• drug development
• translational research
• target identification

• Humans
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Liver Neoplasms/genetics
• Liver Neoplasms/drug therapy
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Signal Transduction/drug effects
• Signal Transduction/genetics
• Protein Kinase Inhibitors/therapeutic use
• Immune Checkpoint Inhibitors/therapeutic use

• 82222047, 82073039 National Natural Science Foundation of China (National Science Foundation of China)

• bioinformatics
• discordant gene-protein abundance
• paradoxical genes
• signaling pathway
• tumor immune microenvironment
• tumor metabolism

• Biomarkers
• Hypoxia
• Mesothelioma
• NOTCH
• PTP4A3

• Humans
• Mesothelioma/genetics
• Mesothelioma/drug therapy
• Mesothelioma/pathology
• Mesothelioma/mortality
• Mesothelioma/metabolism
• Biomarkers, Tumor/metabolism
• Biomarkers, Tumor/genetics
• Pleural Neoplasms/genetics
• Pleural Neoplasms/drug therapy
• Pleural Neoplasms/pathology
• Pleural Neoplasms/mortality
• Pleural Neoplasms/metabolism
• Receptor, Notch2/genetics
• Receptor, Notch2/metabolism
• Prognosis
• Pemetrexed/therapeutic use
• Pemetrexed/pharmacology
• DNA Copy Number Variations
• Female
• Male
• Receptor, Notch1/genetics
• Receptor, Notch1/metabolism
• Cell Line, Tumor
• Aged
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Middle Aged
• Gene Expression Regulation, Neoplastic
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Lung Neoplasms/metabolism
• Lung Neoplasms/mortality
• Mesothelioma, Malignant/drug therapy
• Mesothelioma, Malignant/genetics
• Mesothelioma, Malignant/metabolism
• Mesothelioma, Malignant/pathology

• Cancer therapy
• Carcinogenesis
• Membrane-bound transcription factor
• Nucleocytoplasmic shuttling

• no. 81802952 the National Natural Science Foundation of China
• no. 21B0411 the Scientific Research Project from the Education Department of Hunan Province
• no. KJ-B2023030 the Scientific Research Project from Health Commission of Changsha
• no. YNKY202201 the Scientific Research Project of Changsha Central Hospital

• Hepatocellular carcinoma
• Lipid-based nanoparticles
• Liver cancer
• Nanomedicine
• Signaling pathways
• Therapeutic approaches

• autophagy
• cancer progression
• cell death
• drug resistance
• ferroptosis
• tumor

• Humans
• Ferroptosis/genetics
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/drug therapy
• Liver Neoplasms/pathology
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/drug therapy
• Autophagy
• Animals
• Signal Transduction
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Molecular Targeted Therapy

• Biomarker
• Breast cancer
• Prognosis
• Risk score
• Ubiquitination

• HCC
• Immunotherapy
• Liver Cancer
• Stem cells

• Humans
• Liver Neoplasms/therapy
• Liver Neoplasms/immunology
• Immunotherapy/methods
• Animals
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/immunology
• Stem Cell Transplantation

• Angiogenesis
• Cancer stem cells
• Targeted therapy

• Humans
• Neovascularization, Pathologic/genetics
• Endothelial Cells/pathology
• Angiogenesis
• Neoplasms/genetics
• Neoplastic Stem Cells/pathology

• Germline stem cells
• bone morphogenetic protein (BMP)
• cancer.
• drosophila ovary
• drosophila testis
• somatic stem cells

• Animals
• Female
• Male
• Drosophila/metabolism
• Drosophila melanogaster/metabolism
• Drosophila Proteins/metabolism
• Signal Transduction
• Stem Cells
• Cell Differentiation
• Stem Cell Niche

• DTX4
• Stearoyl-coA desaturase 1
• Target therapy
• Thyroid cancer

• Humans
• Cell Line
• Cell Proliferation
• Stearoyl-CoA Desaturase/genetics
• Thyroid Neoplasms/genetics
• Ubiquitin-Protein Ligases/genetics

