutic target for HCC. In summary, the anti-HCC effect of rAj-Tspin potentially involves the regulation of the ITGB1/ZYX/FAK/AKT pathway, which in turn impacts EMT and apoptosis.Graphical

CRISPR-based dissection of microRNA-23a ~ 27a ~ 24-2 cluster functionality in hepatocellular carcinoma

The miR-23a ~ 27a ~ 24-2 cluster, commonly upregulated in diverse cancers, including hepatocellular carcinoma (HCC), raises questions about the specific functions of its three mature miRNAs and their integrated function. Utilizing CRISPR knockout (KO), CRISPR interference (CRISPRi), and CRISPR activation (CRISPRa) technologies, we established controlled endogenous miR-23a ~ 27 ~ a24-2 cell models to unravel their roles and signaling pathways in HCC. Both miR-23a KO and miR-27a KO displayed reduced cell growth in vitro and in vivo, revealing an integrated oncogenic function. Functional analysis indicated cell cycle arrest, particularly at the G2/M phase, through the downregulation of CDK1/cyclin B activation. High-throughput RNA-seq, combined with miRNA target prediction, unveiled the miR-23a/miR-27a-regulated gene network, validated through diverse technologies. While miR-23a and miR-27a exhibited opposing roles in cell migration and mesenchymal-epithelial transition, an integrated CRISPRi/a analysis suggested an oncogenic role of the miR-23a ~ 27a ~ 24-2 cluster in cell migration. This involvement potentially encompasses two signaling axes: miR-23a-BMPR2 and miR-27a-TMEM170B in HCC cells. In conclusion, our CRISPRi/a study provides a valuable tool for comprehending the integrated roles and underlying mechanisms of endogenous miRNA clusters, paving the way for promising directions in miRNA-targeted therapy interventions.

Targeting the Hippo/YAP1 signaling pathway in hepatocellular carcinoma: From mechanisms to therapeutic drugs (Review).

The Hippo signaling pathway plays a pivotal role in regulating cell growth and organ size. Its regulatory effects on hepatocellular carcinoma (HCC) encompass diverse aspects, including cell proliferation, invasion and metastasis, tumor drug resistance, metabolic reprogramming, immunomodulatory effects and autophagy. Yes‑associated protein 1 (YAP1), a potent transcriptional coactivator and a major downstream target tightly controlled by the Hippo pathway, is influenced by various molecules and pathways. The expression of YAP1 in different cell types within the liver tumor microenvironment exerts varying effects on tumor outcomes, warranting careful consideration. Therefore, research on YAP1‑targeted therapies merits attention. This review discusses the composition and regulation mechanism of the Hippo/YAP1 signaling pathway and its relationship with HCC, offering insights for future research and cancer prevention strategies.

Syngeneic mouse model of YES-driven metastatic and proliferative hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a disease of high unmet medical need that has become a global health problem. The development of targeted therapies for HCC has been hindered by the incomplete understanding of HCC pathogenesis and the limited number of relevant preclinical animal models. We recently unveiled a previously uncharacterized YES kinase (encoded by YES1)-dependent oncogenic signaling pathway in HCC. To model this subset of HCC, we established a series of syngeneic cell lines from liver tumors of transgenic mice expressing activated human YES. The resulting cell lines (referred to as HepYF) were enriched for expression of stem cell and progenitor markers, proliferated rapidly, and were characterized by high SRC family kinase (SFK) activity and activated mitogenic signaling pathways. Transcriptomic analysis indicated that HepYF cells are representative of the most aggressive proliferation class G3 subgroup of HCC. HepYF cells formed rapidly growing metastatic tumors upon orthotopic implantation into syngeneic hosts. Treatment with sorafenib or the SFK inhibitor dasatinib markedly inhibited the growth of HepYF tumors. The new HepYF HCC cell lines provide relevant preclinical models to study the pathogenesis of HCC and test novel small-molecule inhibitor and immunotherapy approaches.

