Fluorescence navigation is a novel technique for accurately identifying hepatocellular carcinoma (HCC) lesions during hepatectomy, enabling real-time visualization. Indocyanine green-based fluorescence guidance has been commonly used to demarcate HCC lesion boundaries, but it cannot distinguish between benign and malignant liver tumors. This review focused on the clinical applications and limitations of indocyanine green, as well as recent advances in novel fluorescent probes for fluorescence-guided surgery of HCC. It covers traditional fluorescent imaging probes such as enzymes, reactive oxygen species, reactive sulfur species, and pH-sensitive probes, followed by an introduction to aggregation-induced emission probes. Aggregation-induced emission probes exhibit strong fluorescence, low background signals, excellent biocompatibility, and high photostability in the aggregate state, but show no fluorescence in dilute solutions. Design strategies for these probes may offer insights for developing novel fluorescent probes for the real-time identification and navigation of HCC during surgery.

Clinically approved treatments for advanced liver cancer often lack potency because of the heterogeneous characteristics of hepatocellular carcinoma (HCC). This complexity is largely driven by context-dependent inflammatory responses brought on by diverse etiologies, such as metabolic dysfunction-associated steatohepatitis (MASH), the genetic makeup of cancer cells, and the versatile adaptability of immune cells, such as myeloid cells. In this review, we discuss the evolutionary dynamics of the immune landscape, particularly that of liver-resident Kupffer cells (KCs), TREM2+, and SPP1+ macrophages with an active role during liver disease progression, which eventually fuels hepatocarcinogenesis. We highlight exploitable immunomodulatory avenues amenable to mitigate both the inherent pathological characteristics of liver cancers and the associated external factors that favor malignancy, paving a roadmap toward improving the management and therapeutic outcome for patients with HCC.

Hepatocellular carcinoma (HCC) corresponds to the vast majority of liver cancer cases, with one of the highest mortality rates. Major advances have been made in this field both in the characterization of the molecular pathogenesis and in the development of systemic therapies. Despite these achievements, biomarkers and more efficient treatments are still needed to improve its management. Heparan sulfate (HS) chains are polysaccharides that are present at the cell surface or in the extracellular matrix that are able to bind various types of molecules, such as soluble factors, affecting their availability and thus their effects, or to contribute to interactions that position cells in their environments. Enzymes can modify HS chains after their synthesis, thus changing their properties. Numerous studies have shown HS-related proteins to be key actors that are associated with cellular effects, such as tumor growth, invasion, and metastasis, including in the context of liver carcinogenesis. The aim of this review is to provide a comprehensive overview of the biology of HS chains and their potential importance in HCC, from biological considerations to clinical development, and the identification of biomarkers, as well as therapeutic perspectives.

Currently, no drugs directly treat liver fibrosis. Previously, we have shown that treatment with miR-29a-3p improved liver fibrosis in a mouse model. To investigate the effectiveness of nucleic acid therapy at a lower dose, a modified nucleic acid was prepared based on miR-29a-3p. The original microRNA was changed to an RNA-DNA hybrid structure: the 2' position of the RNA was modified with a fluorine base, and locked nucleic acid and phosphorothioate were crosslinked (hereafter called modified nucleic acid). In a mouse model of chronic liver disease treated with carbon tetrachloride (CCl4), the inhibitory effect on liver fibrosis was evaluated with oral administration of the modified nucleic acid. The modified nucleic acid was detected in the liver and gastrointestinal tract within 15 min of oral administration. After 5 weeks of stimulation with CCl4, oral administration of the modified nucleic acid for 2 weeks improved liver fibrosis; CCl4 stimulation was continued during this period as well. This treatment also suppressed the worsening of liver fibrosis. We developed a method to improve liver fibrosis orally using nuclease-resistant nucleic acids without using a drug delivery system. This method may be used as a new treatment for inhibiting the progression of liver fibrosis.

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are two distinct types of primary liver cancer (PLC) characterized by considerable extents of cellular and molecular heterogeneities. We recently developed a web-based cell atlas called LiverSCA that possesses a user-friendly interface and comprehensive functionalities. It facilitates the exploration of gene expression patterns, cellular compositions, and intercellular communication within the microenvironments of liver and PLC tumors.

To further enhance the documentation of data pinpointing different phenotypes/subtypes of liver and PLC, we extended the catalog of LiverSCA with additional datasets, e.g., ICC and metabolic dysfunction-associated steatotic liver disease/steatosis (MASLD/MASH).

The current enhanced version of the LiverSCA cell atlas encompasses six phenotypes (normal, HBV-HCC, HCV-HCC, non-viral HCC, ICC, and MASH), 63 patients, and over 248,000 cells. Furthermore, we have incorporated comparative visualization methods that allow users to simultaneously examine and compare gene expression levels between two different phenotypes.

We are committed to the continuous development of LiverSCA and envision that it will serve as a valuable resource to support researchers in convenient investigations into the cellular and molecular landscapes of liver and PLC.

The highly nuanced transition from an inflammatory process to tumorigenesis is of great scientific interest. While it is well known that environmental stimuli can cause inflammation, less is known about the oncogenic modifications that chronic inflammation in the tissue microenvironment can bring about, as well as how these modifications can set off pro-tumorigenic processes. It is clear that no matter where the environmental factors come from, maintaining an inflammatory microenvironment encourages carcinogenesis. In addition to encouraging angiogenesis and metastatic processes, sustaining the survival and proliferation of malignant transformed cells, and possibly altering the efficacy of therapeutic agents, inflammation can negatively regulate the antitumoral adaptive and innate immune responses. Because chronic inflammation has multiple pathways involved in tumorigenesis and metastasis, it has gained recognition as a marker of cancer and a desirable target for cancer therapy. Recent advances in our knowledge of the molecular mechanisms that drive cancer's progression demonstrate that inflammation promotes tumorigenesis and metastasis while suppressing anti-tumor immunity. In many solid tumor types, including breast, lung, and liver cancer, inflammation stimulates the activation of oncogenes and impairs the body's defenses against the tumor. Additionally, it alters the microenvironment of the tumor. As a tactical approach to cancer treatment, these findings have underscored the importance of targeting inflammatory pathways. This review highlights the role of inflammation in cancer development and metastasis, focusing on its impact on tumor progression, immune suppression, and therapy resistance. It examines current anti-inflammatory strategies, including NSAIDs, cytokine modulators, and STAT3 inhibitors, while addressing their potential and limitations. The review emphasizes the need for further research to unravel the complex mechanisms linking inflammation to cancer progression and identify molecular targets for specific cancer subtypes.

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and is associated with poor survival. Formosanin C (FC) is a diosgenin glycoside extracted from Paris polyphylla. Therapeutic effects of FC against HCC malignancies remain unclear.

