Identification of Key Genes Associated With the Process of Hepatitis B Inflammation and Cancer Transformation by Integrated Bioinformatics Analysis

Zhang, Jingyuan; Liu, Xinkui; Zhou, Wei; Lu, Shan; Wu, Chao; Wu, Zhishan; Liu, Runping; Li, Xiaojiaoyang; Wu, Jiarui; Liu, Yingying; Guo, Siyu; Jia, Shanshan; Zhang, Xiaomeng; Wang, Miaomiao

doi:10.3389/fgene.2021.654517

Cited by 14 publications

(12 citation statements)

References 94 publications

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“…Moreover, the SNHG16/miR-30a/RRM2 axis also accelerates BRCA cell proliferation and invasion, while miR-4500 could downregulate RRM2 and inhibit BRCA cell proliferation, invasion, and migration via suppressing the MAPK signaling pathway [ 38 , 39 ]. Moreover, RRM2 has been included in several bioinformatic-based clinical prognostic models [ 40 , 41 ]. In addition, a single gene bioinformatics study and one clinical pathology research study indicated that RRM2 expression could help in evaluating the outcome of BRCA patients [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

The Core-Targeted RRM2 Gene of Berberine Hydrochloride Promotes Breast Cancer Cell Migration and Invasion via the Epithelial–Mesenchymal Transition

Wei

Luan

et al. 2022

Pharmaceuticals

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Berberine hydrochloride (BBR) could inhibit the proliferation, migration, and invasion of various cancer cells. As the only enzyme for the de novo synthesis of ribonucleotides, RRM2 is closely related to the development of tumorigenesis. However, not much is currently known about the functional roles of RRM2 in breast cancer (BRCA), and whether BBR regulates the migration and invasion of BRCA cells by regulating the expression of RRM2 remains to be determined. We study the effects of BBR on BRCA cell proliferation in vitro and tumorigenesis in vivo by using colony formation assays, EdU assays, and xenograft models. Transcriptome sequencing, the random forest algorithm, and KEGG analysis were utilized to explore the therapeutic target genes and relative pathways. The expression of RRM2 in BRCA patients was analyzed with The Cancer Genome Atlas (TCGA) dataset, the GEPIA website tool, the Gene Expression Omnibus (GEO) database, and the UALCAN database. The survival probability of BRCA patients could be predicted by survival curve and nomogram analysis. Molecular docking was used to explore the affinity between BBR and potential targets. Gain- and loss-of-function methods were employed to explore the biological process in RRM2 participants. We comprehensively investigated the pharmacological characteristics of BBR on BRCA cell lines and discovered that BBR could inhibit the proliferation of BRCA cells in vitro and in vivo. Combining transcriptome sequencing and KEGG analysis, we found that BBR mainly affected the biological behavior of BRCA cells via HIF-1α and AMPK signal pathways. Additionally, by using bioinformatics and molecular docking, we demonstrated that RRM2 plays an oncogenic role in BRCA samples and that it acts as the hub gene of BBR on BRCA cells. Knockdown and overexpression studies indicated that RRM2 promoted BRCA cell migration as well as invasion in vitro by affecting the epithelial-to-mesenchymal transition (EMT). Our study demonstrated the significance of BBR regulating HIF-1α and AMPK signaling pathways in BRCA cells. Moreover, we revealed the carcinogenic role and potential mechanism of RRM2 as a core regulatory factor of BBR in BRCA in controlling BRCA invasion, migration, and EMT, suggesting that RRM2 may be a therapeutic target and prognostic biomarker for BRCA therapy.

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Section: Discussionmentioning

confidence: 99%

The Core-Targeted RRM2 Gene of Berberine Hydrochloride Promotes Breast Cancer Cell Migration and Invasion via the Epithelial–Mesenchymal Transition

Wei

Luan

et al. 2022

Pharmaceuticals

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“…DEPDC1 expression was lower in normal adjacent tissue relative to OSCC tissue. In addition, several studies have found that longer survival in patients with multiple myeloma and hepatocellular carcinoma was significantly correlated with a lower DEPDC1 expression, suggesting that DEPDC1 may be a new diagnostic marker ( 30 , 31 ). According to these reports, increased DEPDC1 in OSCC cancer significantly correlated with shorter patient survival times.…”