Integrated Bioinformatic Analysis Reveals the Oncogenic, Survival, and Prognostic Characteristics of TPX2 in Hepatocellular Carcinoma.

Targeting protein for Xenopus kinesin-like protein 2 (TPX2), a well-known mitotic protein, has been linked to carcinogenesis in several cancers. This study investigated the role of TPX2 in hepatocellular carcinoma (HCC) from various aspects using bioinformatic analyses. TPX2 expression and its prognostic value in pan-cancers were analyzed using SangerBox. TPX2 expression and its association with prognosis, immune infiltration, tumor mutations, and signaling pathways in HCC were analyzed using UALCAN, BoxKaplan-Meier Plotter, GEPIA, Human Protein Atlas, TIMER 2.0, and SangerBox. Genes co-expressed with TPX2 in HCC were analyzed using the HCCDB database, followed by functional enrichment using SangerBox. Clinical predictive models were established based on TPX2 and its co-expressed genes using the ACLBI database. TPX2 expression significantly increased in pan-cancers and was associated with survival in nearly half of the cancer types. High TPX2 expression has been linked to poor survival outcomes in patients with HCC. TPX2 expression was positively correlated with abundant infiltration of immune cells (including B cells, CD4 + /CD8 + T cells, macrophages, neutrophils, and dendritic cells), TP53 mutation, and carcinogenesis-related pathways, such as the PI3K/AKT/mTOR pathway, cellular response to hypoxia, and tumor proliferation signature. Nineteen genes were found to be co-expressed with TPX2 in HCC, and these genes showed close positive correlations and were mainly implicated in cell cycle-related functions. A prognostic model established using TPX2 and its expressed genes could stratify HCC patients into high- and low-risk groups, with a significantly shorter survival time in high-risk groups. The prognostic model performed well in predicting 1-, 3-, and 5-year survival of patients with HCC, with areas under the curve of 0.801, 0.725, and 0.711, respectively. TPX2 functions as an oncogene in HCC, and its high expression is detrimental to the survival of patients with HCC. Thus, TPX2 may be a prognostic biomarker and potential therapeutic target for HCC.

Tumor-infiltrating T-Lymphocyte immunity-related immune tolerance and anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy for advanced hepatocellular carcinoma

Abstract Systemic therapy has become the standard treatment for patients with advanced hepatocellular carcinoma (HCC) whose treatment options are limited. However, the long-term patient response to drugs and the survival outcomes remain a concern. With increasing exploration of the HCC microenvironment, particularly in terms of T lymphocyte immunity, a new era of immunomolecular targeted therapy, based on molecular signaling, has arrived for advanced HCC. In the study of immune tolerance of the intrinsic HCC microenvironment, we found that multiple immunosuppressive mechanisms and immune checkpoint inhibitors, such as anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy, have improved clinical outcomes in some patients with advanced HCC. Furthermore, various combination therapies have been investigated, and HCC types have been categorized into different types based on anti–programmed cell death protein 1 (PD-1)/ligand of programmed cell death protein 1 (PD-L1) treatment. In this paper, we first discuss the tumor-infiltrating T lymphocyte immunity and immune tolerance of HCC. We then clarify the basic mechanism of anti–PD-1/PD-L1 therapy and discuss the types of HCC based on anti–PD-1/PD-L1 therapy. Thereafter, we explain the relevant studies and mechanisms of combination therapy of anti–PD-1/PD-L1 with antiangiogenesis drugs or multikinase kinase inhibitors, anti–T lymphocyte–related signaling pathways in HCC, and other anti-CD8+ T cell immune checkpoints. In this way, this review offers a deeper understanding of anti–PD-1/PD-L1 immunotherapy for advanced HCC, in order to provide better individualized treatments for patients with advanced HCC.

Reappraisal of the Roles of the Sonic Hedgehog Signaling Pathway in Hepatocellular Carcinoma.

