Hepatocellular carcinoma (HCC) is a substantial global health challenge owing to its high mortality rate and limited therapeutic options. We aimed to develop an efferocytosis-related gene signature (ER.Sig) and conduct a transcriptomic analysis to predict the prognosis and immunotherapeutic responses of patients with HCC.

Single-cell RNA sequencing data and bulk RNA sequencing data were obtained from public databases. Based on single-sample gene set enrichment analysis and Weighted Gene Co-expression Network analyses, efferocytosis-related genes (ERGs) were selected at both the single-cell and bulk transcriptome levels. A machine-learning framework employing ten different algorithms was used to develop the ER.Sig. Subsequently, a multi-omics approach (encompassing genomic analysis, single-cell transcriptomics, and bulk transcriptomics) was employed to thoroughly elucidate the prognostic signatures.

Analysis of the HCC single-cell transcriptomes revealed significant efferocytotic activity in macrophages, endothelial cells, and fibroblasts within the HCC microenvironment. We then constructed a weighted co-expression network and identified six modules, among which the brown module (168 genes) was most highly correlated with the efferocytosis score (cor = 0.84). Using the univariate Cox regression analysis, 33 prognostic ERGs were identified. Subsequently, a predictive model was constructed using 10 machine-learning algorithms, with the random survival forest model showing the highest predictive performance. The final model, ER.Sig, comprised nine genes and demonstrated robust prognostic capabilities across multiple datasets. High-risk patients exhibited greater intratumoral heterogeneity and higher TP53 mutation frequencies than did low-risk patients. Immune landscape analysis revealed that compared with high-risk patients, low-risk patients exhibited a more favorable immune environment, characterized by higher proportions of CD8+ T and B cells, tumor microenvironment score, immunophenoscore, and lower Tumor Immune Dysfunction and Exclusion scores, indicating better responses to immunotherapy. Additionally, an examination of an independent immunotherapy cohort (IMvigor210) demonstrated that low-risk patients exhibited more favorable responses to immunotherapy and improved prognoses than did their high-risk counterparts.

The developed ER.Sig effectively predicted the prognosis of patients with HCC and revealed significant differences in tumor biology and treatment responses between the risk groups.

Cancer treatment has long been hindered by the complexity of the tumor microenvironment (TME) and the mechanisms that tumors employ to evade immune detection. Recently, the combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic therapies has emerged as a promising approach to improve cancer treatment outcomes. This review delves into the role of immunostimulatory molecules and ICIs in enhancing anti-tumor immunity, while also discussing the therapeutic potential of anti-angiogenic strategies in cancer. In particular, we highlight the critical role of endoplasmic reticulum (ER) stress in angiogenesis. Moreover, we explore the potential of macrophage reprogramming to bolster anti-tumor immunity, with a focus on restoring macrophage phagocytic function, modulating hypoxic tumor environments, and targeting cytokines and chemokines that shape immune responses. By examining the underlying mechanisms of combining ICIs with anti-angiogenic therapies, we also review recent clinical trials and discuss the potential of biomarkers to guide and predict treatment efficacy.

Neuropilin and tolloid-like 2 (NETO2) facilitates the progression of various cancers, but its role in hepatocellular carcinoma (HCC) is not known. This study aimed to assess the potential of targeting NETO2 in HCC and its relationship with the STAT3/C-MYC pathway.

HCC cells (Huh7 and MHCC-97 H) were cultured and transfected with control siRNA (siCtrl), NETO2 siRNA (siNETO2), control overexpression (oeCtrl), or NETO2 overexpression (oeNETO2), with non-transfected cells used as blank controls.

NETO2 mRNA and protein expressions were reduced in both Huh7 and MHCC-97 H cells. EdU and CCK-8 assays indicated that cell proliferation was decreased after siNETO2 transfection in Huh7 and MHCC-97 H cells. TUNEL assay found revealed that the cell apoptosis rate was greater after siNETO2 transfection in MHCC-97 H cells, and tended to be greater in Huh7 cells (but the difference was not statistically significant). Transwell invasion assay revealed that the number of invasive Huh7 and MHCC-97 H cells decreased after siNETO2 transfection. Cell scratch assay revealed that the cell migration rate was reduced after siNETO2 transfection in Huh7 cells but was not significantly different in MHCC-97 H cells. Western blotting revealed that p-STAT3 and C-MYC expressions were decreased after siNETO2 transfection in Huh7 and MHCC-97 H cells. Overexpression experiments revealed that cell proliferation and invasion were promoted but that the cell apoptosis rate was reduced after oeNETO2 transfection in Huh7 and MHCC-97 H cells.

