Search

High levels of acetyl-CoA are considered a key metabolic feature of metastatic cancers. However, the impacts of acetyl-CoA metabolic accumulation on cancer microenvironment remodeling are poorly understood. In this study, using human hepatocellular carcinoma (HCC) tissues and orthotopic xenograft models, we found a close association between high acetyl-CoA levels in HCCs, increased infiltration of tumor-associated neutrophils (TANs) in the cancer microenvironment and HCC metastasis. Cytokine microarray and enzyme-linked immunosorbent assays (ELISA) revealed the crucial role of the chemokine (C-X-C motif) ligand 1(CXCL1). Mechanistically, acetyl-CoA accumulation induces H3 acetylation-dependent upregulation of CXCL1 gene expression. CXCL1 recruits TANs, leads to neutrophil extracellular traps (NETs) formation and promotes HCC metastasis. Collectively, our work linked the accumulation of acetyl-CoA in HCC cells and TANs infiltration, and revealed that the CXCL1-CXC receptor 2 (CXCR2)-TANs-NETs axis is a potential target for HCCs with high acetyl-CoA levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Triggering ferroptosis, an iron-dependent form of cell death, has recently emerged as an approach for treating cancer. A better understanding of the role and regulation of ferroptosis is needed to realize the potential of this therapeutic strategy. Here, we observed extensive activation of ferroptosis in hepatoma cells and human hepatocellular carcinoma (HCC) cases. Patients with low to moderate activation of ferroptosis in tumors had the highest risk of recurrence compared to patients with no or high ferroptosis. Upon encountering ferroptotic liver cancer cells, aggregated macrophages efficiently secreted proinflammatory IL1β to trigger neutrophil-mediated sinusoidal vascular remodeling, thereby creating favorable conditions for aggressive tumor growth and lung metastasis. Mechanistically, hyaluronan fragments released by cancer cells acted via an NF-κB-dependent pathway to upregulate IL1β precursors and the NLRP3 inflammasome in macrophages, and oxidized phospholipids secreted by ferroptotic cells activated the NLRP3 inflammasome to release functional IL1β. Depleting either macrophages or neutrophils or neutralizing IL1β in vivo effectively abrogated ferroptosis-mediated liver cancer growth and lung metastasis. More importantly, the ferroptosis-elicited inflammatory cellular network served as a negative feedback mechanism that led to therapeutic resistance to sorafenib in HCC. Targeting the ferroptosis-induced inflammatory axis significantly improved the therapeutic efficacy of sorafenib in vivo. Together, this study identified a role for ferroptosis in promoting HCC by triggering a macrophage/IL1β/neutrophil/vasculature axis., Significance: Ferroptosis induces a favorable tumor microenvironment and supports liver cancer progression by stimulating an inflammatory cellular network that can be targeted to suppress metastasis and improve the efficacy of sorafenib., (©2024 American Association for Cancer Research.)

Background: As a critical early event in hepatocellular carcinogenesis, telomerase activation might be a promising and critical biomarker for hepatocellular carcinoma (HCC) patients, and its function in the genesis and treatment of HCC has gained much attention over the past two decades., Aim: To perform a bibliometric analysis to systematically assess the current state of research on HCC-related telomerase., Methods: The Web of Science Core Collection and PubMed were systematically searched to retrieve publications pertaining to HCC/telomerase limited to "articles" and "reviews" published in English. A total of 873 relevant publications related to HCC and telomerase were identified. We employed the Bibliometrix package in R to extract and analyze the fundamental information of the publications, such as the trends in the publications, citation counts, most prolific or influential writers, and most popular journals; to screen for keywords occurring at high frequency; and to draw collaboration and cluster analysis charts on the basis of coauthorship and co-occurrences. VOSviewer was utilized to compile and visualize the bibliometric data., Results: A surge of 51 publications on HCC/telomerase research occurred in 2016, the most productive year from 1996 to 2023, accompanied by the peak citation count recorded in 2016. Up to December 2023, 35226 citations were made to all publications, an average of 46.6 citations to each paper. The United States received the most citations ( n = 13531), followed by China ( n = 7427) and Japan ( n = 5754). In terms of national cooperation, China presented the highest centrality, its strongest bonds being to the United States and Japan. Among the 20 academic institutions with the most publications, ten came from China and the rest of Asia, though the University of Paris Cité, Public Assistance-Hospitals of Paris, and the National Institute of Health and Medical Research (INSERM) were the most prolific. As for individual contributions, Hisatomi H, Kaneko S, and Ide T were the three most prolific authors. Kaneko S ranked first by