HCC remains one of the leading causes of cancer-related death globally. The main challenges in treatments of hepatocellular carcinoma (HCC) primarily arise from high rates of postoperative recurrence and the limited efficacy in treating advanced-stage patients. Various signaling pathways involved in HCC have been reported. Among them, the Sonic hedgehog (SHH) signaling pathway is crucial. The presence of SHH ligands is identified in approximately 60% of HCC tumor tissues, including tumor nests. PTCH-1 and GLI-1 are detected in more than half of HCC tissues, while GLI-2 is found in over 84% of HCC tissues. The SHH signaling pathway (including canonical and non-canonical) is involved in different aspects of HCC, including hepatocarcinogenesis, tumor growth, tumor invasiveness, progression, and migration. The SHH signaling pathway also contributes to recurrence, metastasis, modulation of the cancer microenvironment, and sustaining cancer stem cells. It also affects the resistance of HCC cells to chemotherapy, target therapy, and radiotherapy. Reappraisal of the roles of the SHH signaling pathway in HCC may trigger some novel therapies for HCC.

Prognostic value of CD8+T cells related genes and exhaustion regulation of Notch signaling pathway in hepatocellular carcinoma.

Immunotherapy has emerged as the primary treatment modality for patients with advanced Hepatocellular carcinoma (HCC). However, its clinical efficacy remains limited, benefiting only a subset of patients, while most exhibit immune tolerance and face a grim prognosis. The infiltration of immune cells plays a pivotal role in tumor initiation and progression. In this study, we conducted an analysis of immune cell infiltration patterns in HCC patients and observed a substantial proportion of CD8+T cells. Leveraging the weighted gene co-expression network analysis (WGCNA), we identified 235 genes associated with CD8+T cell and constructed a risk prediction model. In this model, HCC patients were stratified into a high-risk and low-risk group. Patients in the high-risk group exhibited a lower survival rate, predominantly presented with intermediate to advanced stages of cancer, displayed compromised immune function, showed limited responsiveness to immunotherapy, and demonstrated elevated expression levels of the Notch signaling pathway. Further examination of clinical samples demonstrated an upregulation of the Notch1+CD8+T cell exhaustion phenotype accompanied by impaired cytotoxicity and cytokine secretion functions that worsened with increasing Notch activation levels. Our study not only presents a prognostic model but also highlights the crucial involvement of the Notch pathway in CD8+T cell exhaustion-a potential target for future immunotherapeutic interventions.

Wnt/β-Catenin signaling pathway in hepatocellular carcinoma: pathogenic role and therapeutic target.

Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor and one of the leading causes of cancer-related deaths worldwide. The Wnt/β-Catenin signaling pathway is a highly conserved pathway involved in several biological processes, including the improper regulation that leads to the tumorigenesis and progression of cancer. New studies have found that abnormal activation of the Wnt/β-Catenin signaling pathway is a major cause of HCC tumorigenesis, progression, and resistance to therapy. New perspectives and approaches to treating HCC will arise from understanding this pathway. This article offers a thorough analysis of the Wnt/β-Catenin signaling pathway's function and its therapeutic implications in HCC.

Abstract 4572: Ginsenoside Rh3 increases the susceptibility of regorafenib-mediated cancer cell death by inhibiting the JAK/STAT3 signaling pathway in hepatocellular carcinoma