NETO2 knockdown suppresses HCC cell proliferation, invasion, and migration and inactivates the STAT3/C-MYC pathway, suggesting that NETO2 is a potential target for HCC treatment.

In addition to radical resection, liver transplantation (LTx) is an effective treatment for hepatocellular carcinoma (HCC). However, tumor recurrence limits the efficacy of LTx in some patients. This study investigated the role of 18F-fludeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in predicting the prognosis of patients with HCC after LTx.

A total of 278 consecutive patients with HCC who underwent pre-LTx PET/CT were divided into derivation (n = 178) and temporal validation (n = 100) cohorts and evaluated for PET/CT values, immunohistochemical (IHC) findings, and DNA sequencing of tumor tissues.

Patients with post-LTx recurrence exhibited significantly higher tumor maximum standardized uptake values (SUVmax) in pre-LTx PET/CT scans. Receiver operating characteristic curve analyses identified the tumor SUVmax to liver SUVmax ratio (TSUVmax/LSUVmax) as the strongest predictor of post-LTx recurrence, with an optimal cutoff value of 1.43. Kaplan-Meier analyses demonstrated that a TSUVmax/LSUVmax >1.43 was associated with a shorter time to recurrence (TTR) and overall survival (OS) in both cohorts (p < 0.001 for both). Multivariate Cox regression analyses confirmed that TSUVmax/LSUVmax >1.43 was an independent risk factor for tumor recurrence in both cohorts. IHC revealed that TSUVmax/LSUVmax >1.43 correlated with higher Ki-67 and CK19 expression. DNA sequencing indicated that tumors with TSUVmax/LSUVmax >1.43 had more mutations and a higher TMB. Furthermore, TSUVmax/LSUVmax >1.43 was significantly associated with mutations in TP53, EPPK1, MDM4, SLAMF7, SDHC, B4GALT3, RXRG, and FCGR family genes, as well as TP53 and PI3K signaling-related alterations.

The preoperative TSUVmax/LSUVmax is a potential predictor of tumor recurrence in patients with HCC following LTx. Its use improves candidate selection and post-LTx management.

Primary hepatocellular carcinoma (PHC) is the sixth most common cancer and the third leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) accounts for 75%-85% of PHC. LARP3 is aberrantly expressed in multiple cancers. We found that it is significantly highly expressed in the liver cancer tissues of HCC patients, but the exact role and specific mechanism of this abnormal expression are not yet clear. In this study, through bioinformatics analysis, we concluded that LARP3 expression is associated with a poor prognosis for patients with HCC. Through cellular experiments such as gene editing and phenotypic functions, we found that LARP3 promotes the occurrence and development of HCC and inhibits apoptosis. Finally, through biological means such as RNA sequencing, flow cytometry, western blotting, and the construction of a subcutaneous tumorigenesis model in nude mice, we concluded that inhibition of HCC apoptosis by LARP3 is related to LARP3 negatively regulating ROS level and inhibiting the PI3K/c-Fos/apoptosis axis. This study will provide potential targets for the treatment of HCC.

The study was designed to evaluate molecular alterations, relevant to the prognosis and personalized therapy of salivary gland cancers (SGCs).

DNA was extracted from archival tissue of 40 patients with various SGCs subtypes. A targeted next-generation sequencing (NGS) panel was used for the identification of small-scale mutations, focal and chromosomal arm-level copy number changes. The final analysis included selected genes with potential actionable aberrations for targeted therapies and outcome predictions in 37 tumours' samples.

The follow-up of the SGCs study cohort revealed disease recurrence or metastasis in 19 patients and indicated poor individual outcomes. The mean disease-free survival (DFS) within the poor outcome group was 2.4 years, and the overall survival (OS) was 5.4 years. The DFS and OS of the remaining 18 patients with favourable outcomes were 8.3 years. The genes most frequently affected with aberrations were NF1 (n = 9, 24%) and TP53 (n = 8, 22%), with increased occurrence observed in the poor outcome group: NF1 (n = 6, 32%) and TP53 (n = 6, 32%). CDKN2A biallelic deletion was the most common copy number variation (n = 5), and was detected in 4 cases with identified disease relapse. TERT promoter mutation and amplification were found in myoepithelial carcinoma. A p.Ile35Thr mutation was discovered in CTNNB1 in two cases of adenoid cystic carcinoma. ERBB2 alterations were remarkable for SDC ex PA. Furthermore, TP53 mutation was established as a relevant negative prognostic factor for overall survival (p = 0,04). The analysis revealed potentially actionable genes in detected alterations in: MECA 100% (1/1), SDC 100% (7/7), AD 92% (11/12), Ca ex PA 82% (18/22), MECA 65% (20/31), AdCC 64% (9/14) and AcCC 0% (0/1).

