Targeting CDC7 potentiates ATR-CHK1 signaling inhibition through induction of DNA replication stress in liver cancer

Guo, Yuchen; Wang, Jun; Benedict, Bente; Yang, Chen; Gemert, F.H.M. van; Ma, Xuhui; Gao, Dongmei; Wang, Hui; Zhang, Shu; Lieftink, Cor; Beijersbergen, Roderick L.; Riele, Hein te; Qiao, Xiaohang; Gao, Qiang; Sun, Chong; Qin, Wenxin; Bernards, René; Wang, Cun

doi:10.1186/s13073-021-00981-0

Cited by 28 publications

(25 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We performed several functional experiments on HCCLM3 and PLC/PRF/5 cells and demonstrated that CHEK1 knockdown inhibited cell viability, invasion, and migration of HCC cells in vitro . Using a colony formation assay, Guo et al demonstrated that the CHEK1 inhibitor, MK-8776, significantly suppresses the proliferation of HCC cells ( 16 ), which is consistent with our findings using the CCK-8 assay.…”

Section: Discussionsupporting

confidence: 91%

“…Thus, a fragile equilibrium prevails, and E2F1 may play opposite roles in different tumors (45). In liver cancer progression, E2F oncogenic signaling was observed to be consistently activated (46) (16), which is consistent with our findings using the CCK-8 assay.…”

Section: Discussionsupporting

confidence: 89%

“…Bao et al found that CHEK1 was negatively regulated by miR-126 in HCC ( 15 ). Guo et al reported that the inhibition of ataxia telangiectasia and Rad3-related protein (ATR)-CHEK1 signaling led to the induction of DNA replication stress in liver cancer ( 16 ). However, these studies undertook only basic research of CHEK1 in HCC.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Expressional and functional characteristics of checkpoint kinase 1 as a prognostic biomarker in hepatocellular carcinoma

Bai¹,

Dong²,

Lin³

et al. 2022

Transl Cancer Res

View full text Add to dashboard Cite

Background: Hepatocellular carcinoma (HCC) is the most common pathological subtype of liver cancer and is the third leading cause of cancer death worldwide. Checkpoint kinase 1 (CHEK1), an essential serine/ threonine kinase that regulates the cell cycle, is reported to be associated with carcinogenesis. However, the biological role and clinical significance of CHEK1 in HCC are still incompletely known.Methods: In this research, CHEK1 messenger RNA (mRNA) levels in various liver hepatocellular carcinoma (LIHC) cohorts from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were evaluated. The Kaplan-Meier database was applied to identify the correlation between survival time and CHEK1 expression in patients with HCC. Gene set enrichment analysis (GSEA)was performed to explore the potential mechanism of CHEK1 in HCC, and NetworkAnalyst v. 3.0 (https:// www.networkanalyst.ca/) was used to construct the regulatory networks of CHEK1 in HCC. Discriminant Regulon Expression Analysis (DoRothEA) was used to detect the activity of transcriptional factors (TFs) in gene-enriched cells (EC) with CHEK1 coexpression. In vitro experiments were conducted to investigate the effects of CHEK1 on the biological function of HCC cells. Results: The CHEK1 mRNA level was overexpressed in HCC, and increased CHEK1 expression correlated with poor survival outcomes. The homo sapiens-microRNA-195 (hsa-miR-195) may have contributed to the upregulation of CHEK1 in HCC. GSEA and NetworkAnalyst v. 3.0 showed that CHEK1 played a crucial part in tumor proliferation of HCC and may be regulated by TF E2F1. DoRothEA showed increased transcriptional activity of E2F1 in gene-EC with CHEK1 coexpression. Moreover, experiments of cell function showed that the knockdown of CHEK1 weakened the aggressive behavior and proliferation of HCC cells. Overexpression of E2F1 increased the proliferation and invasion of HCC cells in vitro, while the silencing of CHEK1 dampened cell invasion induced by E2F1 overexpression. Conclusions: These results identified the prognostic significance and expression characteristics of CHEK1 in HCC through bioinformatics analysis and experimental verification. This lays the foundation for further research on the diagnosis and treatment of HCC.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 89%

See 1 more Smart Citation

Expressional and functional characteristics of checkpoint kinase 1 as a prognostic biomarker in hepatocellular carcinoma

Bai¹,

Dong²,

Lin³

et al. 2022

Transl Cancer Res

View full text Add to dashboard Cite

show abstract

“…GSEA enrichment was performed to further explore potential molecular mechanism of the model, several pathways (e.g., Cell cycle, DNA replication, ECM receptor interaction, and so on) involving the tumorigenesis were enriched in the high-risk group. It is widely recognized that abnormal cell cycle and DNA replication was considered a biomarker of HCC ( 47 , 48 ). GSVA enrichment showed the model genes were significantly enriched in most signaling oncogenic pathways and were positively correlated, suggesting these risk genes play the oncogenic role in HCC.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis and experimental verification of the prognostic and biological significance mediated by fatty acid metabolism related genes for hepatocellular carcinoma