H-index, G-index, and overall publication count, while Zucman-Rossi J ranked first in citation count. The five most popular journals were the World Journal of Gastroenterology , Hepatology , Journal of Hepatology , Oncotarget , and Oncogene , while Nature Genetics , Hepatology , and Nature Reviews Disease Primers had the most citations. We extracted 2293 keywords from the publications, 120 of which appeared more than ten times. The most frequent were HCC, telomerase and human telomerase reverse transcriptase (hTERT). Keywords such as mutational landscape, TERT promoter mutations, landscape, risk, and prognosis were among the most common issues in this field in the last three years and may be topics for research in the coming years., Conclusion: Our bibliometric analysis provides a comprehensive overview of HCC/telomerase research and insights into promising upcoming research., Competing Interests: Conflict-of-interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: Fifteen to 25% of patients with colorectal cancer have combined liver metastases at the time of diagnosis, whereas an additional 15 to 25% will develop liver metastases after curative resection of primary colorectal cancer, with the vast majority (80-90%) of liver metastases unresponsive to curative resection at first. Colorectal cancer liver metastasis is also the leading cause of death in patients with colorectal cancer. In recent years, several studies have demonstrated that intestinal flora, especially Fusobacterium nucleatum, plays a crucial role in the development of colorectal cancer liver metastasis, so we hypothesized that long-term metronidazole use could effectively reduce the incidence of postoperative liver metastasis in colorectal cancer patients., Methods/design: This study is a prospective, single-centre, randomized, double-blind controlled study in which 300 patients will be randomly assigned to the test group or the control group in a 1:1 allocation ratio. The aim of this trial is to demonstrate that long-term oral antibiotics can effectively reduce the incidence of postoperative liver metastasis in patients with colorectal cancer., Ethics and Dissemination: Ethics approval was obtained from the Ethics Committee at the Chinese Ethics Committee of Registering Clinical Trials (ChiECRCT20210229). The results of this study will be disseminated at several research conferences and as published articles in peer-reviewed journals., Trial Registration: Chinese Clinical Trial Registry ChiCTR2100046201. Registered on July 05, 2021., (© 2023. The Author(s).)

The reinvigoration of anti-tumor T cells in response to immune checkpoint blockade (ICB) therapy is well established. Whether and how ICB therapy manipulates antibody-mediated immune response in cancer environments, however, remains elusive. Using tandem mass spectrometric analysis of modification of immunoglobulin G (IgG) from hepatoma tissues, we identified a role of ICB therapy in catalyzing IgG sialylation in the Fc region. Effector T cells triggered sialylation of IgG via an interferon (IFN)-γ-ST6Gal-I-dependent pathway. DC-SIGN + macrophages represented the main target cells of sialylated IgG. Upon interacting with sialylated IgG, DC-SIGN stimulated Raf-1-elicited elevation of ATF3, which inactivated cGAS-STING pathway and eliminated subsequent type-I-IFN-triggered antitumorigenic immunity. Although enhanced IgG sialylation in tumors predicted improved therapeutic outcomes for patients receiving ICB therapy, impeding IgG sialylation augmented antitumorigenic T cell immunity after ICB therapy. Thus, targeting antibody-based negative feedback action of ICB therapy has potential for improving efficacy of cancer immunotherapies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is one of the high incidence cancers and third leading cause of cancer-related mortality. HBV is the top most risk factor accounting for 50-80% of the HCC cases. Kinases: Aurora kinase A (AURKA), cyclin-dependent kinase (CDK1) and Polo-like kinase 1 (PLK1), the key regulators of cell mitosis are overexpressed in varieties of cancers including HCC. However, the exact role of these genes in prognosis of HCC is not fully unveiled. In addition, there is no such an accurate prognostic biomarker for HBV-related HCC. To address this issue, we performed a multidimensional analysis of AURKA, CDK1 and PLK1 with a series of publicly available databases in multiple cancers and with experimental validation in HBV-related HCC tissues. Overexpression of AURKA, CDK1 and PLK1 was found in multiple cancers including HCC. Elevated expression of these genes could result from lowered DNA methylation and genomic alterations. Transcriptional overexpression was significantly correlated with poor prognosis of HCC patients. The expression levels were also significantly positively associated with tumor grades and stages. Furthermore, the expression levels of these genes had a strong correlation with infiltration of immune cells. Our analysis shows that AURKA, CDK1 and PLK1 are correlated with immune infiltration and are the prognostic biomarkers for HBV-induced HCC.Communicated by Ramaswamy H. Sarma.