SGCs are a heterogeneous group of malignancies with distinct molecular landscape that characterized by poor prognosis and inadequate treatment options. Nonstandard strategies might be beneficial for patients who suffer from salivary gland cancers. Wider utilization of NGS analysis may increase the opportunity for patients with those rare cancers to receive more precise, personalized therapy.

Hepatocellular carcinoma (HCC) is recognized globally as one of the most lethal tumors, presenting a significant menace to patients' lives owing to its exceptional aggressiveness and tendency to recur. Transcatheter hepatic arterial chemoembolization (TACE) therapy, as a first-line treatment option for patients with advanced HCC, has been proven effective. However, it is disheartening that nearly 40 % of patients exhibit resistance to this therapy. Consequently, this review delves into the metabolic aspects of glucose metabolism to explore the underlying mechanisms behind TACE treatment resistance and to propose potentially fruitful therapeutic strategies. The ultimate objective is to present novel insights for the development of personalized treatment methods targeting HCC.

Despite recent advances in treatment strategy, lung cancer remains the leading cause of cancer-related mortality worldwide, and it is a serious threat to human health. Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer, and approximately 40-50% of patients with LUAD in Asian populations have epidermal growth factor receptor (EGFR) mutations. The use of EGFR tyrosine kinase inhibitors (EGFR-TKIs) has revolutionarily improved the prognosis of patients with EGFR-mutated LUAD. However, acquired drug resistance is the main cause of treatment failure. Therefore, new therapeutic strategies are necessary to address the resistance to EGFR-TKIs in patients with LUAD. Cancer stemness-related factors lead to multiple-drug resistance in cancer treatment, including EGFR-TKI resistance. Coiled-coil domain-containing 34 (CCDC34) serves as an oncogene in several types of cancer. However, the role and molecular mechanism of CCDC34 in the malignant progression of LUAD have not been reported to date. In the present study, we found that CCDC34 may be associated with LUAD stemness through weighted gene co-expression network analysis (WGCNA). Furthermore, we demonstrated that CCDC34 promoted LUAD stemness properties through β-catenin-mediated regulation of ATG5-induced autophagy, which was conducive to acquired EGFR-TKI resistance in LUAD in vitro and in vivo. Knockdown CCDC34 can synergistically inhibit tumor growth when combined with EGFR-TKIs. This study reveals a positive association between CCDC34 and the stemness phenotype of LUAD, providing new insights into overcoming EGFR-TKI resistance in LUAD by inhibiting CCDC34 expression.

Lenvatinib, an approved first-line regimen, has been widely applied in hepatocellular carcinoma (HCC). However, clinical response towards Lenvatinib was limited, emphasizing the importance of understanding the underlying mechanism of its resistance. Herein, we employed integrated bioinformatic analysis to identify calpain-2 (CAPN2) as a novel key regulator for Lenvatinib resistance in HCC, and its expression greatly increased in both Lenvatinib-resistant HCC cell lines and clinical samples. Further in vitro and in vivo experiments indicated that knocking down CAPN2 greatly sensitized HCC cells to Lenvatinib treatment, while overexpression of CAPN2 achieved opposite effects in a Lenvatinib-sensitive HCC cell line. Interestingly, we observed a close relationship between CAPN2 expression and cancer stem cell (CSC) traits in HCC cells, evidenced by impaired sphere-forming and CSC-related marker expressions after CAPN2 knockdown, and verse vice. Mechanistically, we strikingly discovered that CAPN2 exerted its function by both enzyme-dependent and enzyme-independent manner simultaneously: activating β-Catenin signaling through its enzyme activity, and preventing GLI1/GLI2 degradation through direct binding to YWHAE in an enzyme-independent manner, which disrupting the association between YWHAE and GLI1/GLI2 to inhibit YWHAE-induced degradation of GLIs. Notably, further co-immunoprecipitation assays revealed that YWHAE could promote the protein stability of CAPN2 via recruiting a deubiquitinase COPS5 to prevent ubiquitination-induced degradation of CAPN2. In summary, our data demonstrated that CAPN2 promoted Lenvatinib resistance via both catalytic activity-dependent and -independent approaches. Reducing CAPN2 protein rather than inhibiting its activity might be a promising strategy to improve Lenvatinib treatment efficiency in HCC.