This study aimed to understand the anti-HCC effects of FC and to disclose the underlying mechanisms.

We evaluated the effects of FC on HCC malignancies by using two HCC cell lines, HepG2 and Huh-7, and a xenograft model.

Multiple assessment methods were used, including CCK-8, colony formation, flow cytometry, wound healing, transwell and Western blot. Bioinformatic analyses such as network pharmacology were also employed. Xenograft mouse model was used to evaluate in vivo efficacy.

FC treatment remarkedly suppressed HepG2 and Huh-7 cell proliferation, migration and invasion, and induced cell apoptosis. Such anti-HCC effects of FC mainly attributed to the upregulation of DUSP1 expression and the subsequent activation of autophagy via AMPK/ULK1/Beclin1 axis. Inhibition of autophagy weakened the therapeutic effects of FC. Xenograft model analysis provided in vivo evidence that FC suppressed HCC tumor growth via DUSP1.

FC is therapeutically effective to suppress HCC malignancies principally via activation of the DUSP1/AMPK/ULK1/Beclin1-mediated autophagy. Our findings provide a novel promising drug candidate for treating HCC.

One can recognize multidrug resistance (MDR) and residue as a biggest difficulty in cancer specialist. Chemotherapy-resistant cancer may be successfully treated by combining MDR-reversing phytochemicals with anticancer drugs. Though, clinical application of phytochemicals either alone or in conjunction with chemotherapy is still in its early stages or requires more research to determine their safety and efficacy. In this review we highlighted topics related to MDR in cancer, including an introduction to subject, mechanism of action of efflux pump, specific proteins involved in drug resistance, altered drug targets, increased drug metabolism, and potential role of phytochemicals in overcoming drug resistance.

Viral hepatitis is a public health problem, about 1 million people die due to complications of this viral disease, the etiological agents responsible for inducing cirrhosis and cellular hepatocarcinoma are HBV and HCV, both hepatotropic viruses that cause asymptomatic infection in most cases. The regulation of the microbiota performs many physiological functions, which can induce normal intestinal function and produce essential nutrients for the human body. Metabolites derived from gut microbiota or direct regulation of host immunity and metabolism have been reported to profoundly affect tumorigenesis in liver disease. If the microbiota is unbalanced, both exogenous and symbiotic microorganisms can affect a pathological process. It is well understood that the microbiota plays a role in viral diseases and infections, specifically the hepatic portal pathway has been linked to the gut-liver axis. In HBV and HCV infections, the altered bacterial representatives undergo a state of dysbiosis, with subsequent establishment of the pathobiome with overexpression of taxons such as Bacteroides, Clostridium, Lactobacillus, Enterobacter, and Enterococcus. This dysregulated microbiome induces a microenvironment conducive to the development of hepatic complications in patients with acute and chronic HBV and HCV infection, with subsequent dysregulation of cytokines IFN-α/β, TNF-α, IL-1β, TGF-β, IL-6 and IL-10, which alter the dysfunction and damage of the hepatic portal system. In view of the above, this review aimed to correlate the pathophysiological mechanisms in HBV and HCV infection, the dysregulation of the microbiome in patients infected with HBV and HCV, the most altered cytokines in the microbiome, and the most altered bacterial representatives in the pathobiome of infection.

Cytokeratin 19 (CK19)-positive HCC is a subtype of hepatocellular carcinoma (HCC) with poor biological behavior and resistance to different treatments including transarterial chemoembolization (TACE). The current study aimed to investigate the predictive value of serum CK 19 fragment 21-1 (CYFRA 21-1) and serum CK 19 fragment 2G2 (CK 19-2G2) for TACE response in patients with hepatitis C virus (HCV)-related HCC.

This prospective study assessed the pretreatment serum CYFRA 21-1 and CK 19-2G2 levels in 64 patients with HCV-related naïve HCC who underwent TACE to predict 1-year overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Additionally, 40 healthy individuals were included as controls. Pretreatment alpha-fetoprotein (AFP) was also measured for comparison.

After exclusions, 60 patients completed TACE sessions, and the 1-year OS was 52%, and ORR post TACE was 71.8%. HCC patients with elevated levels of CYFRA 21-1, CK 19-2G2, or baseline AFP measuring ≥400 ng/ml have decreased 1-year OS and PFS after TACE. Serum CK19-2G2 was an independent predictor of 1-year OS using multivariate hazard regression analysis. Pretreatment normal serum CYFRA 21-1 levels (P = 0.047), serum AFP measuring <400 ng/ml (P = 0.016), and lower AST (P = 0.002) were independent predictors of ORR to TACE using multivariate logistic regression analysis. The predictive ability of pretreatment elevated serum CYFRA 21-1, AFP measuring ≥400 ng/ml, AFP + CYFRA 21-1, AFP + CK 19-2G2, or AFP + CYFRA 21-1+ CK19-2G2 to predict nonresponse (progressive disease) to TACE (area under the curve = 0.795, 0.690, 0.830, 0.725, and 0.850, respectively).

This study demonstrated that incorporating the measurement of serum CYFRA 21-1 or CK19-2G2 levels, along with AFP, during the initial diagnosis can aid in predicting poor 1-year OS, PFS, and ORR to TACE in patients with HCV-related HCC.

RNA pseudouridylation, a dynamic and reversible post-transcriptional modification found in diverse RNA species, is crucial for various biological processes, including tRNA homeostasis, tRNA transport, translation initiation regulation, pre-mRNA splicing, enhancement of mRNA translation, and translational fidelity. Disruption of pseudouridylation impairs cellular homeostasis, contributing to pathological alterations. Recent studies have highlighted its regulatory role in human diseases, particularly in tumourigenesis. Cellular stresses trigger RNA pseudouridylation in organisms, suggesting that pseudouridylation-mediated epigenetic reprogramming is essential for maintaining cellular viability and responding to stress. This review examines the regulatory mechanisms and pathological implications of pseudouridylation in human diseases, with a focus on its involvement in tumourigenesis. Additionally, it explores the therapeutic potential of targeting pseudouridylation, presenting novel strategies for disease treatment. HIGHLIGHTS: Methods to detect pseudouridine were introduced from classic mass spectrometry-based methods to newer approaches such as nanopore-based technologies and BID sequencing, each with its advantages and limitations. RNA pseudouridylation is crucial for various biological processes, including tRNA homeostasis, tRNA transport, translation initiation regulation, pre-mRNA splicing, enhancement of mRNA translation, and translational fidelity. Increased pseudouridylation is frequently associated with tumour initiation, progression, and poor prognosis, whereas its reduction is predominantly implicated in non-tumour diseases. A comprehensive understanding of the inducing factors for RNA pseudouridylation will be essential for elucidating its role in diseases. Such insights can provide robust evidence for how pseudouridylation influences disease progression and offer new avenues for therapeutic strategies targeting pseudouridylation dysregulation. The therapeutic potential of RNA pseudouridylation in diseases is enormous, including inhibitors targeting pseudouridine synthases, the application of RNA pseudouridylation in RNA therapeutics, and its role as a biological marker.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, particularly due to the limited effectiveness of current therapeutic options for advanced-stage disease. The efficacy of traditional treatments is often compromised by the intricate liver microenvironment and the inherent heterogeneity. RNA-based therapeutics offer a promising alternative, utilizing the innovative approach of targeting aberrant molecular pathways and modulating the tumor microenvironment. The integration of nanotechnology in this field, through the development of advanced nanocarrier delivery systems, especially lipid nanoparticles (LNPs), polymer nanoparticles (PNPs), and bioinspired vectors, enhances the precision and efficacy of RNA therapies. This review highlights the significant progress in RNA nanotherapeutics for HCC treatment, covering micro RNA (miRNA), small interfering RNA (siRNA), message RNA (mRNA), and small activating RNA (saRNA) mediated gene silencing, therapeutic protein restoration, gene activation, cancer vaccines, and concurrent therapy. It further comprehensively discusses the prevailing challenges within this therapeutic landscape and provides a forward-looking perspective on the potential of RNA nanotherapeutics to transform HCC treatment.

