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Integrated analysis reveals critical glycolytic regulators in hepatocellular carcinoma.

ABSTRACT: BACKGROUND:Cancer cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect. Increased aerobic glycolysis supports cancer cell survival and rapid proliferation and predicts a poor prognosis in cancer patients. METHODS:Molecular profiles from The Cancer Genome Atlas (TCGA) cohort were used to analyze the prognostic value of glycolysis gene signature in human cancers. Gain- and loss-of-function studies were performed to key drivers implicated in hepatocellular carcinoma (HCC) glycolysis. The molecular mechanisms underlying Osteopontin (OPN)-mediated glycolysis were investigated by real-time qPCR, western blotting, immunohistochemistry, luciferase reporter assay, and xenograft and diethyl-nitrosamine (DEN)-induced HCC mouse models. RESULTS:Increased glycolysis predicts adverse clinical outcome in many types of human cancers, especially HCC. Then, we identified a handful of differentially expressed genes related to HCC glycolysis. Gain- and loss-of-function studies showed that OPN promotes, while SPP2, LECT2, SLC10A1, CYP3A4, HSD17B13, and IYD inhibit HCC cell glycolysis as revealed by glucose utilization, lactate production, and extracellular acidification ratio. These glycolysis-related genes exhibited significant tumor-promoting or tumor suppressive effect on HCC cells and these effects were glycolysis-dependent. Mechanistically, OPN enhanced HCC glycolysis by activating the ?v?3-NF-?B signaling. Genetic or pharmacological blockade of OPN-?v?3 axis suppressed HCC glycolysis in xenograft tumor model and hepatocarcinogenesis induced by DEN. CONCLUSIONS:Our findings reveal crucial determinants for controlling the Warburg metabolism in HCC cells and provide a new insight into the oncogenic roles of OPN in HCC. Video Abstract.

SUBMITTER: Lu C

PROVIDER: S-EPMC7310503 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Integrated analysis reveals critical glycolytic regulators in hepatocellular carcinoma.

Lu Chenying C Fang Shiji S Weng Qiaoyou Q Lv Xiuling X Meng Miaomiao M Zhu Jinyu J Zheng Liyun L Hu Yumin Y Gao Yang Y Wu Xulu X Mao Jianting J Tang Bufu B Zhao Zhongwei Z Huang Li L Ji Jiansong J

Cell communication and signaling : CCS 20200623 1

<h4>Background</h4>Cancer cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect. Increased aerobic glycolysis supports cancer cell survival and rapid proliferation and predicts a poor prognosis in cancer patients.<h4>Methods</h4>Molecular profiles from The Cancer Genome Atlas (TCGA) cohort were used to analyze the prognostic value of glycolysis gene signature in human cancers. Gain- and loss-of-function studies were performed to key drivers im ...[more]

PMID: 32576292

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Project description:Background: The carcinogenesis and prognosis of hepatocellular carcinoma (HCC) involve complex molecular mechanisms, and ferroptosis is related to the development and therapeutic efficacy of HCC, but the specific mechanism and prognostic role of ferroptosis-related genes in HCC have not been elucidated. Methods: Differentially expressed gene analysis, Cox regression, and unsupervised consensus clustering were applied to identify crucial ferroptosis regulators and establish ferroptosis-related subtypes in HCC. Random forest analysis and survival analysis were adopted to confirm FTL as the hub prognostic and diagnostic ferroptosis regulator in HCC. Results: The ferroptosis-related subtypes based on the crucial prognostic ferroptosis regulators showed that patients in fescluster A had a higher survival probability (p < 0.001) and better clinical characteristics than patients in fescluster B in the TCGA-LIHC cohort. Patients with a high tumor mutation burden (TMB) in fescluster B presented a significantly poorer prognosis. FTL was the core ferroptosis regulator, and its low expression revealed a significant survival advantage compared with its high expression (p = 0.03). The expression and predictive value of FTL were both closely related to the clinical features (p < 0.05). Expression of FTL accurately distinguished HCC from normal tissues in the TCGA-LIHC cohort, ICGC cohort, and GSE14520 dataset. In addition, higher infiltrating fractions of immune cells, such as activated CD8+ T cells and Gamma delta T cells, mainly enriched immune-related signaling pathways, including the IL2-STAT3 signaling pathway and interferon-gamma response signaling pathway, and higher expression of immune checkpoints, including PDCD1, CTLA4, TIGIT, and CD83, were presented in patients with high FTL expression (p < 0.05). Patients with high FTL were more sensitive to some targeted drugs, such as cisplatin, dasatinib, and sorafenib, than those with low FTL (p < 0.05). A nomogram based on FTL accurately predicted the prognosis of HCC. Further knockdown of FTL was determined to significantly inhibit cell proliferation and migration in HCC. Conclusion: Our study validated ferroptosis-related subtypes and FTL with effective prognostic value in HCC and was beneficial for identifying candidates suitable for targeted drug therapy and immunotherapy, thereby offering further insight into individual treatment strategies to improve disease outcomes in HCC patients.