• P01 CA254867 NCI NIH HHS
• R01 CA228413 NCI NIH HHS

• DTC, Deltex C-terminal (region)
• Degron
• Deltex, DTX
• H2-RING, synonym of C3H2C3-RING
• HC-RING, synonym of C3HC4-RING
• RING, really interesting new gene (motifs)
• RNF, Ring Finger (domain)
• UbE3L, Ubiquitin E3 Ligase
• pDegron, Phospho-Degron
• piDegron, Phospho-inhibited Degron

• Humans
• Ubiquitin-Protein Ligases/metabolism
• Proteins
• Ubiquitins
• Neoplasms/genetics

• R01 GM093290 NIGMS NIH HHS

• notch ligands
• notch receptors
• notch pathway
• cancer therapeutics
• γ-secretase inhibitor
• adam inhibitor
• γ-secretase modulators

• Department of Biotechnology, Ministry of Science and Technology, India

• Notch signaling
• cancer
• hypoxia
• hypoxia-induced factors pathway
• therapeutics

• KCTD10
• Notch
• Numb/P53 balance
• hepatocellular carcinoma
• tumor suppressor

• HeLa cells
• luciferase reporter gene vectors
• natural products
• phenolic acids
• saponins

• Humans
• HeLa Cells
• Pulsatilla
• Genes, Reporter
• Signal Transduction
• Cell Proliferation
• Plant Extracts/pharmacology
• Plant Extracts/chemistry
• Cell Line, Tumor
• Apoptosis
• Neoplasms

• Notch receptors
• Triple Negative Breast Cancer
• immunohistochemistry

• Humans
• Receptors, Notch/metabolism
• Receptors, Notch/therapeutic use
• Triple Negative Breast Neoplasms/genetics
• Triple Negative Breast Neoplasms/drug therapy
• Clinical Relevance
• Disease-Free Survival
• Signal Transduction
• Prognosis
• Biomarkers, Tumor

• Cancer
• Cancer stem cell
• Hedgehog
• Notch
• Tumor microenvironment

• HCC
• VWF
• chronic HBV infection
• hemostasis

• The OCPC program
• National Natural Science Foundation of China
• National natural Science Foundation of Hunan Province

• CSC signaling pathways
• cancer stem cells
• lncRNAs
• non-coding RNAs
• signaling pathways

• Humans
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Phosphatidylinositol 3-Kinases/metabolism
• Neoplastic Stem Cells/pathology
• Signal Transduction/genetics
• Neoplasms/metabolism
• Tumor Microenvironment

• Carcinoma, Hepatocellular/pathology
• Cell Line, Tumor
• Cell Proliferation/genetics
• Cellular Senescence
• Cyclin D/metabolism
• Forkhead Box Protein M1/genetics
• Forkhead Box Protein M1/metabolism
• Forkhead Box Protein O1/genetics
• Forkhead Box Protein O1/metabolism
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms/pathology
• Retinoblastoma Binding Proteins/genetics
• Retinoblastoma Binding Proteins/metabolism
• Ubiquitin-Protein Ligases/metabolism

• I01 BX000131 BLRD VA
• R01 CA211095 NCI NIH HHS
• R01 CA243247 NCI NIH HHS

Bladder cancer (BC) is one of the most prevalent malignancies worldwide, but it lacks effective targeted therapy due to its elusive molecular mechanism. Therefore, it is important to further investigate the molecular mechanisms that mediate BC progression. By performing a tumor tissue–based gene microarray and shRNA library screening, we found that recombination signal binding protein for immunoglobulin kappa J region (RBPJ) interacting and tubulin associated 1 (RITA1) is crucial for the growth of BC cells. Moreover, RITA1 is aberrantly highly expressed in BC tissues and is also correlated with poor prognosis in patients with BC. Mechanistically, we determined that RITA1 recruits tripartite motif containing 25 (TRIM25) to ubiquitinate RBPJ to accelerate its degradation via proteasome, which leads to the transcriptional inhibition of Notch1 downstream targets. Our results suggest that aberrant high expression of RITA1 drives the growth of BC cells via the RITA1/TRIM25/RBPJ axis and RITA1 may serve as a promising therapeutic target for BC.