Primary liver cancers are tumors that develop from different liver cells. Hepatocellular carcinoma (HCC), which develops from hepatocytes, accounts for approximately 75-85% of primary liver cancers.HCC is the 6th leading cause of cancer worldwide and the 3rd leading cause of cancer-related death. Its incidence is low in northern Europe, but high in sub-Saharan Africa and the Far East, where both hepatotropic viruses and exposure to mycotoxins are. It complicates cirrhosis in over 90% of cases and is predominantly male.The prevalence of HCC is increasing due to improved diagnostic techniques and criteria, but also to the persistence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in adults. A worldwide increase in the incidence of steatopathy makes it the leading cause of liver disease worldwide, associated with alcohol abuse and/or steatohepatitis associated with metabolic dysfunction (MASH), including type 2 diabetes.Chronic hepatotropic viral infections, cirrhosis and chemical carcinogens combine to produce an annual incidence of 2-5% of hepatocellular carcinoma arising from cirrhosis. This justifies biannual surveillance of known cirrhosis, without which late diagnosis limits therapeutic options.Major advances have been made in curative treatment (liver transplantation, surgery, radiodestruction) and palliative treatment (chemo- or radioembolization, sorafenib chemotherapy or immunotherapy), depending on how early HCC is diagnosed (size, number of hepatic or extrahepatic lesions) and the severity of underlying liver disease and associated comorbidities.

Tumor necrosis factor receptor-associated factor 3 (TRAF3)-interacting protein 3 (TRAF3IP3) expressed in various tumor cell. However, its role in hepatocellular carcinoma (HCC) was unclear. We aimed to demonstrate the relationship between TRAF3IP3 and HCC and explore the potential role of TRAF3IP3 in HCC.

The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Genotype-Tissue Expression (GTEx), KM-Plotter, University of Alabama at Birmingham Cancer data analysis Portal (UALCAN), and Xiantao Academic Online Website were utilized for the systematic analysis of TRAF3IP3. This analysis included mRNA expression, protein expression, prognostic value, enrichment analysis, and immune cell infiltration in HCC. Subsequently, immunohistochemistry was performed to assess the expression levels of TRAF3IP3 in both cancer and non-cancer tissues of patients with HCC.

Analysis of public databases and immunohistochemical staining on 20 pairs of samples confirmed a decrease in TRAF3IP3 expression in HCC. Both the TCGA database and GSE14520 indicated that patients with high TRAF3IP3 expression had a more favorable prognosis in terms of overall survival (OS) and progression-free interval (PFI), as shown by KM curve results. Multivariate Cox regression analysis further demonstrated that high TRAF3IP3 expression was an independent protective factor for HCC prognosis (hazard ratio (HR): 0.619, 95% confidence interval (CI) [0.399-0.959]; p < 0.05). In the high TRAF3IP3 expression group, various immune response-related molecular pathways, particularly B lymphocyte-mediated pathways, were activated. The level of TRAF3IP3 expression showed a significant correlation with the presence of tumor-infiltrating CD8+ T cells. Additionally, a positive correlation was observed between immunophenoscore (IPS) and TRAF3IP3 expression. Notably, the half-maximal inhibitory concentration (IC50) of commonly used chemotherapeutic drugs, such as lapatinib and mitomycin, was inversely associated with TRAF3IP3 expression in HCC patients.

TRAF3IP3 may be as a novel and promising biomarker for prognosis prediction and immunological evaluation of HCC.

Pretreatment identification of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) is important when selecting treatment strategies.

To improve models for predicting MVI and recurrence-free survival (RFS) by developing nomograms containing three-dimensional (3D) MR elastography (MRE).

Prospective.

188 patients with HCC, divided into a training cohort (n = 150) and a validation cohort (n = 38). In the training cohort, 106/150 patients completed a 2-year follow-up.

1.5T 3D multifrequency MRE with a single-shot spin-echo echo planar imaging sequence, and 3.0T multiparametric MRI (mp-MRI), consisting of diffusion-weighted echo planar imaging, T2-weighted fast spin echo, in-phase out-of-phase T1-weighted fast spoiled gradient-recalled dual-echo and dynamic contrast-enhanced gradient echo sequences.

Multivariable analysis was used to identify the independent predictors for MVI and RFS. Nomograms were constructed for visualization. Models for predicting MVI and RFS were built using mp-MRI parameters and a combination of mp-MRI and 3D MRE predictors.

Student's t-test, Mann-Whitney U test, chi-squared or Fisher's exact tests, multivariable analysis, area under the receiver operating characteristic curve (AUC), DeLong test, Kaplan-Meier analysis and log rank tests. P < 0.05 was considered significant.

Tumor c and liver c were independent predictors of MVI and RFS, respectively. Adding tumor c significantly improved the diagnostic performance of mp-MRI (AUC increased from 0.70 to 0.87) for MVI detection. Of the 106 patients in the training cohort who completed the 2-year follow up, 34 experienced recurrence. RFS was shorter for patients with MVI-positive histology than MVI-negative histology (27.1 months vs. >40 months). The MVI predicted by the 3D MRE model yielded similar results (26.9 months vs. >40 months). The MVI and RFS nomograms of the histologic-MVI and model-predicted MVI-positive showed good predictive performance.

Biomechanical properties of 3D MRE were biomarkers for MVI and RFS. MVI and RFS nomograms were established.