CMTM6 has been closely associated with the onset and progression of various tumor types. However, the precise mechanism by which CMTM6 operates in hepatocellular carcinoma remains elusive, necessitating further investigation.

Expression levels of CMTM6 in hepatocellular carcinoma tissues and cells were analyzed using immunohistochemistry and quantitative real-time PCR. The correlation between CMTM6 expression in hepatocellular carcinoma tissues and clinical pathological characteristics, as well as patient prognosis, was investigated. Proliferation and apoptosis of hepatocellular carcinoma cells with silenced or overexpressed CMTM6 were assessed, alongside measurements of β-catenin and Wnt1 protein expression levels. In vivo research was conducted utilizing a murine subcutaneous transplantation model. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to elucidate the regulatory mechanism of CMTM6. Additionally, CD66b expression levels in tumor tissue were examined using immunohistochemistry, and the immune infiltration of CMTM6 and tumor-associated neutrophils (TANs) was analyzed.

Elevated expression levels of CMTM6 in hepatocellular carcinoma tissues and cells were found to be associated with poor patient prognosis. Overexpression of CMTM6 in hepatocellular carcinoma cells was demonstrated to promote cellular proliferation and inhibit apoptosis. Mechanistically, CMTM6 expression levels in hepatocellular carcinoma tissues were observed to positively correlate with β-catenin expression. GSEA and KEGG analysis revealed significant enrichment of CMTM6 in the Wnt/β-catenin pathway, indicating its involvement in pathway regulation. Furthermore, CMTM6 was found to be associated with immune infiltration of TANs in hepatocellular carcinoma tissues.

CMTM6 plays a pivotal role in the development and progression of hepatocellular carcinoma through regulation of the Wnt/β-catenin pathway via β-catenin. Moreover, CMTM6 demonstrates the capacity to promote immune infiltration of TANs in hepatocellular carcinoma tissues. Consequently, CMTM6 exhibits potential as both an early diagnostic marker and a novel therapeutic target for patients with hepatocellular carcinoma.

Liver cirrhosis (LC) and hepatocellular carcinoma (HCC) resulting from chronic hepatitis B virus (HBV) infection are major health concerns. Identifying critical biomarkers and molecular targets is needed for early diagnosis, prognosis, and therapy of these diseases.

In this study, we explored the gene expression and metabolism in the liver tissues of LC, HCC, and healthy controls, to analyse and identify potential biomarkers of disease progression. Mass spectrometry imaging was used to evaluate the spatial distribution of key metabolites.

The results revealed significant changes in gene expression and metabolic pathways along with disease progression. The upregulated genes were associated with extracellular matrix remodeling and cancer pathways, including LAMC1-3, COL9A2, COL1A1, MYL9, MYH11, and KAT2A. The downregulated genes were linked to immune response and fatty acid metabolism. Metabolomic analysis showed major changes in lipid and choline metabolism. Consistent changes in the expression of specific genes and metabolites were correlated with clinical data. Notably, metabolites such as L-acetylcarnitine, histamine, and 4-trimethylammoniobutanoic acid demonstrated high accuracy (AUC > 0.85) in distinguishing between healthy, LC, and HCC groups. This study identifies key gene and metabolite changes in HBV related LC and HCC, highlighting critical pathways involved in disease progression. Biomarkers like L-acetylcarnitine and KAT2A show promise for early diagnosis and prognosis, potentially improving outcomes for hepatitis liver disease patients.

BACKGROUND This study aimed to investigate the expression of RSPO3 and ß-catenin in preeclampsia and the relationship between RSPO3 and b-catenin levels and maternal-fetal outcomes. MATERIAL AND METHODS We enrolled 60 pregnant women with preeclampsia and 60 pregnant women without preeclampsia. We collected peripheral blood from the patients upon admission; placenta and cord blood were collected after delivery. The expression of RSPO3 and ß-catenin in maternal blood, cord blood, and placenta was measured. We used the Spearman method to examine the correlations between clinical characteristics and RSPO3. Logistic regression modeling was used to identify the independent risk factors for preeclampsia. RESULTS RSPO3 and ß-catenin levels were decreased in the peripheral blood, cord blood, and placentas of women with preeclampsia, with significant differences (P<0.05). The preeclampsia group had more adverse pregnancy outcomes. RSPO3 level of the preeclampsia group was negatively correlated with systolic blood pressure (r=-0.4654, P<0.001) and diastolic blood pressure (r=-0.4617, P<0.001) in cord blood, and systolic blood pressure (r=-0.5373, P<0.05) and diastolic blood pressure (r=-0.4898, P<0.05) in maternal blood. CONCLUSIONS RSPO3 and ß-catenin were decreased in preeclampsia, RSPO3 was negatively correlated with blood pressure, and RSPO3 could be a risk factor for the development of preeclampsia.