Zhu

Zhu²,

Chen³

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

BackgroundLiver cancer is among the leading causes of death related to cancer around the world. The most frequent type of human liver cancer is hepatocellular carcinoma (HCC). Fatty acid (FA) metabolism is an emerging hallmark that plays a promoting role in numerous malignancies. This study aimed to discover a FA metabolism-related risk signature and formulate a better model for HCC patients’ prognosis prediction.MethodsWe collected mRNA expression data and clinical parameters of patients with HCC using the TCGA databases, and the differential FA metabolism-related genes were explored. To create a risk prognostic model, we carried out the consensus clustering as well as univariate and multivariate Cox regression analyses. 16 genes were used to establish a prognostic model, which was then validated in the ICGC dataset. The accuracy of the model was performed using receiver operating characteristic (ROC) analyses, decision curve analysis (DCA) and nomogram. The immune cell infiltration level of risk genes was evaluated with single-sample GSEA (ssGSEA) algorithm. To reflect the response to immunotherapy, immunophenoscore (IPS) was obtained from TCGA-LIHC. Then, the expression of the candidate risk genes (p < 0.05) was validated by qRT-PCR, Western blotting and single-cell transcriptomics. Cellular function assays were performed to revealed the biological function of HAVCR1.ResultsAccording to the TCGA-LIHC cohort analysis, the majority of the FA metabolism-related genes were expressed differentially in the HCC and normal tissues. The prognosis of patients with high-risk scores was observed to be worse. Multivariate COX regression analysis confirmed that the model can be employed as an independent prognosis factor for HCC patients. Furthermore, ssGSEA analysis revealed a link between the model and the levels of immune cell infiltration. Our model scoring mechanism also provides a high predictive value in HCC patients receiving anti-PDL1 immunotherapy. One of the FA metabolism-related genes, HAVCR1, displays a significant differential expression between normal and HCC cell lines. Hepatocellular carcinoma cells (Huh7, and HepG2) proliferation, motility, and invasion were all remarkably inhibited by HAVCR1 siRNA.ConclusionOur study identified a novel FA metabolism-related prognostic model, revealing a better potential treatment and prevention strategy for HCC.

show abstract

“…Preliminary evidence suggests that m6A/m1A/m5C regulated genes play important biological roles in the progression of HCC, which can be used to determine the prognosis and survival of HCC patients. The signaling pathways, including the cell cycle, DNA replication, and WNT are closely associated with cancer progression (28)(29)(30)(31)(32)(33)(34). Previous studies have found that ASF1B is highly expressed in HCC, and elevated ASF1B expression level is associated with poor prognosis in HCC patients.…”

Section: Discussionmentioning

confidence: 99%

The m6A/m5C/m1A Regulated Gene Signature Predicts the Prognosis and Correlates With the Immune Status of Hepatocellular Carcinoma

Zhang

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

RNA modification of m6A/m5C/m1A contributes to the occurrence and development of cancer. Consequently, this study aimed to investigate the functions of m6A/m5C/m1A regulated genes in the prognosis and immune microenvironment of hepatocellular carcinoma (HCC). The expression levels of 45 m6A/m5C/m1A regulated genes in HCC tissues were determined. The functional mechanisms and protein–protein interaction network of m6A/m5C/m1A regulated genes were investigated. The Cancer Genome Atlas (TCGA) HCC gene set was categorized based on 45 m6A/m5C/m1A regulated genes, and survival analysis was used to determine the relationship between the overall survival of HCC patients in subgroups. Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were used to construct the risk model and nomogram for m6A/m5C/m1A regulated genes. The relationships between m6A/m5C/m1A regulated gene subsets and risk model and immune cell infiltration were analyzed using CIBERSORT. m6A/m5C/m1A regulated genes were involved in mRNA and RNA modifications, mRNA and RNA methylation, mRNA and RNA stability, and other processes. There was a statistically significant difference between cluster1 and cluster2 groups of genes regulated by m6A/m5C/m1A. The prognosis of cluster1 patients was significantly better than that of cluster2 patients. There were statistically significant differences between the two cluster groups in terms of fustat status, grade, clinical stage, and T stage of HCC patients. The risk model comprised the overexpression of YBX1, ZC3H13, YTHDF1, TRMT10C, YTHDF2, RRP8, TRMT6, LRPPRC, and IGF2BP3, which contributed to the poor prognosis of HCC patients. The high-risk score was associated with prognosis, fustat status, grade, clinical stage, T stage, and M stage and was an independent risk factor for poor prognosis in HCC patients. High-risk score mechanisms included spliceosome, RNA degradation, and DNA replication, among others, and high-risk was closely related to stromal score, CD4 memory resting T cells, M0 macrophages, M1 macrophages, resting mast cells, CD4 memory activated T cells, and follicular helper T cells. In conclusion, the cluster subgroup and risk model of m6A/m5C/m1A regulated genes were associated with the poor prognosis and immune microenvironment in HCC and are expected to be the new tools for assessing the prognosis of HCC patients.

show abstract

Targeting CDC7 potentiates ATR-CHK1 signaling inhibition through induction of DNA replication stress in liver cancer

Cited by 28 publications

References 69 publications

Expressional and functional characteristics of checkpoint kinase 1 as a prognostic biomarker in hepatocellular carcinoma

Expressional and functional characteristics of checkpoint kinase 1 as a prognostic biomarker in hepatocellular carcinoma

Bioinformatics analysis and experimental verification of the prognostic and biological significance mediated by fatty acid metabolism related genes for hepatocellular carcinoma

The m6A/m5C/m1A Regulated Gene Signature Predicts the Prognosis and Correlates With the Immune Status of Hepatocellular Carcinoma

Contact Info

Product

Resources

About