Investigation of CTNNB1 gene mutations and expression in hepatocellular carcinoma and cirrhosis in association with hepatitis B virus infection

Javanmard, Davod; Najafi, Mohammad; Babaei, Mohammad Reza; Niya, Mohammad Hadi Karbalaie; Esghaei, Maryam; Panahi, Mahshid; Tameshkel, Fahimeh Safarnezhad; Tavakoli, Ahmad; Jazayeri, Seyed Mohammad; Ghaffari, Hadi; Ataei‐Pirkooh, Angila; Monavari, Seyed Hamidreaz; Bokharaei‐Salim, Farah

doi:10.1186/s13027-020-00297-5

Cited by 35 publications

(19 citation statements)

References 49 publications

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“…The deregulation of different Wnt pathway genes has been repeatedly described in the recent decade (1, 31, 32), which supports the result of the current study. (38). Nevertheless, previous studies showed nuclear accumulation of β-catenin in the absence of activating mutations in hot spots of the CTNNB1 gene (39,40).…”

Section: Discussionmentioning

confidence: 94%

Downregulation of GSK3β and Upregulation of URG7 in Hepatitis B-Related Hepatocellular Carcinoma

et al. 2020

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: Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC). The exact molecular contributors to the development of HBV-related HCC are not yet completely understood. Recent studies demonstrated that the deregulation of the Wnt pathway is highly associated with the development of HCC. Besides, HBV is known to have roles in the deregulation of this pathway. The present study evaluated the molecular aspects of the Wnt pathway in HBV-related HCC in liver tissue samples. Viral characterization was done by identifying the HBx mutations and the assessment of intrahepatic viral load. The expression of Wnt pathway genes was assessed using real-time PCR and methylation-specific PCR. The intrahepatic viral load was significantly higher in tumor samples than in normal tissues (P = 0.0008). Aberrant expression was observed in Wnt-1, Wnt-7a, FZD2, FZD7, β-catenin, URG7, c-Myc, SFRP5, and GSK3β, among which Wnt1, FZD2, SFRP5, Gsk3β, and URG7 were associated with HBV. HBx mutations at positions M88, V116, and 127 + 123 were associated with the decreased expression of GSK3β and overexpression of URG7 and Wnt1. Alterations in the expression level of β-catenin, as well as some mutants of HBx, were correlated with the level of c-Myc. HBV-related HCC seems to be mostly coordinated with epigenetic behaviors of HBx, such a multi-functional peptide with suppressing/trans-activating functions.

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Section: Discussionmentioning

confidence: 94%

Downregulation of GSK3β and Upregulation of URG7 in Hepatitis B-Related Hepatocellular Carcinoma

et al. 2020

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“…In clusters 2 and 3, the patients presented with relatively low TMB, however, they carried several different genetic mutations. A previous study demonstrated that CTNNB1 mutation induced the upregulation of β-catenin expression and increased the activity of the Wnt pathway (Javanmard et al, 2020). The upregulation of c-Myc in the Wnt pathway leads to protooncogenic effects in liver malignancies (Kim et al, 2008).…”

Section: Discussionmentioning

confidence: 98%

Novel Molecular Subtypes Associated With 5mC Methylation and Their Role in Hepatocellular Carcinoma Immunotherapy

Cao

Luo

et al. 2020

Front. Mol. Biosci.

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Background: 5-methylcytosine (5mC) has been reported in the prognosis of a variety of cancers, however, its role in hepatocellular carcinoma (HCC) has not been investigated yet. This study aimed at identifying the molecular subtypes associated with 5mC and establishing a relevant score to predict its prognosis in HCC. Methods: Somatic gene mutation data and gene expression data were retrieved from The Cancer Genome Atlas database. Molecular subtypes were identified by unsupervised clustering based on the expression of 5mC regulators, and the molecular features of each subtype were investigated by survival, mutation, gene set variation, and immune cell infiltration analyses. Next, we performed a differentially expressed analysis based on the new subtypes and selected the overlapping genes for further analysis. We undertook univariate Cox analysis to analyze these genes and constructed a prognostic model by lasso regression analysis. Meanwhile, survival and gene set enrichment analyses were used to explore the prognosis and the relevant pathways, respectively. The LIRI cohort from the International Cancer Genome Consortium database was used as a reference to validate the 5mC subtypes and 5mC score. Results: Twenty-one types of 5mC regulators were employed in this study, and three 5mC-associated molecular subtypes were identified. These three subtypes presented significant differences in prognosis, immune cell infiltration, immune checkpoint inhibitors, signaling pathways, and mutational features. Compared with cluster 3, cluster 2 exhibited significantly increased expression of PD-L1, TIM3, Galectin9, CTLA4, and CD80, while PD-L1, TIM3, and CD80 were higher in cluster 2 than in cluster 1. Furthermore, a 5mC-related score, composed of seven genes (SGPP2, SALL4, B3GNT7, ROR1, MYBL2, SLC7A1, and CAND2), was proven to be significantly associated with prognosis. The established subtypes and scores were thus successfully verified by the validated cohort.

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“…Mutations in CTNNB1, the b-catenin encoding gene, is associated with HCC (Javanmard et al, 2020). However, genomic instability caused by HBV infection is more commonly associated with inactivating mutations in AXIN1 leading to HCC (Li et al, 2013).…”

Section: Oncogenic Viruses Subvert Wnt Signaling Through Multiple Mechanismsmentioning

confidence: 99%

When Viruses Cross Developmental Pathways

Trivedi

Patel

Bellavia

et al. 2021

Front. Cell Dev. Biol.

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Aberrant regulation of developmental pathways plays a key role in tumorigenesis. Tumor cells differ from normal cells in their sustained proliferation, replicative immortality, resistance to cell death and growth inhibition, angiogenesis, and metastatic behavior. Often they acquire these features as a consequence of dysregulated Hedgehog, Notch, or WNT signaling pathways. Human tumor viruses affect the cancer cell hallmarks by encoding oncogenic proteins, and/or by modifying the microenvironment, as well as by conveying genomic instability to accelerate cancer development. In addition, viral immune evasion mechanisms may compromise developmental pathways to accelerate tumor growth. Viruses achieve this by influencing both coding and non-coding gene regulatory pathways. Elucidating how oncogenic viruses intersect with and modulate developmental pathways is crucial to understanding viral tumorigenesis. Many currently available antiviral therapies target viral lytic cycle replication but with low efficacy and severe side effects. A greater understanding of the cross-signaling between oncogenic viruses and developmental pathways will improve the efficacy of next-generation inhibitors and pave the way to more targeted antiviral therapies.

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Investigation of CTNNB1 gene mutations and expression in hepatocellular carcinoma and cirrhosis in association with hepatitis B virus infection

Cited by 35 publications

References 49 publications

Downregulation of GSK3β and Upregulation of URG7 in Hepatitis B-Related Hepatocellular Carcinoma

Downregulation of GSK3β and Upregulation of URG7 in Hepatitis B-Related Hepatocellular Carcinoma

Novel Molecular Subtypes Associated With 5mC Methylation and Their Role in Hepatocellular Carcinoma Immunotherapy

When Viruses Cross Developmental Pathways

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