• RBPJ
• RITA1
• TRIM25
• bladder cancer
• proliferation

• Animals
• Carcinogenesis/metabolism
• Carcinoma, Hepatocellular/metabolism
• Hepatocytes/metabolism
• Liver Neoplasms/metabolism
• Proto-Oncogene Proteins p21(ras)/metabolism
• Zebrafish/genetics
• Zebrafish/metabolism
• Zebrafish Proteins/genetics
• Zebrafish Proteins/metabolism

• E3 ubiquitin ligase
• E3-targeting therapy
• hepatocellular carcinoma

Notch signaling is one of the most common drivers of carcinogenesis in many types of cancers, including hepatocellular carcinoma (HCC); however, it occasionally suppresses tumor progression. Moreover, it is virtually unknown how different sets of Notch ligands and receptors regulate the HCC development. In this study, we demonstrate that the expression of the Notch ligands, Delta-like 4 (Dll4) and Jagged-1 (Jag1), is upregulated during diethylnitrosamine-induced hepatocarcinogenesis. Dll4 is detected in the preneoplastic hepatocytes and HCC cells, but not in the normal hepatocytes, while Jag1 is expressed in the desmin-positive mesenchymal cells. Hepatocyte-specific Dll4 knockout abolishes the Notch1 signaling and suppresses the tumor progression. In contrast, Jag1 deletion induces the ectopic expression of Dll4 in hepatocytes along with the loss of Notch2 signaling, leading to the tumor progression. These results indicate that the two distinct Notch signals, Dll4/Notch1 and Jag1/Notch2, are antagonistic to each other, exerting opposite effects on HCC progression.

Dll4/Notch1 signal promotes the progression of HCC, while Jag1/Notch2 signal antagonistically suppresses it in murine chemical hepatocarcinogenesis. Nakano et al. report that two distinct Notch signals regulate the progression of hepatocellular carcinoma (HCC) using tissue specific loss of function mouse mutants. They find Dll4/Notch1 signal promotes HCC progression, while the Jag1/Notch2 signal antagonistically suppresses it.

• Cancer stem cells
• metastasis
• therapy resistance
• tumor heterogeneity

Ubiquitination is a posttranslational modification of proteins that significantly affects protein stability and function. The specificity of substrate recognition is determined by ubiquitin E3 ligase during ubiquitination. Human Deltex (DTX) protein family, which functions as ubiquitin E3 ligases, comprises five members, namely, DTX1, DTX2, DTX3, DTX3L, and DTX4. The characteristics and functional diversity of the DTX family proteins have attracted significant attention over the last decade. DTX proteins have several physiological and pathological roles and are closely associated with cell signal transduction, growth, differentiation, and apoptosis, as well as the occurrence and development of various tumors. Although they have been extensively studied in various species, data on structural features, biological functions, and potential mechanisms of action of the DTX family proteins remain limited. In this review, recent research progress on each member of the DTX family is summarized, providing insights into future research directions and potential strategies in disease diagnosis and therapy.

• Deltex family proteins
• post-translational modification
• protein homeostasis
• ubiquitin E3 ligase
• ubiquitin code
• ubiquitination

Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths. It is often detected at a stage when there are few therapeutic options. Liver cancer stem cells (LCSCs) are highly tumorigenic and resistant to chemotherapy and radiation therapy. Their presence in HCC is a major reason why HCC is difficult to treat. The development of LCSCs is regulated by a variety of factors. This review summarizes recent advances on the factors that regulate the development of LCSCs. Due to the importance of LCSCs in the development of HCC, a better understanding of how LCSCs are regulated will help to improve the treatments for HCC patients.