2 TECHNICAL EFFICACY: Stage 2.

Evolutionary medicine emerged in the late twentieth century, integrating principles of natural selection and adaptation with the health sciences. Today, with a rapidly widening gap between the biology of Homo sapiens and its environment, maladaptation or maladaptive disorders can be detected in almost all diseases, including liver dysfunction. However, in hepatology, as in most medical specialties, evolutionary considerations are neglected because the majority of the medical community is not familiar with evolutionary principles. The aim of this brief review is to highlight an evolutionary approach that may facilitate understanding various liver diseases.

Cancer-associated fibroblasts (CAFs), a predominant stromal cell type in the tumor microenvironment, significantly affect the progression of oral squamous cell carcinoma (OSCC).

The specific mechanisms through which CAFs influence the cancer stem cell phenotype in OSCC are not fully understood. This study explored the effects of lactic acid produced by CAFs on the cancer stem cells (CSCs) phenotype of OSCC cells. Our results demonstrated that CAFs exhibit increased glycolysis and lactic acid production. Lactic acid treatment enhances CSCs-related markers expression, sphere formation, and clonogenic ability of OSCC cells. RNA sequencing revealed that lactic acid treatment elevates Discs Large Homolog 5 (DLG5) expression and markedly affects the Hippo pathway. Further investigation revealed that DLG5 mediates the effects of lactic acid on the CSCs phenotype. DLG5 knockdown results in elevated expression of E3 ubiquitin ligase Cullin 3, which can promote the ubiquitination and degradation of MST1, but the expression of phosphorylated MST1 remains unchanged. This leads to enhanced binding of phosphorylated MST1 to YAP1, increasing YAP1 phosphorylation and activating the Hippo pathway.

Collectively, our findings suggest that lactic acid from CAFs promotes the CSCs phenotype in OSCC through the DLG5/CUL3/MST1 axis. Therefore, targeting lactic acid exchange between CAFs and tumor cells may provide a novel therapeutic approach to suppress the CSCs phenotype in OSCC.

Tumor xenograft animal models play a crucial role in hepatocellular carcinoma (HCC) research. Mice xenograft models are time consuming, laborious and expensive while zebrafish tumor xenograft models are cost-effective and effortless. However, the development of orthotopic xenograft models for HCC in zebrafish embryos has been challenging due to the small size of zebrafish livers. In this study, we utilized 7-day-old goldfish embryos as hosts and successfully established an orthotopic xenograft model of HCC in goldfish livers. Through injecting fluorescence labeled HCC cells into the liver of goldfish, we could visualize the proliferation and migration of tumor cells in vivo. In addition, we found that the temperature of 36 °C was better for tumor cell survival in goldfish larvae compared to 28 °C, assessed by EdU and TUNEL assays. Moreover, macrophage infiltration in the goldfish liver could be evaluated by neutral red staining. Finally, we evaluated the efficacy of the targeted therapy drug Sorafenib and the traditional Chinese medicine, Huaier granules, alone or in combination in the goldfish HCC orthotopic xenograft model. We found that the combination therapy showed the best efficacy against HCC cells in terms of macrophage infiltration, polarization as well as tumor cells proliferation, metastasis and apoptosis. In conclusion, the proposed goldfish HCC orthotopic xenograft model opens new avenues for HCC related research, including evaluation of tumor progression, cell interactions in the immune microenvironment, drug efficacy, and screening of anti-tumor drugs.

WNT1-inducible signalling pathway protein 1 (WISP1) promotes progression of several tumor entities often correlating with worse prognosis. Here its expression regulation and role in the progression of chronic liver diseases (CLD) was investigated.

WISP1 expression was analyzed in human HCC datasets, in biopsies and serum samples and an HCC patient tissue microarray (TMA) including correlation to clinicopathological parameters. Spatial distribution of WISP1 expression was determined using RNAscope analysis. Regulation of WISP1 expression was investigated in cytokine-stimulated primary mouse hepatocytes (PMH) by array analysis and qRT-PCR. Outcome of WISP1 stimulation was analyzed by IncuCyte S3-live cell imaging, qRT-PCR, and immunoblotting in murine AML12 cells.

In a TMA, high WISP1 expression was positively correlated with early HCC stages and male sex. Highest WISP1 expression levels were detected in patients with cirrhosis as compared to healthy individuals, patients with early fibrosis, and non-cirrhotic HCC in liver biopsies, expression datasets and serum samples. WISP1 transcripts were predominantly detected in hepatocytes of cirrhotic rather than tumorous liver tissue. High WISP1 expression was associated with better survival. In PMH, AML12 and HepaRG, WISP1 was identified as a specific TGF-β1 target gene. Accordingly, expression levels of both cytokines positively correlated in human HCC patient samples. WISP1-stimulation induced the expression of Bcl-xL, PCNA and p21 in AML12 cells.

WISP1 expression is induced by TGF-β1 in hepatocytes and is associated with cirrhotic liver disease. We propose a crucial role of WISP1 in balancing pro- and anti-tumorigenic effects during premalignant stages of CLD.

EphrinA5 belongs to a subclass of ephrin ligands. Abnormal signal transduction of EFNA5 shows a relationship to the development of various tumors. In this study, we explored the level of EFNA5 in hepatoma cells and the influence of up regulation of EFNA5 expression level on the proliferation, invasion, and migration of HepG2 and LM3 cells. Additionally, this work focused on examining its possible mechanism of action, and future impacts on clinical practice.

Immunohistochemistry was utilized to explore the connection between EFNA5 and hepatoma. Real-time quantitative polymerase chain reaction was used for determining the expression levels of EFNA5 in several hepatoma cell lines and normal hepatocytes. Cells were transfected with a pCMV3-EFNA5-flag plasmid and an EFNA5 plasmid. The expression efficiency of EFNA5 was identified through qRT-PCR. For the purpose of further identifying cell proliferation, the Cell Counting Kit-8 assay was applied. To identify changes of cell migration and invasion ability, Transwell and Boyden tests were utilized. Western blot was employed to identify the expressions mof EFNA5 and possible downstream molecules.

Data acquired from The Cancer Genome Atlas demonstrated that the level of EFNA5 in hepatoma was significantly downregulated in relative to the normal hepatocytes (P < 0.05). Upregulation of EFNA5 expression in hepatoma cells hindered the proliferative, invasive, and migratory ability of cells (P < 0.05). Additionally, EFNA5 downregulated the level of epithelial-mesenchymal transition-related molecules and EGFR.

The expression of EFNA5 was low in hepatoma cells. An increase in EFNA5 levels hinders the proliferation, invasion, and migration of hepatoma cells. These effects may occur through inhibition of hepatoma epithelial-mesenchymal transition by EFNA5. Moreover, the study on the mechanisms of proliferation, invasion and metastasis of hepatoma provides a novel theoretical basis, and may influence the clinical practice of tumor treatment in the future.