Circadian rhythms regulate various biological processes, such as cell division and metabolism. Circadian rhythm disruption (CRD) is often associated with malignant tumor progression and poor prognosis. However, the effect of CRD on liver cancer prognosis has not been systematically analyzed or fully elucidated. Here, we developed a method to quantify and assess intratumoral CRD in a single-cell transcriptomic analysis of liver cancer and systematically analyzed the role of CRD in tumor progression and prognosis. Furthermore, a LASSO-Cox regression model based on 14 CRD genes was used to predict overall patient survival across multiple datasets. We found that malignant cells with high CRD scores were enriched in specific metabolic pathways, such as fatty acid metabolism and the trichloroacetic acid cycle. Intercellular communication analysis suggested that CRD regulates chemokine-mediated interactions. With the bulk transcriptomic datasets, we determined that LiverCRD scores were significantly correlated with macrophage infiltration levels and could guide targeted immunotherapy and chemotherapy strategies. In addition, LiverCRD is also associated with the mutational landscape-for example, TP53 mutation frequency was higher in high-CRD samples. Finally, the 14-gene-based LASSO-Cox regression model could accurately predict overall patient survival across datasets. In conclusion, Our proposed analysis reflects the relationship between CRD and the immune environment in liver cancer, suggesting that CRD may serve as a potential prognostic indicator. Our results may help guide targeted anti-tumor strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Cui, Cai and Sun.)

Background: Long noncoding RNAs (lncRNAs) are functionally associated with cancer development and progression. Although gene copy number variation (CNV) is common in hepatocellular carcinoma (HCC), it is not known how CNV in lncRNAs affects HCC progression and recurrence. We aimed to identify a CNV-related lncRNA involved in HCC progression and recurrence and illustrate its underlying mechanisms and prognostic value., Methods: We analyzed the whole genome sequencing (WGS) data of matched cancerous and noncancerous liver samples from 49 patients with HCC to identify lncRNAs with CNV. The results were validated in another cohort of 238 paired HCC and nontumor samples by TaqMan copy number assay. We preformed Kaplan-Meier analysis and log-rank test to identify lncRNA CNV with prognostic value. We conducted loss- and gain-of-function studies to explore the biological functions of LINC01133 in vitro and in vivo. The competing endogenous RNAs (ceRNAs) mechanism was clarified by microRNA sequencing (miR-seq), quantitative real-time PCR (qRT-PCR), western blot, and dual-luciferase reporter assays. We confirmed the binding mechanism between lncRNA and protein by RNA pull-down, RNA immunoprecipitation, qRT-PCR, and western blot analyses., Results: Genomic copy numbers of LINC01133 were increased in HCC, which were positively related with the elevated expression of LINC01133. Increased copy number of LINC01133 predicted the poor prognosis in HCC patients. LINC01133 overexpression in HCC cells promoted proliferation and aggressive phenotypes in vitro, and facilitated tumor growth and lung metastasis in vivo, whereas LINC01133 knockdown had the opposite effects. LINC01133 sponged miR-199a-5p, resulting in enhanced expression of SNAI1, which induced epithelial-to-mesenchymal transition (EMT) in HCC cells. In addition, LINC01133 interacted with Annexin A2 (ANXA2) to activate the ANXA2/STAT3 signaling pathway., Conclusions: LINC01133 promotes HCC progression by sponging miR-199a-5p and interacting with ANXA2. LINC01133 CNV gain is predictive of poor prognosis in patients with HCC., (© 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Emerging evidence suggests that long non-coding RNAs (lncRNA) play critical roles in the development and progression of diverse cancers including hepatocellular carcinoma (HCC), but the underlying molecular mechanisms of lncRNAs that are involved in hepatocarcinogenesis have not been fully explored. Methods: In this study, we profiled lncRNA expression in 127 pairs of HCC and nontumor liver tissues (a Discovery Cohort) using a custom microarray. The expression and clinical significance of lncCSMD1-1 were then validated with qRT-PCR and COX regression analysis in a Validation Cohort (n=260) and two External Validation Cohorts (n=92 and n=124, respectively). In vitro and in vivo assays were performed to explore the biological effects of lncCSMD1-1 on HCC cells. The interaction of lncCSMD1-1 with MYC was identified by RNA pull-down and RNA immunoprecipitation. The role of LncCSMD1-1 in the degradation of MYC protein was also investigated. Results: With microarray, we identified a highly upregulated lncRNA, lncCSMD1-1, which was associated with tumor progression and poor prognosis in the Discovery Cohort, and validated in another 3 HCC cohorts. Consistently, ectopic expression of lncCSMD1-1 notably promotes cell proliferation, migration, invasion, tumor growth and metastasis of HCC cells in in vitro and in vivo