• Hepatocellular carcinoma
• Liver cancer stem cells
• Pluripotency transcription factors
• Stem cell signaling
• Genetic regulators
• Epigenetic regulators

• antifatty hepatitis
• antiliver cancer
• antiliver fibrosis
• antiliver steatosis
• molecular mechanism
• quercetin

Cancer cells display massive dysregulation of key regulatory pathways due to now well-catalogued mutations and other DNA-related aberrations. Moreover, enormous heterogeneity has been commonly observed in the identity, frequency and location of these aberrations across individuals with the same cancer type or subtype, and this variation naturally propagates to the transcriptome, resulting in myriad types of dysregulated gene expression programs. Many have argued that a more integrative and quantitative analysis of heterogeneity of DNA and RNA molecular profiles may be necessary for designing more systematic explorations of alternative therapies and improving predictive accuracy. We introduce a representation of multi-omics profiles which is sufficiently rich to account for observed heterogeneity and support the construction of quantitative, integrated, metrics of variation. Starting from the network of interactions existing in Reactome, we build a library of “paired DNA-RNA aberrations” that represent prototypical and recurrent patterns of dysregulation in cancer; each two-gene “Source-Target Pair” (STP) consists of a “source” regulatory gene and a “target” gene whose expression is plausibly “controlled” by the source gene. The STP is then “aberrant” in a joint DNA-RNA profile if the source gene is DNA-aberrant (e.g., mutated, deleted, or duplicated), and the downstream target gene is “RNA-aberrant”, meaning its expression level is outside the normal, baseline range. With M STPs, each sample profile has exactly one of the 2^M possible configurations. We concentrate on subsets of STPs, and the corresponding reduced configurations, by selecting tissue-dependent minimal coverings, defined as the smallest family of STPs with the property that every sample in the considered population displays at least one aberrant STP within that family. These minimal coverings can be computed with integer programming. Given such a covering, a natural measure of cross-sample diversity is the extent to which the particular aberrant STPs composing a covering vary from sample to sample; this variability is captured by the entropy of the distribution over configurations. We apply this program to data from TCGA for six distinct tumor types (breast, prostate, lung, colon, liver, and kidney cancer). This enables an efficient simplification of the complex landscape observed in cancer populations, resulting in the identification of novel signatures of molecular alterations which are not detected with frequency-based criteria. Estimates of cancer heterogeneity across tumor phenotypes reveals a stable pattern: entropy increases with disease severity. This framework is then well-suited to accommodate the expanding complexity of cancer genomes and epigenomes emerging from large consortia projects.

A large variety of genomic and transcriptomic aberrations are observed in cancer cells, and their identity, location, and frequency can be highly indicative of the particular subtype or molecular phenotype, and thereby inform treatment options. However, elucidating this association between sets of aberrations and subtypes of cancer is severely impeded by considerable diversity in the set of aberrations across samples from the same population. Most attempts at analyzing tumor heterogeneity have dealt with either the genome or transcriptome in isolation. Here we present a novel, multi-omics approach for quantifying heterogeneity by determining a small set of paired DNA-RNA aberrations that incorporates potential downstream effects on gene expression. We apply integer programming to identify a small set of paired aberrations such that at least one among them is present in every sample of a given cancer population. The resulting “coverings” are analyzed for six cancer cohorts from the Cancer Genome Atlas, and facilitate introducing an information-theoretic measure of heterogeneity. Our results identify many known facets of tumorigenesis as well as suggest potential novel genes and interactions of interest.

In this review, Nandi et al. revisit the mechanisms by which Notch receptors and ligands contribute to normal mammary gland development and breast tumor progression. The authors also discuss combinatorial approaches aimed at disrupting Notch- and TME-mediated resistance that may improve prognosis in breast cancer patients.

Breast cancer is the second leading cause of cancer-related death in women and is a complex disease with high intratumoral and intertumoral heterogeneity. Such heterogeneity is a major driving force behind failure of current therapies and development of resistance. Due to the limitations of conventional therapies and inevitable emergence of acquired drug resistance (chemo and endocrine) as well as radio resistance, it is essential to design novel therapeutic strategies to improve the prognosis for breast cancer patients. Deregulated Notch signaling within the breast tumor and its tumor microenvironment (TME) is linked to poor clinical outcomes in treatment of resistant breast cancer. Notch receptors and ligands are also important for normal mammary development, suggesting the potential for conserved signaling pathways between normal mammary gland development and breast cancer. In this review, we focus on mechanisms by which Notch receptors and ligands contribute to normal mammary gland development and breast tumor progression. We also discuss how complex interactions between cancer cells and the TME may reduce treatment efficacy and ultimately lead to acquired drug or radio resistance. Potential combinatorial approaches aimed at disrupting Notch- and TME-mediated resistance that may aid in achieving in an improved patient prognosis are also highlighted.