Section: Discussionmentioning

confidence: 99%

FOXM1 is regulated by DEPDC1 to facilitate development and metastasis of oral squamous cell carcinoma

et al. 2022

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The Disheveled, EGL-10, Pleckstrin domain containing 1 (DEPDC1) is a new oncogene that has recently been described. The mechanisms and functions of its expression are yet to be determined in oral squamous cell carcinoma (OSCC). In the present study, the impact of DEPDC1 on the growth and development of OSCC was investigated using animal models, cell lines and human tissue samples. Elevated DEPDC1 expression within cancer cell lines and human OSCC has been identified. Mechanistic examination showed that restored DEPDC1 expression in vivo and in vitro stimulated OSCC tumour development. In addition, FOXM1 interacts with DEPDC1 as indicated by co-immunoprecipitation and immunofluorescence testing. Functionally, DEPDC1 facilitated Wnt/β-catenin signal transduction and β-catenin protein nuclear expression. In summary, the DEPDC1, interacting with FOXM1 via Wnt/β-catenin signaling, the closely regulated OSCC pathogenesis, suggesting that targeting the novel DEPDC1/FOXM1/β-catenin complex is an essential OSCC therapeutic approach.

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“…The formula is a linear combination of the gene expression value of each gene and the regression coefficient (β) [ 20 ]. The R-survminer, R-survival, and R-ggrisk packages were used to draw a risk plot [ 21 , 22 ]. The objective of constructing a Cox proportional hazards regression model was to assess the relative contribution of key prognostic genes to patient survival prediction.…”

Section: Methodsmentioning

confidence: 99%

Significance of Identifying Key Genes Involved in HBV-Related Hepatocellular Carcinoma for Primary Care Surveillance of Patients with Cirrhosis

et al. 2022

Genes

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Cirrhosis is frequently the final stage of disease preceding the development of hepatocellular carcinoma (HCC) and is one of the risk factors for HCC. Preventive surveillance for early HCC in patients with cirrhosis is advantageous for achieving early HCC prevention and diagnosis, thereby enhancing patient prognosis and reducing mortality. However, there is no highly sensitive diagnostic marker for the clinical surveillance of HCC in patients with cirrhosis, which significantly restricts its use in primary care for HCC. To increase the accuracy of illness diagnosis, the study of the effective and sensitive genetic biomarkers involved in HCC incidence is crucial. In this study, a set of 120 significantly differentially expressed genes (DEGs) was identified in the GSE121248 dataset. A protein–protein interaction (PPI) network was constructed among the DEGs, and Cytoscape was used to extract hub genes from the network. In TCGA database, the expression levels, correlation analysis, and predictive performance of hub genes were validated. In total, 15 hub genes showed increased expression, and their positive correlation ranged from 0.80 to 0.90, suggesting they may be involved in the same signaling pathway governing HBV-related HCC. The GSE10143, GSE25097, GSE54236, and GSE17548 datasets were used to investigate the expression pattern of these hub genes in the progression from cirrhosis to HCC. Using Cox regression analysis, a prediction model was then developed. The ROC curves, DCA, and calibration analysis demonstrated the superior disease prediction accuracy of this model. In addition, using proteomic analysis, we investigated whether these key hub genes interact with the HBV-encoded oncogene X protein (HBx), the oncogenic protein in HCC. We constructed stable HBx-expressing LO2-HBx and Huh-7-HBx cell lines. Co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS) results demonstrated that CDK1, RRM2, ANLN, and HMMR interacted specifically with HBx in both cell models. Importantly, we investigated 15 potential key genes (CCNB1, CDK1, BUB1B, ECT2, RACGAP1, ANLN, PBK, TOP2A, ASPM, RRM2, NEK2, PRC1, SPP1, HMMR, and DTL) participating in the transformation process of HBV infection to HCC, of which 4 hub genes (CDK1, RRM2, ANLN, and HMMR) probably serve as potential oncogenic HBx downstream target molecules. All these findings of our study provided valuable research direction for the diagnostic gene detection of HBV-related HCC in primary care surveillance for HCC in patients with cirrhosis.

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Identification of Key Genes Associated With the Process of Hepatitis B Inflammation and Cancer Transformation by Integrated Bioinformatics Analysis

Cited by 14 publications

References 94 publications

The Core-Targeted RRM2 Gene of Berberine Hydrochloride Promotes Breast Cancer Cell Migration and Invasion via the Epithelial–Mesenchymal Transition

The Core-Targeted RRM2 Gene of Berberine Hydrochloride Promotes Breast Cancer Cell Migration and Invasion via the Epithelial–Mesenchymal Transition

FOXM1 is regulated by DEPDC1 to facilitate development and metastasis of oral squamous cell carcinoma

Significance of Identifying Key Genes Involved in HBV-Related Hepatocellular Carcinoma for Primary Care Surveillance of Patients with Cirrhosis

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