Epithelial V‐like antigen 1 promotes hepatocellular carcinoma growth and metastasis via the ERBB‐PI3K‐AKT pathway

Ni, Qian‐Zhi; Chen, Zhenhua; Zheng, Qian-Wen; Xie, Dong; Li, Jingjing; Cheng, Shuqun; Ma, Xiaochun

doi:10.1111/cas.14331

Cited by 14 publications

(14 citation statements)

References 48 publications

(80 reference statements)

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“…Several studies already reported an association between ERBB3 expression and patients’ outcome in different types of cancer, including lung adenocarcinoma, breast, gastric, and colorectal cancer [ 29 , 30 , 31 ]. Consistently, it has been shown that the ERBB3-PI3K-Akt signaling pathway is directly involved in HCC growth, invasion, and migration [ 32 ]. Furthermore, ERBB3 was identified as a compensatory survival factor that was up-regulated after c-Met inhibition in c-Met + HCC cell line [ 33 ].…”

Section: Discussionmentioning

confidence: 70%

The Clinical Role of Serum Epidermal Growth Factor Receptor 3 in Hepatitis C Virus-Infected Patients with Early Hepatocellular Carcinoma

Caviglia

Abate

Rolle³

et al. 2021

Biology

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Epidermal growth factor receptor 3 (ERBB3) is a surface tyrosine kinase receptor belonging to the EGFR/ERBB family, involved in tumor development and progression. We evaluated the diagnostic and prognostic value of serum ERBB3 measurement in hepatitis C virus (HCV)-infected patients with early hepatocellular carcinoma (HCC). A total of 164 HCV-infected patients (82 with cirrhosis and 82 with early HCC) were included in the study. HCC was classified according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Among patients with HCC, 23 (28%) had a diagnosis of very early tumor (BCLC = 0), while 59 (62%) had a diagnosis of early HCC (BCLC = A). Median overall survival (OS) in patients with HCC was 79.2 (95% CI 51.6–124.8) months. While ERBB3 serum values were similar between patients with cirrhosis and those with HCC (p = 0.993), in the latter, serum ERBB3 ≥ 2860 RU resulted significantly and independently associated with OS (Hazard Ratio = 2.24, 95% CI 1.16–4.35, p = 0.017). Consistently, the 1-, 3-, and 5-year OS rates in patients with serum ERBB3 ≥ 2860 RU were 90% (36/40), 53% (19/36), and 28% (8/29) in comparison to patients with serum ERBB3 < 2860 RU, which were 98% (40/41), 80% (32/40), and 74% (26/35) (Log-rank test; p = 0.014). In conclusion, serum ERBB3 values resulted an independent prognostic factor of patients with early HCC and might be useful to tailor more personalized treatment strategies.

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Section: Discussionmentioning

confidence: 70%

The Clinical Role of Serum Epidermal Growth Factor Receptor 3 in Hepatitis C Virus-Infected Patients with Early Hepatocellular Carcinoma

Caviglia

Abate

Rolle³

et al. 2021

Biology

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“…Furthermore, a robust quantitative nomogram plot including the risk score and clinical stage was constructed. GSEA analysis results suggested a potential biological molecular mechanism of risk signature in HCC progression via Wnt ( Dai et al, 2019 ; Hu et al, 2019 ; Huynh et al, 2019 ; Jin et al, 2019 ; Li et al, 2019 ; Tan et al, 2019 ) and ERBB ( Ni et al, 2020 ) signaling pathways and others. Besides, we demonstrated the prognostic risk signature remained a good prognosis predictive accuracy indicator when HCC cases subdivided into subgroups according to clinical features.…”

Section: Discussionmentioning

confidence: 99%

Immunological Significance of Prognostic DNA Methylation Sites in Hepatocellular Carcinoma

Chen

et al. 2021

Front. Mol. Biosci.