The tripartite motif (TRIM) protein family has been shown to play important roles in the occurrence and development of various tumors. However, the biological functions of TRIM47 and its regulatory mechanism in hepatocellular carcinoma (HCC) remain unexplored. Here, we showed that TRIM47 was upregulated in HCC tissues compared with adjacent normal tissues, especially at advanced stages, and associated with poor prognosis in HCC patients. Functional studies demonstrated that TRIM47 enhanced the migration and invasion ability of HCC cells in vitro and in vivo. Mechanistically, TRIM47 promotes HCC metastasis through interacting with SNAI1 and inhibiting its degradation by proteasome. Moreover, TRIM47 was di-methylated by CARM1 at its arginine 210 (R210) and arginine 582 (R582), which protected TRIM47 from the ubiquitination and degradation mediated by E3 ubiquitin ligase complex CRL4CRBN. Collectively, our study reveals a pro-metastasis role of TRIM47 in HCC, unveils a unique mechanism controlling TRIM47 stability by CARM1 mediated arginine methylation, and highlights the role of the CARM1-CRL4CRBN-TRIM47-SNAI1 axis in HCC metastasis. This work may provide potential therapeutic targets for metastatic HCC treatment.

Hepatocellular carcinoma (HCC) is a leading liver cancer that significantly impacts global life expectancy and remains challenging to treat due to often late diagnoses. Despite advances in treatment, the prognosis is still poor, especially in advanced stages. Studies have pointed out that investigations into the molecular mechanisms underlying HCC, including mitochondrial dysfunction and epigenetic regulators, are potentially important targets for diagnosis and therapy. Mitoepigenetics, or the epigenetic modifications of mitochondrial DNA, have drawn wide attention for their role in HCC progression. Besides, molecular biomarkers such as mitochondrial DNA alterations and non-coding RNAs showed early diagnosis and prognosis potential. Additionally, natural compounds like alkaloids, resveratrol, curcumin, and flavonoids show promise in HCC show promise in modulating mitochondrial and epigenetic pathways involved in cancer-related processes. This review discusses how mitochondrial dysfunction and epigenetic modifications, especially mitoepigenetics, influence HCC and delves into the potential of natural products as new adjuvant treatments against HCC.

Per- and polyfluoroalkyl substances (PFASs) are a family of "forever chemicals" including perfluorooctane sulfonate (PFOS). These toxic chemicals do not break down in the environment or in our bodies. In the human body, PFOS and perfluoroctanoic acid (PFOA) have a half-life (T1/2) of about 4-5 yr so low daily consumption of these chemicals can accumulate in the human body to a harmful level over a long period. Although the use of PFOS in consumer products was banned in the United States in 2022/2023, this forever chemical remains detectable in our tap water and food products. Every American tested has a high level of PFAS in their blood (https://cleanwater.org/pfas-forever-chemicals). In this report, we used a Sertoli cell blood-testis barrier (BTB) model with primary Sertoli cells cultured in vitro with an established functional tight junction (TJ)-permeability barrier that mimicked the BTB in vivo. Treatment of Sertoli cells with PFOS was found to perturb the TJ-barrier, which was the result of cytoskeletal disruption across the cell cytoplasm, disrupting actin and microtubule polymerization. These changes thus affected the proper localization of BTB-associated proteins at the BTB. Using RNA-Seq transcriptome profiling, bioinformatics analysis, and pertinent biochemical and cell biology techniques, it was discovered that PFOS -induced Sertoli cell toxicity through the c-Jun N-terminal kinase (JNK; also known as stress-activated protein kinase, SAPK) and its phosphorylated/active form p-JNK signaling pathway. More importantly, KB-R7943 mesylate (KB), a JNK/p-JNK activator, was capable of blocking PFOS-induced Sertoli cell injury, supporting the notion that PFOS-induced cell injury can possibly be therapeutically managed.NEW & NOTEWORTHY PFOS induces Sertoli cell injury, including disruption of the 1) blood-testis barrier function and 2) cytoskeletal organization, which, in turn, impedes male reproductive function. These changes are mediated by JNK/p-JNK signaling pathway. However, the use of KB-R7943, a JNK/p-JNK activator was capable of blocking PFOS-induced Sertoli cell injury, supporting the possibility of therapeutically managing PFOS-induced reproductive dysfunction.