experiments. Gene expression profiling on HCC cells and gene sets enrichment analysis indicated that the MYC target gene set was significantly enriched in HCC cells overexpressing lncCSMD1-1, and lncCSMD1-1 was found to directly bind to MYC protein in the nucleus of HCC cells, which resulted in the elevation of MYC protein. Mechanistically, lncCSMD1-1 interacted with MYC protein to block its ubiquitin-proteasome degradation pathway, leading to activation of its downstream target genes. Conclusion: lncCSMD1-1 is upregulated in HCC and promotes progression of HCC by activating the MYC signaling pathway. These results provide the evidence that lncCSMD1-1 may serve as a novel prognostic marker and potential therapeutic target for HCC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background & Aims: Little is known about the composition and generation of plasma cell subsets in patients with hepatocellular carcinoma (HCC) and how these associate with outcomes. We investigated whether, or how, plasma cells differentiate and function in patients with HCC and mice with liver tumors., Methods: We analyzed subset composition and distribution of plasma cells in HCC samples from 342 patients who underwent curative resection at the Cancer Center of Sun Yat-sen University in China; samples of non-tumor liver tissue were used as controls. We associated plasma cell profiles with patient outcomes. Tissue-derived leukocytes were analyzed by flow cytometry and real-time polymerase chain reaction. The ability of macrophages to regulate plasma cell differentiation was determined in ex vivo cultures of cells from human HCC tissues. C57BL/6 and BALB/c mice were given injections of Hepa1-6 cells, which formed hepatomas, or H22 cells, which formed ascitic hepatomas. Gene expression patterns were analyzed in human HCC, mouse hepatoma, and non-tumor tissues by real-time polymerase chain reaction. Mice with hepatomas were given injections of GSK126 (an inhibitor of histone H3 lysine 27 methyltransferase [EZH2]) and 5-AZA-dC (an inhibitor of DNA methyltransferases); tumor tissues were analyzed by immunofluorescence and immunohistochemistry for the presence of immune cells and cytokines., Results: B cells isolated from HCCs had somatic hypermutations and class-switch recombinations to the IgG phenotype that were not observed in non-tumor tissues. Increased level of plasma cells correlated with poor outcomes of patients. Activated CD4 + T cells from HCCs stimulated C-X-C motif chemokine 10 (CXCL10) production by macrophages. CXCL10 bound CXC chemokine receptor 3 on B cells and signaled via extracellular signal-regulated kinase to cause them to become IgG-producing plasma cells. IgG activated Fc receptors on macrophages and induced them to produce interleukin 6, interleukin 10, and C-C motif chemokine ligand 20 (CCL20). In mice with hepatomas, depletion of B cells prevented generation of these macrophage, increased the anti-tumor T cell response, and reduced growth of hepatomas. However, these effects were lost after injection of CXC chemokine receptor 3-positive plasma cells. Human HCC and mouse hepatoma tissues had increased expression of DNA methyltransferase 1 and EZH2 compared with non-tumor tissues. Injection of mice with GSK126 and 5-AZA-dC induced expression of CXCL10 by tumor cells and caused plasma cell polarization, suppression of the anti-tumor T cell response, and hepatoma growth., Conclusions: Human HCC tissues contain B cells with class-switch recombinations to the IgG phenotype. Activated CD4 + T cells from HCCs stimulate CXCL10 production by macrophages; CXCL10 binds CXC chemokine receptor 3 on B cells and causes them to become IgG-producing plasma cells. IgG activates Fc receptor in macrophages to produce cytokines that reduce the anti-tumor immune response. In mice with hepatomas, depletion of B cells prevented generation of these macrophages, increased the anti-tumor T cell response, and reduced growth of hepatomas. This pathway involves increased expression of DNA methyltransferase 1 and EZH2 by HCC and hepatoma cells., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

B cells are prominent components of human solid tumours, but activation status and functions of these cells in human cancers remain elusive. Here we establish that over 50% B cells in hepatocellular carcinoma (HCC) exhibit an FcγRII low/- activated phenotype, and high infiltration of these cells positively correlates with cancer progression. Environmental semimature dendritic cells, but not macrophages, can operate in a CD95L-dependent pathway to generate FcγRII low/- activated B cells. Early activation of monocytes in cancer environments is critical for the generation of semimature dendritic cells and subsequent FcγRII low/- activated B cells. More importantly, the activated FcγRII low/- B cells from HCC tumours, but not the resting FcγRII high B cells, without external stimulation suppress autologous tumour-specific cytotoxic T-cell immunity via IL-10 signals. Collectively, generation of FcγRII low/- activated B cells may represent a mechanism by which the immune activation is linked to immune tolerance in the tumour milieu.