Abstract Ginsenosides, bioactive compounds derived from Panax ginseng, exhibit diverse pharmacological effects, including anti-cancer properties. Regorafenib, a potent multi-kinase inhibitor, is employed as a second-line therapy for advanced hepatocellular carcinoma (HCC). However, the modest survival benefits observed in treated patients may be attributed to drug resistance. In this study, we screened a panel of 40 ginsenosides for their activity in combination with regorafenib in HCC cell lines and investigated their underlying cellular mechanisms. Synergistic effects were evaluated using the WST-8 assay, and optimal drug concentrations were determined through synergy scoring. A phospho-kinase assay was conducted to elucidate the mechanism of action, and in vivo experiments validated our findings. Ginsenoside Rh3 emerged as a promising candidate, enhancing the sensitivity of HCC cells to regorafenib-induced anticancer effects by promoting apoptosis. The phospho-kinase array revealed that the combined treatment's apoptotic effect was associated with the inhibition of signal transducer and activator of transcription 3 (STAT3) activation through the Janus kinase pathway. In vivo results demonstrated the combination treatment's inhibitory effects on tumor growth. Our study proposes a novel treatment strategy, highlighting the potential efficacy of combining regorafenib and ginsenoside Rh3 for HCC treatment. Citation Format: Youngsic Jeon, Hyukjoon Kwon, Young Nyun Park, Dong-Young Woo, Taejung Kim, Jungyeob Ham, Young-Joo Kim. Ginsenoside Rh3 increases the susceptibility of regorafenib-mediated cancer cell death by inhibiting the JAK/STAT3 signaling pathway in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4572.

Abstract 1102: Amentoflavone enhances regorafenib-induced apoptosis and -inhibited invasion via inactivating STAT3/NF-ΚB signaling pathway in Hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is an aggressive tumor and ranks as the third leading cause of cancer-related deaths worldwide. Amentoflavone, a biflavonoid compound, possesses antiviral, angiogenesis-inhibitory, and anticancer properties. Prior studies have illustrated that amentoflavone effectively restrains tumor growth and promotes apoptosis in various cancers, including brain cancer and osteosarcoma. Regorafenib, a small molecule inhibitor of multi-kinases, can inhibit angiogenesis, tumor growth, and anti-tumor metastasis. While regorafenib is a targeted drug approved for the treatment of metastatic colorectal cancer and has also been approved for use in HCC, its effectiveness in HCC is limited. Consequently, our goal is to investigate whether amentoflavone may enhance the sensitivity of regorafenib in treating HCC and explore the underlying mechanisms. In our study, through the combined treatment and combination index analysis, we proved that the combination of regorafenib and amentoflavone may induce cytotoxicity more effectively compared to monotherapy, as assessed by the MTT assay in Huh7 and HepG2 cells. The invasion and migration assays also demonstrated a superior inhibitory effect in the combination group. Additionally, apoptosis markers such as "cleaved caspase-3, -8, -9, Fas and FasL" assayed by flow cytometry, confirm that the combination treatment may induce the extrinsic/intrinsic apoptosis pathway in HCC. In our Western blotting analysis, we observed that the phosphorylation of STAT3 and NF-κB proteins was effectively suppressed by the combination of regorafenib and amentoflavone in Huh7 and HepG2 cells, respectively. Furthermore, our in vivo study confirmed a superior tumor inhibition rate and control rate with the combination of regorafenib and amentoflavone. Importantly, no signs of general toxicity were observed in any of the treatment groups, as evidenced by body weight monitoring and Hematoxylin and Eosin stain (H&E) pathology evaluation. We believe that the combined treatment of these two drugs effectively triggers cell death and suppresses metastatic patterns through the inactivation of the STAT3/NF-κB signaling pathway. These results suggest that amentoflavone has the potential to serve as an adjuvant that sensitizes regorafenib for the treatment of HCC without causing any side effects. Citation Format: Yan ting Tsai, Ying-Tzu Chen, Fei-Ting Hsu, Jai-Jen Tsai, Yu-Chiang Liu. Amentoflavone enhances regorafenib-induced apoptosis and -inhibited invasion via inactivating STAT3/NF-ΚB signaling pathway in Hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1102.

The underlying mechanism and targeted therapy strategy of miRNAs cross-regulating EMT process through multiple signaling pathways in hepatocellular carcinoma.