Advanced hepatocellular carcinoma (HCC) is one of the most challenging cancers because of its heterogeneous and aggressive nature, precluding the use of curative treatments. Sorafenib (SOR) is the first approved molecular targeting agent against the mitogen-activated protein kinase (MAPK) pathway for the noncurative therapy of advanced HCC; yet, any clinically meaningful benefits from the treatment remain modest, and are accompanied by significant side effects. Here, we hypothesized that using a nanomedicine platform to co-deliver SOR with another molecular targeting drug, metformin (MET), could tackle these issues. A micelle self-assembled with amphiphilic polypeptide methoxy poly(ethylene glycol)-block-poly(L-phenylalanine-co-l-glutamic acid) (mPEG-b-P(LP-co-LG)) (PM) was therefore designed for combinational delivery of two molecular targeted drugs, SOR and MET, to hepatomas. Compared with free drugs, the proposed, dual drug-loaded micelle (PM/SOR+MET) enhanced the drugs' half-life in the bloodstream and drug accumulation at the tumor site, thereby inhibiting tumor growth effectively in the preclinical subcutaneous, orthotopic and patient-derived xenograft hepatoma models without causing significant systemic and organ toxicity. Collectively, these findings demonstrate an effective dual-targeting nanomedicine strategy for treating advanced HCC, which may have a translational potential for cancer therapeutics. STATEMENT OF SIGNIFICANCE: Treatment of advanced hepatocellular carcinoma (HCC) remains a formidable challenge due to its aggressive nature and the limitations inherent to current therapies. Despite advancements in molecular targeted therapies, such as Sorafenib (SOR), their modest clinical benefits coupled with significant adverse effects underscore the urgent need for more efficacious and less toxic treatment modalities. Our research presents a new nanomedicine platform that synergistically combines SOR with metformin within a specialized diblock polypeptide micelle, aiming to enhance therapeutic efficacy while reducing systemic toxicity. This innovative approach not only exhibits marked antitumor efficacy across multiple HCC models but also significantly reduces the toxicity associated with current treatments. Our dual-molecular targeting approach unveils a promising nanomedicine strategy for the molecular treatment of advanced HCC, potentially offering more effective and safer treatment alternatives with significant translational potential.

Hepatocyte nuclear factor 4-alpha (HNF4α), a well-preserved member of the nuclear receptor superfamily of transcription factors, is found in the liver. It is recognized as a central controller of gene expression specific to the liver and plays a key role in preserving the liver's homeostasis. Irregular expression of HNF4α is increasingly recognized as a crucial factor in the proliferation, cell death, invasiveness, loss of specialized functions, and metastasis of cancer cells. An increasing number of studies are pointing to abnormal HNF4α expression as a key component of cancer cell invasion, apoptosis, proliferation, dedifferentiation, and metastasis. Understanding HNF4α's intricate involvement in liver carcinogenesis provides a promising avenue for therapeutic intervention. This chapter attempts to shed light on the diverse aspects of HNF4's role in liver carcinogenesis and demonstrate how this knowledge can be harnessed for approaches to prevent and treat liver cancer. This comprehensive chapter will offer an elaborate perspective on HNF4's function in liver cancer, delineating its molecular mechanisms that aid in the emergence of liver cancer. Furthermore, it will highlight the potential to help create more effective and precisely targeted therapeutic strategies, rekindling fresh optimism in the fight against this formidable condition.

Wnt/FZD-mediated signaling pathways are activated in more than 90% of hepatocellular carcinoma (HCC) cell lines. As a well-known secretory glycoprotein, Wnt3 can interact with FZD receptors on the cell surface, thereby activating the Wnt/β-catenin signaling pathway. However, the N-glycosylation modification site of Wnt3 and the effect of this modification on the biological function of the protein are still unclear.

To investigate the effect of Wnt3 N-glycosylation on the biological function of HCC cells.