Since most Hepatocellular Carcinoma (HCC) typically arises as a consequence of long-term liver damage, the hepatic molecular characteristics are closely related to the occurrence of HCC. Gaining comprehensive information about the location, morphology, and hepatic molecular alterations related to HCC is essential for accurate diagnosis. However, there is a dearth of technological advancements capable of concurrently providing precise HCC diagnosis and discerning the accompanying hepatic molecular alterations. In this study, an integrated information system is developed for the pathological-level diagnosis of HCC and the revelation of critical molecular alterations in the liver. This system utilizes computed tomography/Surface-enhanced Raman scattering combined with an artificial intelligence strategy to establish connections between the occurrence of HCC and alterations in hepatic biomolecules. Employing artificial intelligence techniques, the SERS spectra from both healthy and HCC groups are successfully classified into two distinct categories with a remarkable accuracy rate of 91.38%. Based on molecular profiling, it is identified that the nucleotide-to-lipid signal ratio holds significant potential as a reliable indicator for the occurrence of HCC, thereby serving as a promising tool for prevention and therapeutic surveillance.

Atezolizumab/bevacizumab is the first line of treatment for unresectable hepatocellular carcinoma (HCC), combining immune checkpoint inhibitor and anti-VEGF monoclonal antibodies. Hepatic arterial infusion chemotherapy (HAIC) is administered when the above-described combination fails to confer sufficient clinical benefit. The present study aimed to explore the association between tumor programmed cell death-ligand 1 (PD-L1) positivity and HAIC response. A total of 40 patients with HCC who had undergone HAIC with available biopsy samples obtained between January 2020 and May 2023 were retrospectively enrolled. Tumor response, progression-free survival (PFS), disease control rate (DCR) and overall survival (OS) were evaluated. PD-L1 expression in tumor samples was assessed using a combined positivity score. The response rates of HAIC-treated patients with advanced HCC after failure of atezolizumab/bevacizumab combination therapy were recorded. OS (P=0.9717) and PFS (P=0.4194) did not differ between patients with and without PD-L1 positivity. The objective response rate (P=0.7830) and DCR (P=0.7020) also did not differ based on PD-L1 status. In conclusion, the current findings highlight the consistent efficacy of HAIC, regardless of PD-L1 positivity.

This study examines the relationship between red blood cell distribution width (RDW) and the prognosis of patients undergoing hepatectomy for hepatocellular carcinoma (HCC). Additionally, it explores the potential effect of RDW for the early identification of high-risk patients after surgery, advocating for timely interventions to improve outcomes. A comprehensive literature search was conducted on May 16, 2022, across PubMed (23 studies), Embase (45 studies), the Cochrane Library (1 study), and CNKI (17 studies), resulting in 6 relevant articles after screening. This analysis primarily focused on the postoperative outcomes of patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled to assess prognosis, with survival indicators including overall survival (OS) and disease-free survival (DFS). All 6 studies reported on OS, and 2 addressed DFS. A total of 1645 patients from 6 studies were included. The pooled analysis revealed that RDW is an independent prognostic factor for both OS (HR = 1.50, I² = 84%, 95% CI = 1.23-1.77, P < .01) and DFS (HR = 2.06, I² = 15%, 95% CI = 1.51-2.82, P < .01). Patients in the high RDW group exhibited significantly poorer OS and DFS compared to those in the low RDW group. RDW is a prognostic factor for HCC patients after surgery. Elevated RDW levels are associated with a poorer prognosis, adversely affecting both OS and DFS. RDW may serve as a valuable marker for stratifying risk and guiding intervention strategies in the postoperative management of HCC patients.

Immune checkpoint inhibitors (ICIs) represent a promising treatment for hepatocellular carcinoma (HCC) due to their capacity for abundant lymphocyte infiltration. However, some patients with HCC respond poorly to ICI therapy due to the presence of various immunosuppressive factors in the tumor microenvironment. Our research reveals that a macrophage-coated tumor cluster (MCTC) signifies a unique spatial structural organization in HCC correlating with diminished recurrence-free survival and overall survival in a total of 572 HCC cases from 3 internal cohorts and 2 independent external validation cohorts. Mechanistically, tumor-derived macrophage-associated lectin Mac-2 binding protein (M2BP) induces MCTC formation and traps immunocompetent cells at the edge of MCTCs to induce intratumoral cytotoxic T cell exclusion and local immune deprivation. Blocking M2BP with a Mac-2 antagonist might provide an effective approach to prevent MCTC formation, enhance T cell infiltration, and thereby improve the efficacy of ICI therapy in HCC.

Liver cancer (LC) is the sixth most common disease and the third most common cause of cancer-related mortality. The WHO predicts that more than 1 million deaths will occur from LC by 2030. Hepatocellular carcinoma (HCC) is a common form of primary LC. Today, the management of LC involves multiple disciplines, and multimodal therapy is typically selected on an individual basis, considering the intricate interactions between the patient's overall health, the stage of the tumor, and the degree of underlying liver disease. Currently, the treatment of cancers, including LC, has undergone a paradigm shift in the last ten years because of immuno-oncology. To treat HCC, immune therapy approaches have been developed to enhance or cause the body's natural immune response to specifically target tumor cells. In this context, immune checkpoint pathway inhibitors, engineered cytokines, adoptive cell therapy, immune cells modified with chimeric antigen receptors, and therapeutic cancer vaccines have advanced to clinical trials and offered new hope to cancer patients. The outcomes of these treatments are encouraging. Additionally, treatment using stem cells is a new approach for restoring deteriorated tissues because of their strong differentiation potential and capacity to release cytokines that encourage cell division and the formation of blood vessels. Although there is no proof that stem cell therapy works for many types of cancer, preclinical research on stem cells has shown promise in treating HCC. This review provides a recent update regarding the impact of immunotherapy and stem cells in HCC and promising outcomes.

Sorafenib, an FDA-approved drug for advanced hepatocellular carcinoma (HCC) treatment, encounters resistance in many patients. Deciphering the mechanisms underlying sorafenib resistance is crucial for devising alternative strategies to overcome it.

This study aimed to investigate sorafenib resistance mechanisms using a diverse panel of HCC cell lines.

HCC cell lines were subjected to continuous sorafenib treatment, and stable cell lines (Huh 7.5 and Huh 7PX) exhibiting sustained growth in its presence were isolated. The investigation of drug resistance mechanisms involved a comparative analysis of drug-targeted signal transduction pathways (EGFR/RAF/MEK/ERK/Cyclin D), sorafenib uptake, and membrane expression of the drug uptake transporter.

