Genetic alterations and expression of PTEN and its relationship with cancer stem cell markers to investigate pathogenesis and to evaluate prognosis in hepatocellular carcinoma

Chen, Dingbao; Zhao, Li; Qian, Cheng; Wang, Ying; Qian, Liwei; Gao, Jie; Zhu, Jinmin

doi:10.1136/jclinpath-2019-205769

Cited by 24 publications

(18 citation statements)

References 26 publications

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“…At the initial stage of our investigation, it was found that PTEN was expressed at low levels in HCC tissues and cell lines and it was in association with shorter overall survival of patients, staging and metastasis. PTEN has been reported to be downregulated in nearly half of the cases of HCC tissues while reduction of PTEN expression is identified as an independent biomarker for the recurrence and overall survival of HCC as it leads to reduced recurrence-free survival and overall survival of patients [17]. Concordant with our results, PTEN has been proposed as a promising biomarker of the tumor grade and disease stage in patients with HCC considering its role in counterbalancing apoptosis and proliferation [18].…”

Section: Discussionsupporting

confidence: 87%

Loss of PTEN expression is associated with PI3K pathway-dependent metabolic reprogramming in hepatocellular carcinoma

et al. 2020

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Background: Metabolic reprogramming, in which energetic metabolism changes from oxidative phosphorylation to glycolysis, is well-accepted as a hallmark of cancers including hepatocellular carcinoma (HCC). A growing body of evidence suggests the involvement of oncogenes and tumor suppressor genes in the control of metabolic reprogramming. In this study, we attempt to investigate whether loss of PTEN, a recognized tumor suppressor, drives metabolic reprogramming of HCC. Methods: Cancerous liver tissues were surgically resected from 128 HCC patients, with 43 adjacent noncancerous liver tissues as control. Aerobic glycolysis (Warburg effect) was reflected by measurements of glucose uptake and lactate production, mitochondrial membrane potential collapse was observed by JC-1 staining, glycolytic rate and mitochondrial respiration were evaluated by determining glycolytic proton efflux rate (glycoPER) and oxygen consumption rate (OCR) in cultured human HHCC cells. Results: Reciprocal expression of PTEN and PI3K was determined in cancer liver tissues. Overexpression of PTEN suppressed the Warburg effect, as evidenced by reductions in glucose uptake and lactate production, maintenance of mitochondrial function, and transformation of energetic metabolism from glycolysis to oxidative phosphorylation in cultured PTEN-negative HHCC cells. Importantly, 740 Y-P, a PI3K agonist that leads to activation of the PI3K pathway, partially abrogated the function of PTEN and reprogramed glucose metabolism in cultured HHCC cells. Conclusions: The discovery that loss of PTEN allows the tumor metabolic program has been a major advance in understanding the carcinogenesis of HCC.

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Section: Discussionsupporting

confidence: 87%

Loss of PTEN expression is associated with PI3K pathway-dependent metabolic reprogramming in hepatocellular carcinoma

et al. 2020

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“…In the validation phase, GNAS, MSH2, and survivin displayed better diagnostic performances than other TAAs, while PTEN was not a good performer, which was consistent with previous verification results, and may have been caused by the reduction of PTEN expression in HCC tissue [49,50]. Although autoantibodies against PAX5 and GNA11 showed little difference between the HCC and NC groups in the process of univariate analysis in the validation dataset, they were still selected as statistically significant predictors (risk factors) for HCC in multivariate analysis by logistic regression in the training dataset.…”

Section: Discussionsupporting

confidence: 88%

Serological Biomarkers for Early Detection of Hepatocellular Carcinoma: A Focus on Autoantibodies against Tumor-Associated Antigens Encoded by Cancer Driver Genes

Wang

Qin

et al. 2020

Cancers

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Substantial evidence manifests the occurrence of autoantibodies to tumor-associated antigens (TAAs) in the early stage of hepatocellular carcinoma (HCC), and previous studies have mainly focused on known TAAs. In the present study, protein microarrays based on cancer driver genes were customized to screen TAAs. Subsequently, autoantibodies against selected TAAs in sera were tested by enzyme-linked immunosorbent assays (ELISA) in 1175 subjects of three independent datasets (verification dataset, training dataset, and validation dataset). The verification dataset was used to verify the results from the microarrays. A logistic regression model was constructed within the training dataset; seven TAAs were included in the model and yielded an area under the receiver operating characteristic curve (AUC) of 0.831. The validation dataset further evaluated the model, exhibiting an AUC of 0.789. Remarkably, as the aggravation of HCC increased, the prediction probability (PP) of the model tended to decrease, the trend of which was contrary to alpha-fetoprotein (AFP). For AFP-negative HCC patients, the positive rate of this model reached 67.3% in the training dataset and 50.9% in the validation dataset. Screening TAAs with protein microarrays based on cancer driver genes is the latest, fast, and effective method for finding indicators of HCC. The identified anti-TAA autoantibodies can be potential biomarkers in the early detection of HCC.

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“…Reportedly, the inactivation of PTEN, which is known to suppress PI3K, was associated with the expression of PD-L1 in glioma [37]. More importantly, a recent report suggested that inactivating the mutation of PTEN and activating that of PI3K were associated with the expression of CK19 in HCC [38], where PD-L1 expression was frequent. In addition, the activation of the PI3K-Akt pathway is one of the characteristics of CSCs [39].…”

Section: Discussionmentioning

confidence: 99%

Association between Genetic and Immunological Background of Hepatocellular Carcinoma and Expression of Programmed Cell Death-1

et al. 2020

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Background and Aim: Immune checkpoint inhibitors are promising agents for the treatment of hepatocellular carcinomas (HCC) refractory to conventional therapies. To enhance the efficacy of this treatment, immunological and molecular characteristics of HCC with programmed cell death ligand 1 (PD-L1) should be explored. Methods: Clinical backgrounds, PD-L1 expression, and the amount of CD8+ tumor-infiltrating mononuclear cells (TIMCs) were analyzed in 154 HCCs. The expression of 3 stem cell markers and co-inhibitory receptors on tumor cells and TIMCs, respectively, were examined by immunohistochemical analysis. Somatic mutations in the 409 cancer-associated genes and TERT promoter were determined; HCCs were classified based on the presence of gene alterations affecting the 8 oncogenic pathways. The results were validated using the dataset from the Cancer Genome Atlas. Results: The expression of PD-L1 in the HCCs was positively correlated with progressive tumor features, the presence of cytokeratin 19 (CK19), Sal-like protein 4 (SALL4), and the mutations of genes involving the phosphatidyl inositol 3-kinase (PI3K)-Akt pathway. Although CD8+ cells were densely infiltrated in PD-L1-positive tumors, these TIMCs frequently expressed multiple co-inhibitory receptors. However, a subset of PD-L1-positive tumors characterized by activating mutations of

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Genetic alterations and expression of PTEN and its relationship with cancer stem cell markers to investigate pathogenesis and to evaluate prognosis in hepatocellular carcinoma

Cited by 24 publications

References 26 publications

Loss of PTEN expression is associated with PI3K pathway-dependent metabolic reprogramming in hepatocellular carcinoma

Loss of PTEN expression is associated with PI3K pathway-dependent metabolic reprogramming in hepatocellular carcinoma

Serological Biomarkers for Early Detection of Hepatocellular Carcinoma: A Focus on Autoantibodies against Tumor-Associated Antigens Encoded by Cancer Driver Genes

Association between Genetic and Immunological Background of Hepatocellular Carcinoma and Expression of Programmed Cell Death-1

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