Site-directed mutagenesis was used to verify the Wnt3 N-glycosylation sites, actinomycin D treatment was used to detect the stability of Wnt3 after site-directed mutation, the binding of the N-glycosylation site-directed mutant Wnt3 to FZD7 was observed by laser confocal microscopy, and the effects of the N-glycosylation site-directed mutation of Wnt3 on the Wnt/β-catenin signaling pathway and the progression of HCC cells were detected by western blot and cell function experiments.

Wnt3 has two N-glycosylation-modified sites (Asn90 and Asn301); when a single site at amino acid 301 is mutated, the stability of Wnt3 is weakened; the binding ability of Wnt3 to FZD7 decreases when both sites are mutated simultaneously; and the level of proteins related to the Wnt/β-catenin signaling pathway is downregulated. Cell proliferation, migration and invasion are also weakened in the case of single 301 site and double-site mutations.

These results indicate that by inhibiting the N-glycosylation of Wnt3, the proliferation, migration, invasion and colony formation abilities of liver cancer cells can be weakened, which might provide new therapeutic strategies for clinical liver cancer in the future.

Leukocyte cell-derived chemotaxin-2 (LECT2) is an important cytokine synthesized by liver. Significant research interest is stimulated by its crucial involvement in inflammatory response, immune regulation, disease occurrence and development. However, bibliometric study on LECT2 is lacking. In order to comprehend the function and operation of LECT2 in human illnesses, we examined pertinent studies on LECT2 investigation in the Web of Science database, followed by utilizing CiteSpace, VOSview, and Scimago Graphica for assessing the yearly quantity of papers, countries/regions involved, establishments, authors, publications, citations, and key terms. Then we summarized the current research hotspots in this field. Our study found that the literature related to LECT2 has a fluctuating upward trend. "Angiogenesis", "ALECT2", "diagnosis", and "biliary atresia" are the current investigative frontiers. Our findings indicated that liver diseases (e.g. liver fibrosis and hepatic cell carcinoma), systemic inflammatory disease, and amyloidosis are the current research focus of LECT2. The current LECT2 research outcomes are not exceptional. We hope to promote the scientific research of LECT2 and exploit its potential for clinical diagnosis and treatment of related diseases through a comprehensive bibliometric review.

Hepatocellular carcinoma (HCC) is the fifth most common malignancies worldwide, and its high morbidity and mortality have brought a heavy burden to the global public health system. Due to the concealment of its onset, the limitation of treatment, the acquisition of multi-drug resistance and radiation resistance, the treatment of HCC cannot achieve satisfactory results. Epithelial mesenchymal transformation (EMT) is a key process that induces progression, distant metastasis, and therapeutic resistance to a variety of malignant tumors, including HCC. Therefore, targeting EMT has become a promising tumor immunotherapy method for HCC. The NF-κB pathway is a key regulatory pathway for EMT. Targeting this pathway has shown potential to inhibit HCC infiltration, invasion, distant metastasis, and therapeutic resistance. At present, there are still some controversies about this pathway and new ideas of combined therapy, which need to be further explored. This article reviews the progress of immunotherapy in improving EMT development in HCC cells by exploring the mechanism of regulating EMT.

In this review, we summarized published articles on the role of tripartite motif (TRIM) family members in the initiation and development of human malignancies.

The ubiquitin-proteasome system (UP-S) plays a critical role in cellular activities, and UP-S dysregulation contributes to tumorigenesis. One of the key regulators of the UP-S is the tripartite motif TRIM protein family, most of which are active E3 ubiquitin ligases. TRIM proteins are critical for the biological functions of cancer cells, including migration, invasion, metastasis, and therapy resistance. Therefore, it is important to understand how TRIM proteins function at the molecular level in cancer cells.

We provide a comprehensive and up-to-date overview about the role TRIMs play in cancer progression and therapy resistance. We propose TRIM family members as potential new markers and targets to overcome therapy failure.