• Notch signaling
• breast cancer
• resistance

Transcription factors (TFs) are known to be involved in regulating the expression of several classes of genes during folliculogenesis. However, the regulatory role of TFs during oxidative stress (OS) is not fully understood. The current study was aimed to investigate the regulation of the TFs in bovine granulosa cells (bGCs) during exposure to OS induced by H₂O₂ in vitro. For this, bGCs derived from ovarian follicles were cultured in vitro till their confluency and then treated with H₂O₂ for 40 min. Twenty-four hours later, cells were subjected to various phenotypic and gene expression analyses for genes related to TFs, endoplasmic reticulum stress, apoptosis, cell proliferation, and differentiation markers. The bGCs exhibited higher reactive oxygen species accumulation, DNA fragmentation, and endoplasmic reticulum stress accompanied by reduction of mitochondrial activity after exposure to OS. In addition, higher lipid accumulation and lower cell proliferation were noticed in H₂O₂-challenged cells. The mRNA level of TFs including NRF2, E2F1, KLF6, KLF9, FOS, SREBF1, SREBF2, and NOTCH1 was increased in H₂O₂-treated cells compared with non-treated controls. However, the expression level of KLF4 and its downstream gene, CCNB1, were downregulated in the H₂O₂-challenged group. Moreover, targeted inhibition of NRF2 using small interference RNA resulted in reduced expression of KLF9, FOS, SREBF2, and NOTCH1 genes, while the expression of KLF4 was upregulated. Taken together, bovine granulosa cells exposed to OS exhibited differential expression of various transcription factors, which are mediated by the NRF2 signaling pathway.

• Apoptosis and differentiation
• Granulosa cells
• NRF2 signaling
• Oxidative stress
• Transcription factors

• HCC
• HDAC
• HDACI
• anticancer
• deacetylase
• epigenetic
• hepatocellular carcinoma
• histone
• inhibitors
• targeted
• therapeutics

• Hepatocellular carcinoma
• Prognostic factor
• Systems biology
• TCGA database
• mRNA-miRNA-lncRNA regulatory network

• Fibrosis
• Hepatocellular carcinoma
• Mouse Model
• Nonalcoholic steatohepatitis
• Notch signaling
• β-catenin

• Animals
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/metabolism
• Drug Delivery Systems/methods
• Drug Delivery Systems/trends
• Humans
• Immunotherapy/methods
• Immunotherapy/trends
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplasms/therapy
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/immunology
• Neoplastic Stem Cells/metabolism
• Receptors, Notch/immunology
• Receptors, Notch/metabolism
• Signal Transduction/drug effects
• Signal Transduction/physiology

The purple sea urchin Strongylocentrotus purpuratus has been used for over 150 years as a model organism in developmental biology. Using this model species, scientists have been able to describe, in detail, the mechanisms of cell cycle control and cell adhesion, fertilization, calcium signaling, cell differentiation, and death. Massive parallel sequencing of the sea urchin genome enabled the deciphering of the main components of gene regulatory networks during the activation of embryonic signaling pathways. This knowledge helped to extrapolate aberrations in somatic cells that may lead to diseases, including cancer in humans. Furthermore, since many, if not all, developmental signaling pathways were shown to be controlled by non-coding RNAs (ncRNAs), the sea urchin organism represents an attractive experimental model. In this review, we discuss the main discoveries in the genetics, genomics, and transcriptomics of sea urchins during embryogenesis with the main focus on the role of ncRNAs. This information may be useful for comparative studies between different organisms, and may help identify new regulatory networks controlled by ncRNAs.