Project description:BackgroundGlycosylation plays an essential role in driving the progression and treatment resistance of hepatocellular carcinoma (HCC). However, its function in regulating the acquisition and maintenance of the cancer stemness-like phenotype in HCC remains largely unknown. There is also very little known about how CAD and other potential glycosylation regulators may influence stemness. This study explores the relationship between glycosylation and stemness in HCC.MethodsGene set variance analysis (GSVA) was used to assess the TCGA pan-cancer enrichment in glycosylation-related pathways. Univariate, LASSO, and multivariate COX regression were then used to identify prognostic genes in the TCGA-LIHC and construct a prognostic signature. HCC patients were classified into high- and low-risk subgroups based on the signature. The relationship between gene expression profiles and stemness was confirmed using bulk and single-cell RNA-sequencing data. The role of CAD and other genes in regulating the stemness of HCC was also validated by RT-qPCR, CCK-8, and colony formation assay. Copy number variation (CNV), immune infiltration, and clinical features were further analyzed in different subgroups and subsequent gene expression profiles. Sensitive drugs were also screened.ResultsIn the pan-cancer analysis, HCC was shown to have specific glycosylation alterations. Five genes, CAD, SLC51B, LGALS3, B3GAT3, and MT3, identified from 572 glycosylation-related genes, were used to construct a gene signature and predict HCC patient survival in the TCGA cohort. The results demonstrated a significant positive correlation between patients in the high-risk group and both elevated gene expression and HCC dedifferentiation status. A significant reduction in the stemness-related markers, CD24, CD44, CD20, FOXM1, and EpCAM, was found after the knockdown of CAD and other genes in HepG2 and Huh7 cells. Frequent mutations increased CNVs, immune-suppressive responses, and poor prognosis were also associated with the high-risk profile. The ICGC-LIRI-JP cohort confirmed a similar relationship between glycosylation-related subtypes and stemness. Finally, 84 sensitive drugs were screened for abnormal glycosylation of HCC, and carfilzomib was most highly correlated with CAD.ConclusionsGlycosylation-related molecular subtypes are associated with HCC stemness and disease prognosis. These results provide new directions for further research on the relationship between glycosylation and stemness phenotypes.

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Project description:BackgroundHint1 is a novel tumor suppressor gene, and inactivation of its expression is closely associated with the carcinogenesis of a variety of malignancies. The effects of Hint1 deficiency on the competing endogenous RNA (ceRNA) regulatory network in the context of HCC remains to be fully characterized. This study aims to explore Hint1-related hub lncRNAs in HCC and to establish a reliable prognostic model for HCC patients based on these hub lncRNAs.MethodslncRNA + mRNA microarray was used to identify differentially expressed (DE) lncRNAs and mRNAs in Huh7 cells before and after Hint1 knockdown. A Hint1-related ceRNA network was mapped by bioinformation technology. The DEmRNAs in the network were analyzed via GO and KEGG enrichment analyses. Hub DElncRNAs associated with HCC patient prognosis were then detected through univariate and multivariate Cox regression analyses and were incorporated into a prognostic model. The prognostic value of this model was then assessed through the use of Kaplan-Meier curves, time-related ROC analyses, and nomograms. We also utilized Kaplan-Meier curves to validate the relationship between hub lncRNAs and the overall survival (OS) of HCC patients. Finally, A Hint1-related core ceRNA network based on the hub DElncRNAs and DEmRNAs was mapped.ResultsWe identified 417 differentially expressed DElncRNAs and 2096 DEmRNAs in Huh7 cells before and after Hint1 knockdown. Three hub DElncRNAs (LINC00324, SNHG3, and DIO3OS) in the Hint1-associated ceRNA network were screened out using univariate and multivariate Cox regression analyses. A hepatocellular carcinoma (HCC) prognostic risk-scoring model and nomogram were constructed using these three hub lncRNAs, and it was confirmed that the risk score of the model could be used as an independent predictor of HCC prognosis. A Hint1-related core ceRNA network based on the hub DElncRNAs and DEmRNAs was also mapped.ConclusionWe constructed a reliable prognostic model for HCC patients based on three Hint1-related hub lncRNAs, and we believe these three hub lncRNAs may play critical roles in hepatocarcinogenesis, and progression.

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Integrated analysis reveals critical glycolytic regulators in hepatocellular carcinoma.

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Integrated analysis reveals critical glycolytic regulators in hepatocellular carcinoma.

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