Profiles of m6A RNA methylation regulators for the prognosis of hepatocellular carcinoma

Li, Wang; Chen, Qi‐Feng; Huang, Tao; Shen, Lujun; Huang, Zijing; Wu, Peihong

doi:10.3892/ol.2020.11435

Cited by 11 publications

(12 citation statements)

References 31 publications

(65 reference statements)

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“…Molecular-level pan-cancer analyses have provided insights into the common features and heterogeneity of various human malignancies ( 2 ). For example, Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) were developed based on epigenomic, genomic, proteomic, and transcriptomic data from multiple human cancer cell lines and tissues ( 3 – 5 ). Pan-cancer analyses have also revealed the significance of specific genes and signaling pathways in cancers.…”

Section: Introductionmentioning

confidence: 99%

Clinical Implications of Aberrant PD-1 and CTLA4 Expression for Cancer Immunity and Prognosis: A Pan-Cancer Study

et al. 2020

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Combination therapy with inhibitors of cytotoxic T lymphocyte-associated protein (CTLA)4 and programmed death (PD)-1 has demonstrated efficacy in cancer patients. However, there is little information on CTLA4 and PD-1 expression levels and their clinical significance across diverse cancers. In this study, we addressed this question by analyzing PD-1 and CTLA4 levels in 33 different types of cancer along with their prognostic significance using The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia datasets. Liver hepatocellular carcinoma (LIHC) patients receiving cytokine-induced killer cell (CIK) immunotherapy at Sun Yat-sen University cancer center were enrolled for survival analysis. The correlation between PD-1/CTLA4 expression and cancer immunity was also analyzed. The results showed that PD-1 and CTLA4 transcript levels varied across cancer cell lines, with aberrant expression detected in certain cancer types; Kaplan–Meier analysis with the Cox proportional hazards model showed that this was closely related to overall survival in breast invasive carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, acute myeloid leukemialymphoma, uterine corpus endometrial carcinoma, and uveal melanoma in TCGA. High serum PD-1 and CTLA4 levels predicted better survival in LIHC patients receiving CIK therapy. PD-1 and CTLA4 levels were found to be significantly correlated with the degree of tumor cell infiltration using Tumor Immune Estimation Resource, Estimating Relative Subsets of RNA Transcripts, and Estimation of Stromal and immune Cells in Malignant Tumor Tissues Using Expression Data as well as with tumor-infiltrating lymphocyte marker expression; they were also related to tumor mutation burden, microsatellite instability, mismatch repair, and the expression of DNA methyltransferases in some cancer types. Gene set enrichment analysis of 33 cancer types provided further evidence for associations between PD-1/CTLA4 levels and cancer development and immunocyte infiltration. Thus, PD-1 and CTLA4 play important roles in tumorigenesis and tumor immunity and can serve as prognostic biomarkers in different cancer types.

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Section: Introductionmentioning

confidence: 99%

Clinical Implications of Aberrant PD-1 and CTLA4 Expression for Cancer Immunity and Prognosis: A Pan-Cancer Study

et al. 2020

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“…5,13,28 Recent papers also examined the role of m6A-regulated regulators in HCC prognosis. [16][17][18][19] However, the present study systematically analysed the prognostic value and expression profile of m6A regulators in HCC from the TCGA database and validated the results in the GEO database and clinical surgical samples.…”

Section: Discussionmentioning

confidence: 76%

“…15 Recent studies examined the role of m6A regulatory genes in HCC prognosis. [16][17][18][19] The present study systematically analysed the clinical and RNA-seq pertaining to HCC from The Cancer Genome Atlas (TCGA) database and evaluated the alterations of 13 m6A regulatory genes in HCC and their association with clinicopathological features. All of the results were validated in the Gene Expression Omnibus (GEO) database and clinical samples.…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Profile and Prognostic Value of m6A RNA Methylation Regulators in Hepatocellular Carcinoma