HCC cell lines (Huh 7.5 and Huh 7PX) with a higher IC50 (10μM) displayed a more frequent development of sorafenib resistance compared to those with a lower IC50 (2-4.8μM), indicating a potential impact of IC50 variation on initial treatment response. Our findings reveal that activated overexpression of Raf1 kinases and impaired sorafenib uptake, mediated by reduced membrane expression of organic cation transporter-1 (OCT1), contribute to sorafenib resistance in HCC cultures. Stable expression of the drug transporter OCT1 through cDNA transfection or adenoviral delivery of OCT1 mRNA increased sorafenib uptake and successfully overcame sorafenib resistance. Additionally, consistent with sorafenib resistance in HCC cultures, cirrhotic liver-associated human HCC tumors often exhibited impaired membrane expression of OCT1 and OCT3.

Intrinsic differences among HCC cell clones, affecting sorafenib sensitivity at the expression level of Raf kinases, drug uptake, and OCT1 transporters, were identified. This study underscores the potential of HCC tumor targeted OCT1 expression to enhance sorafenib treatment response.

Cucurbitacins, natural compounds highly abundant in the Cucurbitaceae plant family, are characterized by their anticancer, anti-inflammatory, and hepatoprotective properties. These compounds have potential as therapeutic agents in the treatment of liver cancer. This study investigated the association of cucurbitacin D, I, and E (CuD, CuI, and CuE) with the caspase cascade, Bcl-2 family, and oxidative stress modulators in the HepG2 cell line. We evaluated the antiproliferative effects of CuD, CuI, and CuE using the MTT assay. We analyzed Annexin V/PI double staining, cell cycle, mitochondrial membrane potential, and wound healing assays at different doses of the three compounds. To examine the modulation of the caspase cascade, we determined the protein and gene expression levels of Bax, Bcl-xL, caspase-3, and caspase-9. We evaluated the total antioxidant status (TAS), total oxidant status (TOS), superoxide dismutase (SOD), glutathione (GSH), Total, and Native Thiol levels to measure cellular redox status. CuD, CuI, and CuE suppressed the proliferation of HepG2 cells in a dose-dependent manner. The cucurbitacins induced apoptosis by increasing caspase-3, caspase-9, and Bax activity, inhibiting Bcl-xL activation, causing loss of ΔΨm, and suppressing cell migration. Furthermore, cucurbitacins modulated oxidative stress by increasing TOS levels and decreasing SOD, GSH, TAS, and total and native Thiol levels. Our findings suggest that CuD, CuI, and CuE exert apoptotic effects on the hepatocellular carcinoma cell line by regulating Bax/Bcl-xL, caspase-3/9 signaling, and causing intracellular ROS increase in HepG2 cells.

Immune checkpoint inhibitors (ICIs) combined with antiangiogenic therapy have shown encouraging clinical benefits for the treatment of unresectable or metastatic hepatocellular carcinoma (HCC). Nevertheless, therapeutic efficacy and wide clinical applicability remain a challenge due to "cold" tumors' immunological characteristics. Tumor immunosuppressive microenvironment (TIME) continuously natural force for immune escape by extracellular matrix (ECM) infiltration, tumor angiogenesis, and tumor cell proliferation. Herein, we proposed a novel concept by multi-overcoming immune escape to maximize the ICIs combined with antiangiogenic therapy efficacy against HCC. A self-delivery photothermal-boosted-NanoBike (BPSP) composed of black phosphorus (BP) tandem-augmented anti-PD-L1 mAb plus sorafenib (SF) is meticulously constructed as a triple combination therapy strategy. The simplicity of BPSP's composition, with no additional ingredients added, makes it easy to prepare and presents promising marketing opportunities. (1) NIR-II-activated BPSP performs photothermal therapy (PTT) and remodels ECM by depleting collagen I, promoting deep penetration of therapeutics and immune cells. (2) PTT promotes SF release and SF exerts anti-vascular effects and down-regulates PD-L1 via RAS/RAF/ERK pathway inhibition, enhancing the efficacy of anti-PD-L1 mAb in overcoming immune evasion. (3) Anti-PD-L1 mAb block PD1/PD-L1 recognition and PTT-induced ICD initiates effector T cells and increases response rates of PD-L1 mAb. Highly-encapsulated BPSP converted 'cold' tumors into 'hot' ones, improved CTL/Treg ratio, and cured orthotopic HCC tumors in mice. Thus, multi-overcoming immune escape offers new possibilities for advancing immunotherapies, and photothermal/chemical/immune synergistic therapy shows promise in the clinical development of HCC.

The ERK1/2 pathway is involved in epithelial-mesenchymal transformation and cell cycle of tumor cells in hepatocellular carcinoma (HCC). In the present study, we investigated the involvement of ERK1/2 activation on hepatic stellate cells (HSCs). We identified ERK1/2 phosphorylation in activated HSCs of HCC samples. We found that tumor cells promoted the migration and invasion capacity of HSCs by activating ERK1/2 phosphorylation. Using high throughput transcriptome sequencing analysis, we found that ERK1/2 inhibition altered genes significantly correlated to signaling pathways involved in extracellular matrix remodeling. We screened genes and demonstrated that the ERK1/2 inhibition-related gene set significantly correlated to cancer-associated fibroblast infiltration in TCGA HCC tumor samples. Moreover, inhibition of ERK1/2 suppressed tumor cell-induced enhancement of HSC migration and invasion by regulating expression of fibrosis markers FAP, FN1 and COL1A1. In a tumor cell and HSC splenic co-transplanted xenograft mouse model, inhibition of ERK1/2 suppressed liver tumor formation by downregulating fibrosis, indicating ERK1/2 inhibition suppresses tumor-stromal interactions in vivo. Taken together, our data indicate that inhibition of ERK1/2 in tumor-associated HSCs suppresses tumor-stromal interactions and progression. Furthermore, inhibition of ERK1/2 may be a potential target for HCC treatment.

Magnetic nanomaterial-mediated magnetic hyperthermia is a localized heating treatment modality that has been applied to treat aggressive cancer in clinics. In addition to being taken up by tumor cells to function in cancer therapy, magnetic nanomaterials can also be internalized by immune cells in the tumor microenvironment, which may contribute to regulating the anti-tumor immune effects. However, there exists little studies on the distribution of magnetic nanomaterials in different types of cells within tumor tissue. Herein, ferrimagnetic vortex-domain iron oxide nanorings (FVIOs) with or without the liver-cancer-targeting peptide SP94 have been successfully synthesized as a model system to investigate the effect of surface modification of FVIOs (with or without SP94) on the distribution of tumor cells and different immune cells in hepatocellular carcinoma (HCC) microenvironment of a mouse. The distribution ratio of FVIO-SP94s in tumor cells was 1.3 times more than that of FVIOs. Immune cells in the liver tumor microenvironment took up fewer FVIO-SP94s than FVIOs. In addition, myeloid cells were found to be much more amenable than lymphoid cells in terms of their ability to phagocytose nanoparticles. Specifically, the distributions of FVIOs/FVIO-SP94s in tumor-associated macrophages, dendritic cells, and myeloid-derived suppressor cells were 13.8%/12%, 3.7%/0.9%, and 6.3%/1.2%, respectively. While the distributions of FVIOs/FVIO-SP94s in T cells, B cells, and natural killer cells were 5.5%/0.7%, 3.0%/0.7%, and 0.4%/0.3%, respectively. The results described in this article enhance our understanding of the distribution of nanomaterials in the tumor microenvironment and provide a strategy for rational design of magnetic hyperthermia agents that can effectively regulate anti-tumor immune effects.

