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Increased expression of G9A contributes to carcinogenesis and indicates poor prognosis in hepatocellular carcinoma.

ABSTRACT: Euchromatic histone-lysine N-methyltransferase (G9A), the primary histone methyltransferase for histone H3 Lys9, has been identified to be upregulated in numerous types of cancer. The aim of the present study was to analyze the clinical significance of G9A, and preliminarily explore its function in hepatocellular carcinoma (HCC). An increased expression level of G9A was demonstrated in the HCC samples and also in 5 publically available datasets. By analyzing GSE14520, it was revealed that its expression level was significantly associated with serum ?-fetoprotein level of patients with HCC, and may serve as a potential prognostic indicator for patients with multinodular HCC. Bioinformatics tools were utilized to predict the potential function of G9A, and the results indicated that G9A may modulate gene sets involved in RNA processing and DNA replication. G9A inhibition may suppress cell proliferation by arresting cells in G1 phase and increasing the expression level of microtubule-associated protein light chain 3? (MAP1LC3B) in Huh7 and HepG2 cells. In addition, an inverse association between the expression of G9A and LC3B was demonstrated in HCC tumor samples in the publically available GSE14520 dataset, which indicated that G9A may also have the potential to regulate MAP1LC3B expression in HCC tumor tissues. The results of the present study led to hypothesis that the G9A expression level may be of assistance in diagnosing HCC, and be a potential therapeutic target for HCC. The results provided novel evidence for additional understanding of the crucial role of G9A in tumorigenesis.

SUBMITTER: Qin J

PROVIDER: S-EPMC6004641 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Increased expression of G9A contributes to carcinogenesis and indicates poor prognosis in hepatocellular carcinoma.

Qin Jian J Li Qingyun Q Zeng Zhi Z Wu Ping P Jiang Yanping Y Luo Tao T Ji Xiang X Zhang Qiuping Q Hao Yarong Y Chen Lang L

Oncology letters 20180425 6

Euchromatic histone-lysine N-methyltransferase (G9A), the primary histone methyltransferase for histone H3 Lys<sup>9</sup>, has been identified to be upregulated in numerous types of cancer. The aim of the present study was to analyze the clinical significance of G9A, and preliminarily explore its function in hepatocellular carcinoma (HCC). An increased expression level of G9A was demonstrated in the HCC samples and also in 5 publically available datasets. By analyzing GSE14520, it was revealed ...[more]

PMID: 29928350

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Project description:Objective:Hepatocellular carcinoma (HCC) is a disease that is associated with high mortality; currently, there is no curative and reliable treatment. Cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) is the key signaling molecule in the wingless and INT-1/planar cell polarity (WNT/PCP) pathway. This study aimed to elucidate the prognostic significance of CELSR3 in HCC patients. Methods:The Cancer Genome Atlas (TCGA) database, the Cancer Cell Line Encyclopedia (CCLE) database and the Gene Expression Omnibus (GEO) database were used to analyze the expression of CELSR3 mRNA in HCC samples and cells. The relationship between CELSR3 mRNA and clinical features was assessed by the chi-square test. the diagnostic and predictive value of CELSR3 mRNA expression were analyzed using the receiver operating characteristic (ROC) curve. Kaplan-Meier curve and Cox regression analyses were performed to assess the prognostic value of CELSR3 mRNA in HCC patients. Finally, all three cohorts database was used for gene set enrichment analysis(GSEA) and the identification of CELSR3-related signal transduction pathways. Results:The expression of CELSR3 mRNA was upregulated in HCC, and its expression was correlated with age (P = 0.025), tumor status (P = 0.022), clinical stage (P = 0.003), T classification (P = 0.010), vital status (P = 0.001), and relapse (P = 0.005). The ROC curve assessment indicated that CELSR3 mRNA expression has high diagnostic value in HCC and in the subgroup analysis of stage. In addition, the Kaplan-Meier curve and Cox analyses suggested that patients with high CELSR3 mRNA expression have a poor prognosis, indicating that CELSR3 mRNA is an independent prognostic factor for the overall survival of HCC patients. GSEA showed that GO somatic diversification of immune receptors, GO endonuclease activity, GO DNA repair complex and GO somatic cell DNA recombination, were differentially enriched in the meta-GEO cohort, the HCC cell line cohort and the TCGA cohort of the high CELSR3 mRNA expression phenotype. Conclusion:Our results indicate that CELSR3 mRNA is involved in the progression of cancer and can be used as a biomarker for the prognosis of HCC patients.

Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is fibrotic lung disease with no effective treatment. It is characterized by destruction of alveolar structure and pulmonary interstitial fibrosis, leading to dyspnea and even asphyxia death of patients. Epithelial-mesenchymal transition (EMT) is considered to be a driving factor in the pathogenesis of IPF. Osteopontin (OPN) is a secreted protein widely present in the extracellular matrix and involved in the occurrence and development of a variety of diseases.MethodsThe original datasets were obtained from NCBI GEO databases analyzed with the online tool GEO2R and EasyGEO. Bleomycin induced mouse pulmonary fibrosis model and OPN/OPN-biotin treated mouse model were established to investigate the role of OPN in mouse pulmonary fibrosis and the target cells of OPN. A549 cells and HBE cells were used to explore the mechanism of OPN-induced epithelial-mesenchymal transition (EMT) in epithelial cells and mass spectrometry was used to detect OPN downstream receptors. Precision-cut lung slices and lentivirus-treated mice with pulmonary fibrosis were used to examine the therapeutic effect of OPN and its downstream pathways on pulmonary fibrosis.ResultsWe demonstrate that the content of OPN in IPF bronchoalveolar lavage fluid (BALF) is high compared to the normal groups, and its expression level is correlated with prognosis. At the animal level, OPN was highly expressed at all stages of pulmonary fibrosis in mice, and the bronchoalveolar lavage fluid (BALF) could accurately reflect its expression in the lung. Next, we reveal that OPN was mainly expressed by macrophages and the main target cells of OPN were epithelial cells. Mice developed pulmonary fibrosis accompanied after treating the mice with OPN. Both in vitro and in vivo experiments confirmed that OPN could induce EMT of alveolar epithelial cells. Mechanistically, OPN binding triggered phosphorylation of FAK by CD44, thus activating snail1-mediated profibrotic protein synthesis. Inhibition of FAK phosphorylation and its downstream pathways can effectively alleviate pulmonary fibrosis in precision sections of lung tissue (PCLS) assay. OPN knockdown in bleomycin-induced lung fibrosis mice led to significantly less fibrosis.ConclusionOur data suggest that OPN mediates lung fibrosis through EMT, implicating its potential therapeutic target and prognostic indicator role for IPF. OPN may be a target for the diagnosis and treatment of IPF.

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Increased expression of G9A contributes to carcinogenesis and indicates poor prognosis in hepatocellular carcinoma.

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Increased expression of G9A contributes to carcinogenesis and indicates poor prognosis in hepatocellular carcinoma.

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