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Background: Hepatocellular carcinoma (HCC) is a tumor with high morbidity and high mortality worldwide. DNA methylation, one of the most common epigenetic changes, might serve a vital regulatory role in cancer.Methods: To identify categories based on DNA methylation data, consensus clustering was employed. The risk signature was yielded by systematic bioinformatics analyses based on the remarkably methylated CpG sites of cluster 1. Kaplan–Meier analysis, variable regression analysis, and ROC curve analysis were further conducted to validate the prognosis predictive ability of risk signature. Gene set enrichment analysis (GSEA) was performed for functional annotation. To uncover the context of tumor immune microenvironment (TIME) of HCC, we employed the ssGSEA algorithm and CIBERSORT method and performed TIMER database exploration and single-cell RNA sequencing analysis. Additionally, quantitative real-time polymerase chain reaction was employed to determine the LRRC41 expression and preliminarily explore the latent role of LRRC41 in prognostic prediction. Finally, mutation data were analyzed by employing the “maftools” package to delineate the tumor mutation burden (TMB).Results: HCC samples were assigned into seven subtypes with different overall survival and methylation levels based on 5′-cytosine-phosphate-guanine-3′ (CpG) sites. The risk prognostic signature including two candidate genes (LRRC41 and KIAA1429) exhibited robust prognostic predictive accuracy, which was validated in the external testing cohort. Then, the risk score was significantly correlated with the TIME and immune checkpoint blockade (ICB)–related genes. Besides, a prognostic nomogram based on the risk score and clinical stage presented powerful prognostic ability. Additionally, LRRC41 with prognostic value was corroborated to be closely associated with TIME characterization in both expression and methylation levels. Subsequently, the correlation regulatory network uncovered the potential targets of LRRC41 and KIAA1429. Finally, the methylation level of KIAA1429 was correlated with gene mutation status.Conclusion: In summary, this is the first to identify HCC samples into distinct clusters according to DNA methylation and yield the CpG-based prognostic signature and quantitative nomogram to precisely predict prognosis. And the pivotal player of DNA methylation of genes in the TIME and TMB status was explored, contributing to clinical decision-making and personalized prognosis monitoring of HCC.

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“…EGFR inhibition has been shown in studies to inhibit HCC cell survival, migration, and invasion ( Chen et al, 2019 ; Jin et al, 2021 ). The ErBB-PI3K-AKT pathway can promote the growth and spread of hepatocellular carcinoma ( Ni et al, 2020 ). Overexpression of focal adhesion kinase (FAK) occurs frequently in human HCC tissues, and simultaneous overexpression of FAK increases AR expression, which leads to HCC formation in mice ( Shang et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

Study on the molecular mechanism of anti-liver cancer effect of Evodiae fructus by network pharmacology and QSAR model

Chen

Han

2023

Front. Chem.

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Introduction: Evodiae Fructus (EF) is the dried, near ripe fruit of Euodia rutaecarpa (Juss.) Benth in Rutaceae. Numerous studies have demonstrated its anti-liver cancer properties. However, the molecular mechanism of Evodiae fructus against liver cancer and its structure-activity connection still require clarification.Methods: We utilized network pharmacology and a QSAR (2- and 3-dimensional) model to study the anti-liver cancer effect of Evodiae fructus. First, by using network pharmacology to screen the active substances and targets of Evodiae fructus, we investigated the signaling pathways involved in the anti-liver cancer actions of Evodiae fructus. The 2D-QSAR pharmacophore model was then used to predict the pIC50 values of compounds. The hiphop method was used to create an ideal 3D-QSAR pharmacophore model for the prediction of Evodiae fructus compounds. Finally, molecular docking was used to validate the rationality of the pharmacophore, and molecular dynamics was used to disclose the stability of the compounds by assessing the trajectories in 10 ns using RMSD, RMSF, Rg, and hydrogen bonding metrics.Results: In total, 27 compounds were acquired from the TCMSP and TCM-ID databases, and 45 intersection targets were compiled using Venn diagrams. Network integration analysis was used in this study to identify SRC as a primary target. Key pathways were discovered by KEGG pathway analysis, including PD-L1 expression and PD-1 checkpoint pathway, EGFR tyrosine kinase inhibitor resistance, and ErbB signaling pathway. Using a 2D-QSAR pharmacophore model and the MLR approach to predict chemical activity, ten highly active compounds were found. Two hydrophobic features and one hydrogen bond acceptor feature in the 3D-QSAR pharmacophore model were validated by training set chemicals. The results of molecular docking revealed that 10 active compounds had better docking scores with SRC and were linked to residues via hydrogen and hydrophobic bonds. Molecular dynamics was used to show the structural stability of obacunone, beta-sitosterol, and sitosterol.Conclusion:Pharmacophore 01 has high selectivity and the ability to distinguish active and inactive compounds, which is the optimal model for this study. Obacunone has the optimal binding ability with SRC. The pharmacophore model proposed in this study provides theoretical support for further screening effective anti-cancer Chinese herbal compounds and optimizing the compound structure.

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Epithelial V‐like antigen 1 promotes hepatocellular carcinoma growth and metastasis via the ERBB‐PI3K‐AKT pathway

Cited by 14 publications

References 48 publications

The Clinical Role of Serum Epidermal Growth Factor Receptor 3 in Hepatitis C Virus-Infected Patients with Early Hepatocellular Carcinoma

The Clinical Role of Serum Epidermal Growth Factor Receptor 3 in Hepatitis C Virus-Infected Patients with Early Hepatocellular Carcinoma

Immunological Significance of Prognostic DNA Methylation Sites in Hepatocellular Carcinoma

Study on the molecular mechanism of anti-liver cancer effect of Evodiae fructus by network pharmacology and QSAR model

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