Y-box binding protein 1 (YBX1) plays a variety of roles in progression of multiple tumors. However, the role of YBX1 in prognostic value and immune regulation for liver hepatocellular carcinoma (LIHC) remains unclear. The present study aimed to examine the effect of YBX1 on the regulation of tumor immunity and survival prediction in LIHC patients.

YBX1-related expression profiles and single-cell and bulk sequencing analysis were performed using online databases. YBX1 expression was validated by a quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry. Univariate/multivariate Cox regression analysis was performed to determine independent predictors of overall survival (OS). The ESTIMATE (i.e., Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) algorithm and Tumor Immune Dysfunction and Exclusion (TIDE) analysis were used to assess the relationships between YBX1 and LIHC immunity.

YBX1 was over-expressed in LIHC tissues and cell lines. High YBX1 expression was significantly associated with poor OS. Univariate/multivariate Cox regression analysis revealed that YBX1 was an independent prognostic factor for LIHC. Gene set enrichment analysis revealed that YBX1 was associated with multiple signaling pathways correlated to LIHC. Additionally, YBX1 was expressed in multiple immune cells and was significantly correlated with immune cells, immune checkpoint markers and tumor immune microenvironment. The TIDE analysis demonstrated that LIHC patients with high YBX1 expression showed a higher T-cell dysfunction score and a higher exclusion score, as well as poorer immunotherapy response.

YBX1 plays crucial oncogenic roles in LIHC and is closely associated with the immune defense system. YBX1 inhibition may serve as a potential treatment for LIHC.

Metabolic associated fatty liver disease (MAFLD) is a significant risk factor for the development of hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs), as key mediators in liver injury response, are believed to play a crucial role in the repair process of liver injury. However, in MAFLD patients, the normal metabolic and immunoregulatory mechanisms of HSCs become disrupted, leading to disturbances in the local microenvironment. Abnormally activated HSCs are heavily involved in the initiation and progression of HCC. The metabolic disorders and abnormal activation of HSCs not only initiate liver fibrosis but also contribute to carcinogenesis. In this review, we provide an overview of recent research progress on the relationship between the abnormal metabolism of HSCs and the local immune system in the liver, elucidating the mechanisms of immune imbalance caused by abnormally activated HSCs in MAFLD patients. Based on this understanding, we discuss the potential and challenges of metabolic-based and immunology-based mechanisms in the treatment of MAFLD-related HCC, with a specific focus on the role of HSCs in HCC progression and their potential as targets for anti-cancer therapy. This review aims to enhance researchers' understanding of the importance of HSCs in maintaining normal liver function and highlights the significance of HSCs in the progression of MAFLD-related HCC.

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.

The inflammation-related tumor microenvironment (TME) is one of the major driving forces of hepatocarcinogenesis. We aimed to investigate cell-to-cell communication among Hepatocellular Carcinoma (HCC) through re-analyzing HCC single-cell RNA-seq data, and to confirm such cellular interaction through in vitro and in vivo study. We found a subset of Regulatory B cells with PD-L1 expression (PD-L1+ Bregs), mainly located in adjacent HCC tissues. In co-localization with PD-L1+ Bregs, a subset of Tumor Associated Macrophages with high expression of CXCL12 (CXCL12+ TAMs) was also mainly located in adjacent HCC tissues. Moreover, CXCL12+ TAMs can be stimulated in vitro using an HCC conditional medium. Using CellChat analysis and Multiplex Immunohistochemistry staining (mIHC), CXCL12+ TAMs were found to be first recruited by Cancer-Associated Fibroblasts (CAFs) through a CD74/macrophage migration inhibitory factor (MIF) pattern, and further differentiated into TGF-β-enriched tissues. Furthermore, CXCL12+ TAMs recruited PD-L1+ Bregs via the CXCL12/CXCR4 axis, and CXCR4 expression was significantly positively correlated to PD-L1 expression in PD-L1+ Bregs. At last, we confirmed the communications among CAFs, Macrophages and B cells and their tumor-promoting effects by using an orthotopic mouse model of HCC. Immunosuppressive HCC TME involving cell-to-cell communications comprised MIF-secreting CAFs, CXCL12-secreting TAMs, and PD-L1-producing Bregs, and their regulation could be promising therapeutic targets in future immunotherapy for human HCC.

Glycogen metabolism plays a key role in the development of hepatocellular carcinoma (HCC), but the function of glycogen metabolism genes in the tumor microenvironment (TME) is still to be elucidated. Single-cell RNA-seq data were obtained from ten HCC tumor samples totaling 64,545 cells, and 65 glycogen metabolism genes were analyzed by a nonnegative matrix factorization (NMF). The prognosis and immune response of new glycogen TME cell clusters were predicted by using HCC and immunotherapy cohorts from public databases. HCC single-cell analysis was divided into fibroblasts, NT T cells, macrophages, endothelial cells, and B cells, which were separately divided into new cell clusters by glycogen metabolism gene annotation. Pseudo-temporal trajectory analysis demonstrated the temporal differentiation trajectory of different glycogen subtype cell clusters. Cellular communication analysis revealed extensive interactions between endothelial cells with glycogen metabolizing TME cell-related subtypes and different glycogen subtype cell clusters. SCENIC analysis of transcription factors upstream of TME cell clusters with different glycogen metabolism. In addition, TME cell clusters of glycogen metabolism were found to be enriched in expression in CAF subtypes, CD8 depleted, M1, and M2 types. Bulk-seq analysis showed the prognostic significance of glycogen metabolism-mediated TME cell clusters in HCC, while a significant immune response was found in the immunotherapy cohort in patients treated with immune checkpoint blockade (ICB), especially for CAFs, T cells, and macrophages. In summary, our study reveals for the first time that glycogen metabolism mediates intercellular communication in the hepatocellular carcinoma microenvironment while elucidating the anti-tumor mechanisms and immune prognostic responses of different subtypes of cell clusters.

