Notch Signaling Regulation in HCC: From Hepatitis Virus to Non-Coding RNAs

Giovannini, Catia; Fornari, Francesca; Piscaglia, Fabio; Gramantieri, Laura

doi:10.3390/cells10030521

Cited by 14 publications

(15 citation statements)

References 152 publications

(86 reference statements)

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“…The above-mentioned biological functions and signaling pathways play an important role in promoting tumor development. For example, HIPPO ( 70 ), NOCTH ( 71 ), TGF-β ( 72 ) and WNT ( 73 ) are crucial signaling pathways that regulate various cancer-related processes, including cell proliferation, invasion, metastasis, and immunologic escape. The abnormal activation of these signaling pathways promotes cancer malignancy and leads to a poor prognosis ( 74 – 77 ).…”

Section: Discussionmentioning

confidence: 99%

Histone Acetylation Regulator-Mediated Acetylation Patterns Define Tumor Malignant Pathways and Tumor Microenvironment in Hepatocellular Carcinoma

Liao

Luo

et al. 2022

Front. Immunol.

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BackgroundHistone acetylation modification is one of the most common epigenetic methods used to regulate chromatin structure, DNA repair, and gene expression. Existing research has focused on the importance of histone acetylation in regulating tumorigenicity, tumor progression, and tumor microenvironment (TME) but has not explored the potential roles and interactions of histone acetylation regulators in TME cell infiltration, drug sensitivity, and immunotherapy.MethodsThe mRNA expression and genetic alterations of 36 histone acetylation regulators were analyzed in 1599 hepatocellular carcinoma (HCC) samples. The unsupervised clustering method was used to identify the histone acetylation patterns. Then, based on their differentially expressed genes (DEGs), an HAscore model was constructed to quantify the histone acetylation patterns and related subtypes of individual samples. Lastly, the relationship between HAscore and transcription background, tumor clinical features, characteristics of TME, drug response, and efficacy of immunotherapy were analyzed.ResultsWe identified three histone acetylation patterns characterized by high, medium, and low HAscore. Patients with HCC in the high HAscore group experienced worse overall survival time, and the cancer-related malignant pathways were more active in the high HAscore group, comparing to the low HAscore group. The high HAscore group was characterized by an immunosuppressive subtype because of the high infiltration of immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells. Following validation, the HAscore was highly correlated with the sensitivity of anti-tumor drugs; 116 therapeutic agents were found to be associated with it. The HAscore was also correlated with the therapeutic efficacy of the PD-L1 and PD-1 blockade, and the response ratio was significantly higher in the low HAscore group.ConclusionTo the best of our knowledge, our study is the first to provide a comprehensive analysis of 36 histone acetylation regulators in HCC. We found close correlations between histone acetylation patterns and tumor malignant pathways and TME. We also analyzed the therapeutic value of the HAscore in targeted therapy and immunotherapy. This work highlights the interactions and potential clinical utility of histone acetylation regulators in treatment of HCC and improving patient outcomes.

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Section: Discussionmentioning

confidence: 99%

Histone Acetylation Regulator-Mediated Acetylation Patterns Define Tumor Malignant Pathways and Tumor Microenvironment in Hepatocellular Carcinoma

Liao

Luo

et al. 2022

Front. Immunol.

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“…Notch signaling pathway regulates hepatocellular carcinoma cell apoptosis by “crosstalk” with other cell signaling pathways or directly affecting internal and external apoptosis pathways ( 38 ). Notch signaling pathway also play an indispensable part in mammalian immunity and cellular homeostasis ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

Necroptosis-Related Genes Signatures Identified Molecular Subtypes and Underlying Mechanisms in Hepatocellular Carcinoma

Wei

Hou²,

et al. 2022

Front. Oncol.

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BackgroundAlthough emerging evidence supports the relationship between necroptosis (NEC) related genes and hepatocellular carcinoma (HCC), the contribution of these necroptosis-related genes to the development, prognosis, and immunotherapy of HCC is unclear.MethodsThe expression of genes and relevant clinical information were downloaded from TCGA-LIHC, LIRI-JP, GSE14520/NCI, GSE36376, GSE76427, GSE20140, GSE27150, and IMvigor210 datasets. Next, we used an unsupervised clustering method to assign the samples into phenotype clusters base on 15 necroptosis-related genes. Subsequently, we constructed a NEC score based on NEC phenotype-related prognostic genes to quantify the necroptosis related subtypes of individual patients.ResultsWe divided the samples into the high and low NEC score groups, and the high NEC score showed a poor prognosis. Simultaneously, NEC score is an effective and stable model and had a good performance in predicting the prognosis of HCC patients. A high NEC score was characterized by activation of the stroma and increased levels of immune infiltration. A high NEC score was also related to low expression of immune checkpoint molecules (PD-1/PD-L1). Importantly, the established NEC score would contribute to predicting the response to anti-PD-1/L1 immunotherapy.ConclusionsOur study provide a comprehensive analysis of necroptosis-related genes in HCC. Stratification based on the NEC score may enable HCC patients to benefit more from immunotherapy and help identify new cancer treatment strategies.

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“…Abnormalities in Notch signalling were previously described in melanoma, glioblastoma, pancreatic, breast, ovarian cancers and HCC [ 106 ]. Notch signalling is involved in liver progenitor cell differentiation in the setting of cirrhosis with increased inflammation and fibrosis.…”

Section: Progressive Familial Intrahepatic Cholestasis-related Genesmentioning

confidence: 99%

Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature

Vitale

Mattiaccio

Conti

et al. 2022

Cancers

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The family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport defects. Specific genetic pathways potentially cause many otherwise unexplained cholestasis or hepatobiliary tumours in a healthy liver. Lately, next-generation sequencing and whole-exome sequencing have improved the diagnostic procedures of familial intrahepatic cholestasis (FIC), as well as the discovery of several genes responsible for FIC. Moreover, mutations in these genes, even in the heterozygous status, may be responsible for cryptogenic cholestasis in both young and adults. Mutations in FIC genes can influence serum and hepatic levels of bile acids. Experimental studies on the NR1H4 gene have shown that high bile acids concentrations cause excessive production of inflammatory cytokines, resistance to apoptosis, and increased cell regeneration, all risk conditions for developing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). NR1H4 gene encodes farnesoid X-activated receptor having a pivotal role in bile salts synthesis. Moreover, HCC and CCA can emerge in patients with several FIC genes such as ABCB11, ABCB4 and TJP2. Herein, we reviewed the available data on FIC-related hepatobiliary cancers, reporting on genetics to the pathophysiology, the risk factors and the clinical presentation.

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Notch Signaling Regulation in HCC: From Hepatitis Virus to Non-Coding RNAs

Cited by 14 publications

References 152 publications

Histone Acetylation Regulator-Mediated Acetylation Patterns Define Tumor Malignant Pathways and Tumor Microenvironment in Hepatocellular Carcinoma

Histone Acetylation Regulator-Mediated Acetylation Patterns Define Tumor Malignant Pathways and Tumor Microenvironment in Hepatocellular Carcinoma

Necroptosis-Related Genes Signatures Identified Molecular Subtypes and Underlying Mechanisms in Hepatocellular Carcinoma

Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature

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