Liver cancer, predominantly hepatocellular carcinoma (HCC), globally ranks sixth in incidence and third in cancer-related deaths. HCC risk factors include non-viral hepatitis, alcohol abuse, environmental exposures, and genetic factors. No specific genetic alterations are unequivocally linked to HCC tumorigenesis. Current standard therapies include surgical options, systemic chemotherapy, and kinase inhibitors, like sorafenib and regorafenib. Immunotherapy, targeting immune checkpoints, represents a promising avenue. FDA-approved checkpoint inhibitors, such as atezolizumab and pembrolizumab, show efficacy, and combination therapies enhance clinical responses. Despite this, the treatment of hepatocellular carcinoma (HCC) remains a challenge, as the complex tumor ecosystem and the immunosuppressive microenvironment associated with it hamper the efficacy of the available therapeutic approaches. This review explores current and advanced approaches to treat HCC, considering both known and new potential targets, especially derived from proteomic analysis, which is today considered as the most promising approach. Exploring novel strategies, this review discusses antibody drug conjugates (ADCs), chimeric antigen receptor T-cell therapy (CAR-T), and engineered antibodies. It then reports a systematic analysis of the main ligand/receptor pairs and molecular pathways reported to be overexpressed in tumor cells, highlighting their potential and limitations. Finally, it discusses TGFβ, one of the most promising targets of the HCC microenvironment.

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterised by the immune-mediated destruction of small and medium intrahepatic bile ducts, with variable outcomes and progression. This review summarises the state of the art regarding the risk of neoplastic progression in PBC patients, with a particular focus on the molecular alterations present in PBC and in hepatocellular carcinoma (HCC), which is the most frequent liver cancer in these patients. Major risk factors are male gender, viral infections, e.g., HBV and HCV, non-response to UDCA, and high alcohol intake, as well as some metabolic-associated factors. Overall, HCC development is significantly more frequent in patients with advanced histological stages, being related to liver cirrhosis. It seems to be of fundamental importance to unravel eventual dysfunctional molecular pathways in PBC patients that may be used as biomarkers for HCC development. In the near future, this will possibly take advantage of artificial intelligence-designed algorithms.

A meta-analysis was performed to assess the benefits and safety profile of approved immune checkpoint inhibitors in hepatocellular carcinoma patients. Eligible studies were searched from Cochrane, Embase, and PubMed databases based on a well-established strategy. Following the exclusion of ineligible studies, 12 studies were included in this meta-analysis. Compared with control group, immune checkpoint inhibitors were associated with improved ORR (OR 3.03, 95% CI 2.26-4.05, P < 0.00001), SD (OR 0.77, 95% CI 0.62-0.95, P = 0.02), OS (HR 0.75, 95% CI 0.68-0.83, P < 0.00001), and PFS (HR 0.74, 95% CI 0.63-0.87, P < 0.0003). However, no significant differences were observed in DCR (OR 1.33, 95% CI 0.97-1.81, P = 0.07), PD (OR 0.90, 95% CI 0.67-1.21, P = 0.48), and all caused any-grade adverse events (OR 1.22, 95% CI 0.62-2.39, P = 0. 57), all caused ≥ grade 3 adverse events (OR 1.10, 95% CI 0.97-1.25, P = 0.14), treatment-related any-grade adverse events (OR 1.13, 95% CI 0.55-2.32, P = 0.73), and treatment-related ≥ grade 3 events (OR 0.82, 95% CI 0.34-1.97, P = 0.65) between the two groups. After subgroup analysis conducted, patients in the immune checkpoint inhibitor group compared with targeted drug group showed significant improvements in OS (HR 0.74, 95% CI 0.66-0.84, P < 0.00001) and PFS (HR 0.75, 95% CI 0.61-0.91, P = 0.004). Immune checkpoint inhibitors have demonstrated peculiar benefits in the treatment of HCC with an acceptable safety profile. Compared to targeted drugs, immune checkpoint inhibitors still offer advantages in the treatment of hepatocellular carcinoma. However, there is still considerable room for further improvement.

Hepatocellular Carcinoma (HCC) is a pressing health concern, demanding a deep understanding of various mediators' roles in its development for therapeutic progress. Notably, interleukin-6 (IL-6) has taken center stage in investigations due to its intricate and context-dependent functions. This review delves into the dual nature of IL-6 in HCC, exploring its seemingly contradictory roles as both a promoter and an inhibitor of disease progression. We dissect the pro-tumorigenic effects of IL-6, including its impact on tumor growth, angiogenesis, and metastasis. Concurrently, we examine its anti-tumorigenic attributes, such as its role in immune response activation, cellular senescence induction, and tumor surveillance. Through a comprehensive exploration of the intricate interactions between IL-6 and the tumor microenvironment, this review highlights the need for a nuanced comprehension of IL-6 signaling in HCC. It underscores the importance of tailored therapeutic strategies that consider the dynamic stages and diverse surroundings within the tumor microenvironment. Future research directions aimed at unraveling the multifaceted mechanisms of IL-6 in HCC hold promise for developing more effective treatment strategies and improving patient outcomes.