The PD-L1/PD-1 axis is a classic immunotherapy target. However, anti-PD-L1/PD-1 therapy alone can not achieve satisfactory results in solid tumors, especially liver cancer. Among the several factors involved in tumor anti-PD-L1/PD-1 treatment resistance, tumor-associated macrophages (TAMs) have attracted attention because of their immunosuppressive ability. TAMs with a macrophage receptor with a collagenous structure (MARCO) are a macrophage subset group with strong immunosuppressive abilities. Clinical specimens and animal experiments revealed a negative correlation between MARCO + TAMs and patient prognosis with liver cancer. Transcriptional data and in vitro and in vivo experiments revealed that MARCO + TAM immunosuppressive ability was related to secretion. MARCO suppressed IFN-β secretion from TAMs, reducing antigen presentation molecule expression, infiltration, and CD8+T cell dysfunction, thus producing an immunosuppressive microenvironment in liver cancer. MARCO can promote dying tumor cell clearance by macrophages, reducing tumor-derived cGAMP and ATP accumulation in the tumor microenvironment and inhibiting sting-IFN-β pathway activation mediated by P2X7R in MARCO+TAMs. Animal experiments revealed that the MARCO and PD-L1 monoclonal antibody combination could significantly inhibit liver cancer growth. Conclusively, targeting MARCO+TAMs can significantly improve anti-PD-L1 resistance in liver cancer, making it a potential novel immune target for liver cancer therapy.

Tumor angiogenesis is one of the typical hallmarks of tumor occurrence and development, and tumor neovascularization also exhibits distinct characteristics from normal blood vessels. As the number of cells and matrix inside the tumor increases, the biomechanical force is enhanced, specifically manifested as solid stress, fluid stress, stiffness, and topology. This mechanical microenvironment also provides shelter for tumors and intensifies angiogenesis, providing oxygen and nutritional support for tumor progression. During tumor development, the biomechanical microenvironment also emerges, which in turn feeds back to regulate the tumor progression, including tumor angiogenesis, and biochemical and biomechanical signals can regulate tumor angiogenesis. Blood vessels possess inherent sensitivity to mechanical stimuli, but compared to the extensive research on biochemical signal regulation, the study of the regulation of tumor neovascularization by biomechanical signals remains relatively scarce. Biomechanical forces can affect the phenotypic characteristics and mechanical signaling pathways of tumor blood vessels, directly regulating angiogenesis. Meanwhile, they can indirectly regulate tumor angiogenesis by causing an imbalance in angiogenesis signals and affecting stromal cell function. Understanding the regulatory mechanism of biomechanical forces in tumor angiogenesis is beneficial for better identifying and even taming the mechanical forces involved in angiogenesis, providing new therapeutic targets for tumor vascular normalization. Therefore, we summarized the composition of biomechanical forces and their direct or indirect regulation of tumor neovascularization. In addition, this review discussed the use of biomechanical forces in combination with anti-angiogenic therapies for the treatment of tumors, and biomechanical forces triggered delivery systems.

Image-guided intra-arterial locoregional therapies (LRTs) such as transarterial embolization, transarterial chemoembolization, and transarterial radioembolization exhibit effects on the immune system. Understanding the humoral (cytokine, chemokine, and growth factor) and cellular (T cell, neutrophil, dendritic cell, and macrophage) mechanisms underlying the immune effects of LRT is crucial to designing rational and effective combinations of immunotherapy and interventional radiology procedures. This article aims to review the immune effects of intra-arterial LRTs and provide insight into strategies to combine LRTs with systemic immunotherapy.

There has been an increased focus on regulating cell function with Rho family GTPases, including proliferation, migration/invasion, polarity, and adhesion. Due to the challenges involved in targeting Rho family GTPases directly, it may be more effective to target their regulators, such as Rho GTPase-activating protein 1 (ARHGAP1). This present research was performed to define the clinical significance of ARHGAP1 expression, as well as its regulatory mechanisms in hepatocellular carcinoma.

ARHGAP1 and miR-101-3p expression of liver cancer patients, and their relevance with clinicopathological characteristics and prognosis were analyzed by the Cancer Genome Atlas sequencing data, and verified using samples of hepatocellular carcinoma patients. The interactions between miR-101-3p and ARHGAP1 or circPIP5K1A were validated by bioinformatic analyses, as well as confirmed by quantitative reverse transcription polymerase chain reaction, western blotting, and dual-luciferase reporter analysis. Plate clonality assays, cell adhesion and migration experiments, and proliferation experiments were used for assessing the participation of the circPIP5K1A/miR-101-3p/ARHGAP1 pathway in cell proliferation and motility.

Elevated ARHGAP1 and reduced miR-101-3p expression are related to poorer survival. MiR-101-3p targets ARHGAP1 to suppress hepatocellular carcinoma cell colony formation and invasion, whereas miR-101-3p inhibitor reverses liver cancer proliferation and metastasis suppression caused by ARHGAP1 knockdown. In addition, circPIP5K1A, which is mainly distributed in the cytosol, showed carcinogenic effects by sponging miR-101-3p, thus regulating ARHGAP1 expression.

ARHGAP1 serves as an oncogenic gene in liver cancer, and the expression thereof is regulated by circPIP5K1A through sponging miR-101-3p.

Tumor-associated macrophages (TAMs) have unique functions in the development of hepatocellular carcinoma (HCC). The tumor microenvironment is in a complex state in chronic disease. As a major participant in tumor-associated inflammation, TAMs have a unique effect on promoting tumor cell proliferation, angiogenesis and immunosuppression. The in-depth study of TAMs has important scientific and clinical value and provides new ideas for the treatment of cancer.

Bioinformatics analysis, dual-luciferase reporter assays, RT-qPCR and clinical samples were used to analyze the potential mechanism of the miR-21-5p/SP1/XBP1 molecular axis in HCC. In this study, miR-21-5p was highly expressed in HCC exosomes compared with normal hepatocyte exosomes, and HCC exosomes containing miR-21-5p promoted the proliferation and migration of HCC cells and inhibited cell apoptosis. In addition, this treatment promoted the M2 polarization of macrophages, induced the expression of transcription factor-specific protein 1 (SP1), and inhibited the expression of X-box binding protein 1 (XBP1). However, these expression trends were reversed after inhibition of miR-21-5p expression in exosomes of hepatoma cells, and the effects of exosomal miR-21-5p were partially restored after overexpression of SP1. Animal experiments also verified that exosomal miR-21-5p in HCC cells affected the expression level of the SP1/XBP1 protein and promoted M2 polarization of TAMs.

Exosomal miR-21-5p in HCC cells can affect the development of HCC cells by regulating SP1/XBP1 and promoting the M2 polarization of TAMs, thereby affecting the adverse prognostic response of HCC patients.