The consistent notion holds that hepatocellular carcinoma (HCC) initiation, progression, and clinical treatment failure treatment failure are affected by the accumulation of various genetic and epigenetic alterations. MicroRNAs (miRNAs) play an irreplaceable role in a variety of physiological and pathological states. meanwhile, epithelial-mesenchymal transition (EMT) is a crucial biological process that controls the development of HCC. miRNAs regulate the intermediation state of EMTor mesenchymal-epithelial transition (MTE)thereby regulating HCC progression. Notably, miRNAs regulate key HCC-related molecular pathways, including the Wnt/β-catenin pathway, PTEN/PI3K/AKT pathway, TGF-β pathway, and RAS/MAPK pathway. Therefore, we comprehensively reviewed how miRNAs produce EMT effects by multiple signaling pathways and their potential significance in the pathogenesis and treatment response of HCC. emphasizing their molecular pathways and progression in HCC initiation. Additionally, we also pay attention to regulatory mechanisms that are partially independent of signaling pathways. Finally, we summarize and propose miRNA-targeted therapy and diagnosis and defense strategies forHCC. The identification of the mechanism leading to the activation of EMT programs during HCC disease processes also provides a new protocol for the plasticity of distinct cellular phenotypes and possible therapeutic interventions. Consequently, we summarize the latest progress in this direction, with a promising path for further insight into this fast-moving field.

Identification of hub genes within the CCL18 signaling pathway in hepatocellular carcinoma through bioinformatics analysis.

Hepatocellular carcinoma (HCC) is an aggressive malignancy, and CCL18, a marker of M2 macrophage activation, is often associated with tumor immune suppression. However, the role of CCL18 and its signaling pathway in HCC is still limited. Our study focuses on investigating the prognostic impact of CCL18 and its signaling pathway in HCC patients and biological functions in vitro. HCC-related RNA-seq data were obtained from TCGA, ICGC, and GEO. The 6 hub genes with the highest correlation to prognosis were identified using univariate Cox and LASSO regression analysis. Multivariate Cox regression analysis was performed to assess their independent prognostic potential and a nomogram was constructed. In vitro experiments, including CCK8, EdU, RT-qPCR, western blot, and transwell assays, were conducted to investigate the biological effects of exogenous CCL18 and 6 hub genes. A core network of highly expressed proteins in the high-risk group of tumors was constructed. Immune cell infiltration was evaluated using the ESTIMATE and CIBERSORT packages. Finally, potential treatments were explored using the OncoPredict package and CAMP database. We identified 6 survival-related genes (BMI1, CCR3, CDC25C, CFL1, LDHA, RAC1) within the CCL18 signaling pathway in HCC patients. A nomogram was constructed using the TCGA_LIHC cohort to predict patient survival probability. Exogenous CCL18, as well as overexpression of BMI1, CCR3, CDC25C, CFL1, LDHA, and RAC1, can promote proliferation, migration, invasion, stemness, and increased expression of PD-L1 protein in LM3 and MHCC-97H cell lines. In the high-risk group of patients from the TCGA_LIHC cohort, immune suppression was observed, with a strong correlation to 21 immune-related genes and suppressive immune cells. Exogenous CCL18 promotes LM3 and MHCC-97H cells proliferation, migration, invasion, stemness, and immune evasion. The high expression of BMI1, CCR3, CDC25C, CFL1, LDHA, and RAC1 can serve as a biomarkers for immune evasion in HCC.

Accumulation of TOX high mobility group box family member 3 promotes the oncogenesis and development of hepatocellular carcinoma through the MAPK signaling pathway.

Microvascular invasion (MVI) has been widely valued in the field of liver surgery because MVI positivity indicates poor prognosis in hepatocellular carcinoma (HCC) patients. However, the potential molecular mechanism underlying the poor prognosis of MVI-positive HCC patients is unclear. Therefore, this study focused on identifying the key genes leading to poor prognosis in patients with a high degree of malignancy of HCC by examining the molecular signaling pathways in MVI-positive HCC patients. Through RNA sequencing, TOX high mobility group box family member 3 (TOX3) was demonstrated to be significantly highly expressed in MVI-positive HCC tissues, which was associated with poor prognosis. The results of in vivo and in vitro showed that TOX3 can promote the oncogenesis and development of HCC by targeting key molecules of the MAPK and EMT signaling pathways. The IP-MS results indicated that proteasome degradation of TOX3 in HCC cells is potentially mediated by a tripartite motif containing 56 (TRIM56, an E3 ligase) in HCC cells. Inhibiting TRIM56 enhances TOX3 protein levels. Overall, our study identified TOX3 as a key gene in the MAPK and EMT signaling pathways in HCC, and its overexpression confers significant proliferation and invasiveness to tumor cells.