• cell signaling
• gene expression
• genomics
• long non-coding RNA
• sea urchin

The Notch pathway involves evolutionarily conserved signaling regulating the development of the female tract organs such as breast, ovary, cervix, and uterine endometrium. A great number of studies revealed Notch aberrancies in association with their carcinogenesis and disease progression, the management of which is still challenging. The present study is a comprehensive review of the available literature on Notch signaling during the normal development and carcinogenesis of the female tract organs. The review has been enriched with our analyses of the TCGA data including breast, cervical, ovarian, and endometrial carcinomas concerning the effects of Notch signaling at two levels: the core components and downstream effectors, hence filling the lack of global overview of Notch-driven carcinogenesis and disease progression. Phenotype heterogeneity regarding Notch signaling was projected in two uniform manifold approximation and projection algorithm dimensions, preceded by the principal component analysis step reducing the data burden. Additionally, overall and disease-free survival analyses were performed with the optimal cutpoint determination by Evaluate Cutpoints software to establish the character of particular Notch components in tumorigenesis. In addition to the review, we demonstrated separate models of the examined cancers of the Notch pathway and its targets, although expression profiles of all normal tissues were much more similar to each other than to its cancerous compartments. Such Notch-driven cancerous differentiation resulted in a case of opposite association with DFS and OS. As a consequence, target genes also show very distinct profiles including genes associated with cell proliferation and differentiation, energy metabolism, or the EMT. In conclusion, the observed Notch associations with the female tract malignancies resulted from differential expression of target genes. This may influence a future analysis to search for new therapeutic targets based on specific Notch pathway profiles.

• breast cancer
• carcinogenesis
• cervical cancer
• endometrial cancer
• female tract
• notch signaling
• ovarian cancer

Background: Papillary thyroid carcinoma (PTC) is one of the most common endocrine malignant tumors. Poor prognoses such as high recurrence rate always appear in PTC patients with cervical lymph node metastasis. The process of ubiquitination plays important roles in PTC. As ubiquitin E3 ligases, Deltex (DTX) family proteins were reported to associate with multiple cancers. However, functions and mechanisms of DTX3 in PTC are currently unknown.

Methods: In this study, DTX3 expressions were examined in 114 PTC and paired paracancerous normal tissues through quantitative real-time polymerase chain reaction and western blot. The clinical significances of DTX3 expressions in PTC patients were also investigated. After stable transfection with either short hairpin RNA to knock down DTX3 expression or full-length complementary DNA to upregulate DTX3 expression, changes of malignant phenotypes in two PTC cell lines K1 and TPC-1 were observed using cell viability, flow cytometry, wound healing and transwell assays. Afterwards, altered expressions of epithelial-mesenchymal transition (EMT) and AKT signal pathway related proteins were measured by western blot. Immunoprecipitation and mass spectrometry (IP-MS), immunofluorescence and Co-IP were utilized to identify the possible DTX3 interacting proteins.

Results: Both mRNA and protein expressions of DTX3 were lower in PTC tissues and correlated with the presence of cervical lymph node metastasis (P<0.05). DTX3 overexpression inhibited migration and invasion of PTC cells, decreased Vimentin and phosphorylated AKT expressions, but promoted E-cadherin expression (P<0.05). Moreover, knockdown of DTX3 led to opposite changes (P<0.05). Total 46 probable DTX3 interacting proteins were identified by IP-MS. Among them, X-ray repair cross-complementing protein 5 (XRCC5) and NADH: Ubiquinone Oxidoreductase Complex Assembly Factor 5 (NDUFAF5) were verified to be associated with DTX3. Moreover, DTX3 was proved to be co-localized with XRCC5 in nucleus and promote ubiquitination of XRCC5.

Conclusions: DTX3 suppresses EMT by partially facilitating ubiquitination of XRCC5 to inhibit AKT signal pathway in PTC.

• AKT signal pathway
• Deltex3
• XRCC5
• epithelial-mesenchymal transition
• papillary thyroid carcinoma

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and its specific mechanism has not been fully elucidated. Inactivation of tumor suppressors may contribute to the occurrence, progression, and recurrence of HCC. DNA methylation is a crucial mechanism involved in regulating the occurrence of HCC. Herein, we aimed to identify the key methylation-related tumor suppressors as well as potential biomarkers and therapeutic targets in HCC.