Riccardin D-26 is a synthesized macrocyclic bisbibenzyl compound. We investigated the effect of Riccardin D-26 on human hepatocellular carcinomas. Riccardin D-26 possessed stronger activity against SMMC-7721 cells than human normal liver cells. Riccardin D-26 injection effectively delayed the growth of SMMC-7721 xenografts in mice without significant toxicity. This effect of Riccardin D-26 was associated with the status of p53 and its targets, bax and p21(Waf1)(/)(Cip1). Riccardin D-26 activated p53 expression and induced cancer cells to apoptosis through the p53-mediated transcription-dependent and -independent pathway. Overall, Riccardin D-26 may inhibit hepatocellular carcinoma growth through induction of apoptosis in p53-dependent pathway., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Aim: To investigate the association between GSTM1 and GSTT1 polymorphisms and the risk of hepatocellular carcinoma (HCC) in Chinese population., Methods: Literature databases including PubMed, ISI web of science and other databases were searched. Pooled odds ratio (OR) and 95% CI were calculated using random- or fixed- effects model. Subgroup analysis and sensitivity analysis were also performed., Results: Nineteen studies of GSTM1 (2660 cases and 4017 controls) and 16 studies of GSTT1 (2410 cases and 3669 controls) were included. The GSTM1/GSTT1 null genotypes were associated with increased risk of HCC in Chinese population (for GSTM1, OR = 1.487, 95% CI: 1.159 to 1.908, P = 0.002; for GSTT1, OR = 1.510, 95% CI: 1.236 to 1.845, P = 0.000). No publication bias was detected. In subgroup analysis, glutathione S-transferases polymorphisms were significantly associated with HCC risk among the subjects living in high-incidence areas, but not among the subjects living in low-incidence areas., Conclusion: The present meta-analysis suggests that GSTM1/GSTT1 null genotypes are associated with increased risk of HCC in Chinese population.

Aim: To investigate p53 mutation and p21 expression in hepatocarcinogenesis induced by hepatitis B virus (HBV) and aflatoxin B(1) (AFB(1)) in tree shrews, and to reveal the role of these genes in hepatocarcinogenesis., Methods: Tree shrews were divided into four groups: group A, those infected with HBV and fed with AFB(1) (n = 39); group B, those infected with HBV alone (n = 28); group C, those fed with AFB(1) alone (n = 29); and group D, normal controls (n = 20). The tree shrews underwent liver biopsies once every 15 wk. Expression of p53 and p21 proteins and genes in the biopsies and tumor tissues of the experimental tree shrews was detected, respectively, by immunohistochemistry, and by Southern blotting and reverse transcription-polymerase chain reaction and sequencing., Results: The incidence of hepatocellular carcinomas (HCC) was higher in group A (66.7%) than that in group B (3.57%) and C (30%). The time of HCC occurrence was also earlier in group A than that in group C (120.0+/-16.6 wk vs 153.3+/-5.8 wk, respectively, P<0.01). p53 protein was not detected by immunohistochemistry in all groups before the 75(th) wk of the experiment. At the 105(th) wk, the positive rates fo p53 were 78.6%, 60% and 71.4% in groups A, B and C, respectively, which were significantly higher than that in group D (10%) (all P<0.05). An abnormal band of p53 gene was observed in groups A and C. The mutation points of p53 gene in tree shrews with HCC were at codons 275, 78 and 13. The nucleotide sequence and amino acid sequence of tree shrew's wild-type p53 showed 91.7% and 93.4% homologies with those of human p53, respectively. The immunopositivity for p21 was found before HCC development. The incidence of HCC was significantly higher in tree shrews that were positive for p21 than those negative for p21 (80.0% vs 11.0%, P<0.001). The incidence of HCC in p21 positive animals in group A was significantly higher than those positive for p21 in group C (P<0.05)., Conclusion: A remarkable synergistic effect on HCC development exists between HBV and AFB(1). p53 mutation promotes the development of HCC. HBV and AFB(1) may synergistically induce p53 gene mutation, and stimulate ras gene expression. ras gene is activated at the earlier stage during hepatocarcinogenesis. p21 protein may be an early marker, and the alterations of p53 may be a late event in the development of HCC.