The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism

Cancer cells integrate multiple biosynthetic demands to drive unrestricted proliferation. How these cellular processes crosstalk to fuel cancer cell growth is still not fully understood. Here, we uncover the mechanisms by which the transcription factor Carbohydrate responsive element binding protein (ChREBP) functions as an oncogene during hepatocellular carcinoma (HCC) development. Mechanistically, ChREBP triggers the expression of the PI3K regulatory subunit p85α, to sustain the activity of the pro-oncogenic PI3K/AKT signaling pathway in HCC. In parallel, increased ChREBP activity reroutes glucose and glutamine metabolic fluxes into fatty acid and nucleic acid synthesis to support PI3K/AKT-mediated HCC growth. Thus, HCC cells have a ChREBP-driven circuitry that ensures balanced coordination between PI3K/AKT signaling and appropriate cell anabolism to support HCC development. Finally, pharmacological inhibition of ChREBP by SBI-993 significantly suppresses in vivo HCC tumor growth. Overall, we show that targeting ChREBP with specific inhibitors provides an attractive therapeutic window for HCC treatment.

REVIEWING ADVANCES IN UNDERSTANDING AND TARGETING THE MAPK SIGNALING PATHWAY IN HEPATOCELLULAR CARCINOMA PROGRESSION AND THERAPEUTICS

Hepatocellular carcinoma (HCC) is a severe and increasingly prevalent health issue affecting individuals globally. Recent research endeavors in the clinical domains have lately focused more on the MAPK signaling pathway in HCC. Activating mutations in the RAS and RAF genes, which greatly activate the MAPK pathway in malignancies, are rare in HCC patients, yet over 50% of them have activated the pathway. This suggests that other factors may be responsible for the activation of the signaling pathway in HCC. MAPK signaling is important to carcinogenesis, and it is often altered in human cancers. The drug resistance in targeted therapy against RTKs in HCC may arise from mutations in downstream components (RAS, RAF, MEK, ERK), resistant mutations within RTKs, and additional alternative pathways like PI3K and YAP may also develop the resistance. Epigenetic processes and chromatin remodeling are crucial to pharmacological tolerance to MAPK regulation. This review will focus on the latest developments in our knowledge of the cellular and molecular processes to activate the MAPK signaling pathway, as well as possible treatment approaches that specifically target this pathway in relation to HCC. The study also investigates the clinical efficacy of molecular-targeted treatments, including tyrosine kinase inhibitors and immunological checkpoint inhibitors and highlights the use of combination therapy for HCC.

Integrated analysis of lactate-related genes identifies POLRMT as a novel marker promoting the proliferation, migration and energy metabolism of hepatocellular carcinoma via Wnt/β-Catenin signaling.

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

Role of Ubiquitin-specific Proteases in Hepatocellular Carcinoma Pathogenesis.

Signaling pathways in hepatocellular carcinoma are primarily mediated by the phosphorylation and ubiquitination of post-translational proteins. In mammalian cells, ubiquitin-specific proteases (USPs) account for the majority of protein deubiquitination activities. In addition to transcriptional and post-translational regulation, ubiquitination plays an important role in the regulation of key proteins. There is a possibility that altered biological processes may lead to serious human diseases, including cancer. Recent studies have revealed the role of USPs in hepatocellular carcinoma tumorigenesis. The purpose of this review is to summarize the involvement of this class of enzymes in the regulation of cell signaling in hepatocellular carcinoma and the therapeutic development of inhibitors that target USPs, which may lead to novel therapies to treat hepatocellular carcinoma.