Chang

et al. 2021

JHC

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Background: N6-methyladenosine (m6A) RNA methylation is the most prevalent modification of mammalian RNA, and it is associated with tumorigenesis and cancer progression. Its regulation is mediated via m6A-related regulators, including "erasers," "readers," and "writers". The present study evaluated the expression profile, risk signature and prognostic value of 13 m6A regulators in hepatocellular carcinoma (HCC) using different datasets, including The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and clinical samples. Methods: We used 374 HCC samples derived from the TCGA database, 569 HCC samples from 2 GEO datasets, and clinical tumour and nontumour tissues derived from 60 patients with HCC who underwent surgery in Xinqiao Hospital Chongqing to assess the gene expression profiles and prognostic values of m6A-related regulators in HCC. Results: Eight of 13 core m6A-related regulators were overexpressed in all databases, including TCGA, GSE, clinical tumour and nontumour tissues of HCC. Two clusters (Cluster 1 and Cluster 2) were identified via consensus clustering. Cluster 2 was associated with poorer prognosis, higher tumour grade, higher AFP levels, and worse outcome compared to Cluster 1, which indicates that these m6A-related regulators are highly correlated with HCC malignancy. We performed survival analyses using the Log rank tests and a Cox regression model. Gene enrichment analysis was used to detect the related KEGG and GO pathways. We derived a prognostic risk signature using five selected m6A-related regulators. Conclusion: Our work suggested that m6A-related regulators might be key participants in the tumour progression of HCC and potential biomarkers with prognostic value.

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“…Emerging evidence has strongly suggested that CDK2/4/6, in particular the CDK2, are involved in RNA modifications. As m6A RNA methylation participates in the pathogenesis of multiple diseases including cancer, the potential roles of CDK2/4/6 in m6A RNA modification in human HCC require further investigations (Li et al 2020 ). Furthermore, CDK2 has been reported to phosphorylate the p27 KIP1 and RB proteins in cell cycle progression, the replication factors A and C in DNA replication, the NPAT in histone synthesis, and the nucleophosmin (NPM) in centrosome duplication (Meraldi et al 1999 ).Taken together these studies strongly suggested an important role of CDK2 in human HCC, and a CDK2/4/6 triple inhibitor, vanoxerine dihydrochloride, may have additional advantages and broader anti-cancer activities than CDK4/6 dual inhibitors for the treatment of human HCC.…”

Section: Discussionmentioning

confidence: 99%

Discovery of vanoxerine dihydrochloride as a CDK2/4/6 triple-inhibitor for the treatment of human hepatocellular carcinoma

Zhu

Xia

et al. 2021

Mol Med

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Background Cyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC). Methods We used the combination of computational and experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for the treatment of HCC. Results We identified vanoxerine dihydrochloride as a new CDK2/4/6 inhibitor, and a strong cytotoxicdrugin human HCC QGY7703 and Huh7 cells (IC50: 3.79 μM for QGY7703and 4.04 μM for Huh7 cells). In QGY7703 and Huh7 cells, vanoxerine dihydrochloride treatment caused G1-arrest, induced apoptosis, and reduced the expressions of CDK2/4/6, cyclin D/E, retinoblastoma protein (Rb), as well as the phosphorylation of CDK2/4/6 and Rb. Drug combination study indicated that vanoxerine dihydrochloride and 5-Fu produced synergistic cytotoxicity in vitro in Huh7 cells. Finally, in vivo study in BALB/C nude mice subcutaneously xenografted with Huh7 cells, vanoxerine dihydrochloride (40 mg/kg, i.p.) injection for 21 days produced significant anti-tumor activity (p < 0.05), which was comparable to that achieved by 5-Fu (10 mg/kg, i.p.), with the combination treatment resulted in synergistic effect. Immunohistochemistry staining of the tumor tissues also revealed significantly reduced expressions of Rb and CDK2/4/6in vanoxerinedihydrochloride treatment group. Conclusions The present study isthe first report identifying a new CDK2/4/6 triple inhibitor vanoxerine dihydrochloride, and demonstrated that this drug represents a novel therapeutic strategy for HCC treatment.

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Profiles of m6A RNA methylation regulators for the prognosis of hepatocellular carcinoma

Cited by 11 publications

References 31 publications

Clinical Implications of Aberrant PD-1 and CTLA4 Expression for Cancer Immunity and Prognosis: A Pan-Cancer Study

Clinical Implications of Aberrant PD-1 and CTLA4 Expression for Cancer Immunity and Prognosis: A Pan-Cancer Study

Gene Expression Profile and Prognostic Value of m6A RNA Methylation Regulators in Hepatocellular Carcinoma

Discovery of vanoxerine dihydrochloride as a CDK2/4/6 triple-inhibitor for the treatment of human hepatocellular carcinoma

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