Methods: Combined analysis of TCGA and GEO databases was performed to obtain potential methylation-related tumor suppressors in HCC. Methyl-target sequencing was performed to analyze the methylation level of the GNA14 promoter. The diagnostic value of GNA14 as a predictor of HCC was evaluated in HCC tumor samples and compared with normal tissues. The functional role of GNA14 and its upstream and downstream regulatory factors were investigated by gain-of-function and loss-of-function assays in vitro. Subcutaneous tumorigenesis, lung colonization, and orthotopic liver tumor model were performed to analyze the role of GNA14 in vivo.

Results: The expression of GNA14 was found to be downregulated in HCC and it was negatively correlated with hepatitis B virus (HBV) infection, vascular invasion, and prognosis of HCC. DNA methylation was demonstrated to be responsible for the altered expression of GNA14 and was regulated by HBV-encoded X protein (HBx). GNA14 regulated the RB pathway by promoting Notch1 cleavage to inhibit tumor proliferation, and might inhibit tumor metastasis by inhibiting the expression of JMJD6.

Conclusion: GNA14 could be regulated by HBx by modulating the methylation status of its promoter. We identified GNA14 as a potential biomarker and therapeutic target for HCC.

• DNA methylation
• GNA14
• HBV
• HBx
• HCC

Alagille syndrome (ALGS) is a multisystem autosomal dominant developmental disorder caused predominantly by pathogenic variants in JAGGED1 (JAG1), and also by pathogenic variants in NOTCH2 in a much smaller number of individuals. Clinical presentation is highly variable and includes liver, heart, eye, skeleton, and facial abnormalities, with a subset of individuals also presenting with kidney, vascular, and central nervous system phenotypes. Hepatocellular carcinoma (HCC) is a rare complication of ALGS, though little is known about its incidence or etiology among affected individuals. Previous reports have identified HCC occurrence in both pediatric and adult cases of ALGS. We present a case report of HCC in a 58‐year‐old woman with a pathogenic JAG1 variant and no overt hepatic features of ALGS. Through a comprehensive literature review, we compile all reported pediatric and adult cases, and further highlight one previously reported case of HCC onset in an adult ALGS patient without any hepatic disease features, similar to our own described patient. Our case report and literature review suggest that ALGS‐causing variants could confer risk for developing HCC regardless of phenotypic severity and highlight a need for a cancer screening protocol that would enable early detection and treatment in this at‐risk population.

• JAG1
• cholestasis
• hepatocellular carcinoma
• liver disease
• notch signaling

Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality and poor prognoses around the world. Ferroptosis is a new form of cell death, and some studies have found that it is related to cancer immunotherapy. The aim of our research was to find immunity- and ferroptosis-related biomarkers to improve the treatment and prognosis of HCC by bioinformatics analysis.

First, we obtained the original RNA sequencing (RNA-seq) expression data and corresponding clinical data of HCC from The Cancer Genome Atlas (TGCA) database and performed differential analysis. Second, we used immunity- and ferroptosis-related differentially expressed genes (DEGs) to perform a computational difference algorithm and Cox regression analysis. Third, we explored the potential molecular mechanisms and properties of immunity- and ferroptosis-related DEGs by computational biology and performed a new prognostic index based on immunity- and ferroptosis-related DEGs by multivariable Cox analysis. Finally, we used HCC data from International Cancer Genome Consortium (ICGC) data to perform validation.

We obtained 31 immunity (p < 0.001)- and 14 ferroptosis (p < 0.05)-related DEGs correlated with overall survival (OS) in the univariate Cox regression analysis. Then, we screened five immunity- and two ferroptosis-related DEGs (HSPA4, ISG20L2, NRAS, IL17D, NDRG1, ACSL4, and G6PD) to establish a predictive model by multivariate Cox regression analysis. Receiver operating characteristic (ROC) and Kaplan–Meier (K–M) analyses demonstrated a good performance of the seven-biomarker signature. Functional enrichment analysis including Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that the seven-biomarker signature was mainly associated with HCC-related biological processes such as nuclear division and the cell cycle, and the immune status was different between the two risk groups.

Our results suggest that this specific seven-biomarker signature may be clinically useful in the prediction of HCC prognoses beyond conventional clinicopathological factors. Moreover, it also brings us new insights into the molecular mechanisms of HCC.

• biomarker
• ferroptosis
• hepatocellular carcinoma
• immunity
• overall survival