Hypoxia-inducible Factor-1α Mediates Hyperglycemia-induced Pancreatic Cancer Glycolysis

Liu, Cheng; Qin, Tao; Ma, Jiguang; Duan, Wanxing; Xu, Qinhong; Li, Xuqi; Han, Liang; Li, Wei; Wang, Zheng; Zhang, Dong; Ma, Qingyong; Liu, Jing

doi:10.2174/1871520619666190626120359

Cited by 23 publications

(13 citation statements)

References 39 publications

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“…Many studies have shown that hyperglycemia stimulates tumor cell glycolysis by regulating the expression levels of glycolytic enzymes. For example, a new study reported that hyperglycemia could enhance glycolysis by increasing LDHA activity and HK2, PFKP expression to promote pancreatic cancer progression [29]. Increased expression of LDHA was also detected in the colorectal epithelium of patients with DM, which suggested increased aerobic glycolysis [30].…”

Section: Discussionmentioning

confidence: 99%

Hyperglycemia promotes Snail-induced epithelial–mesenchymal transition of gastric cancer via activating ENO1 expression

Xu¹,

Chen²,

Zhu³

et al. 2019

Cancer Cell Int

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Background: Gastric cancer (GC) is one of the most common gastrointestinal malignancies worldwide. Emerging evidence indicates that hyperglycemia promotes tumor progression, especially the processes of migration, invasion and epithelial-mesenchymal transition (EMT). However, the underlying mechanisms of GC remain unclear. Method: Data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to detect the expression of glycolysis-related enzymes and EMT-related transcription factors. Small interfering RNA (siRNA) transfection was performed to decrease ENO1 expression. Immunohistochemistry (IHC), Western blot and qRT-PCR analyses were used to measure gene expression at the protein or mRNA level. CCK-8, wound-healing and Transwell assays were used to assess cell proliferation, migration and invasion. Results: Among the glycolysis-related genes, ENO1 was the most significantly upregulated in GC, and its overexpression was correlated with poor prognosis. Hyperglycemia enhanced GC cell proliferation, migration and invasion. ENO1 expression was also upregulated with increasing glucose concentrations. Moreover, decreased ENO1 expression partially reversed the effect of high glucose on the GC malignant phenotype. Snail-induced EMT was promoted by hyperglycemia, and suppressed by ENO1 silencing. Moreover, ENO1 knockdown inhibited the activation of transforming growth factor β (TGF-β) signaling pathway in GC. Conclusions: Our results indicated that hyperglycemia induced ENO1 expression to trigger Snail-induced EMT via the TGF-β/Smad signaling pathway in GC.

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Section: Discussionmentioning

confidence: 99%

Hyperglycemia promotes Snail-induced epithelial–mesenchymal transition of gastric cancer via activating ENO1 expression

Xu¹,

Chen²,

Zhu³

et al. 2019

Cancer Cell Int

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“…Because of the dense connective tissue and vascular microenvironment of PDAC, PDAC cells are difficult to penetrate and in a low-perfusion environment, which promotes metabolic rearrangement in the PDAC so that tumor cells can make full use of oxygen even in a hypoxia state (Fu et al, 2018 ; Weniger et al, 2018 ). Thus, PDAC generally displays enhanced glycolysis, including overexpression of glycolytic enzymes and increased lactic acid production, which is caused by mitochondrial dysfunction, abnormal expression of oncogenic genes, specific transcription factors, hypoxic tumor microenvironment, and tumor-associated macrophage (Cheng et al, 2019 ; Karasinska et al, 2020 ; Yang et al, 2020 ). This energy metabolic pathway not only provides energy to cancer cells, but also produces metabolic intermediates that promote cell proliferation, invasion and drug resistance of cancer (Deberardinis et al, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

Glycolysis-Related Gene Expression Profiling Screen for Prognostic Risk Signature of Pancreatic Ductal Adenocarcinoma

Song

Gong

et al. 2021

Front. Genet.

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Objective: Pancreatic ductal adenocarcinoma (PDAC) is highly lethal. Although progress has been made in the treatment of PDAC, its prognosis remains unsatisfactory. This study aimed to develop novel prognostic genes related to glycolysis in PDAC and to apply these genes to new risk stratification.Methods: In this study, based on the Cancer Genome Atlas (TCGA) PAAD cohort, the expression level of glycolysis-related gene at mRNA level in PAAD and its relationship with prognosis were analyzed. Non-negative matrix decomposition (NMF) clustering was used to cluster PDAC patients according to glycolytic genes. Prognostic glycolytic genes, screened by univariate Cox analysis and LASSO regression analysis were established to calculate risk scores. The differentially expressed genes (DEGs) in the high-risk group and the low-risk group were analyzed, and the signal pathway was further enriched to analyze the correlation between glycolysis genes. In addition, based on RNA-seq data, CIBERSORT was used to evaluate the infiltration degree of immune cells in PDAC samples, and ESTIMATE was used to calculate the immune score of the samples.Results: A total of 319 glycolysis-related genes were retrieved, and all PDAC samples were divided into two clusters by NMF cluster analysis. Survival analysis showed that PDAC patients in cluster 1 had shorter survival time and worse prognosis compared with cluster 2 samples (P < 0.001). A risk prediction model based on 11 glycolysis genes was constructed, according to which patients were divided into two groups, with significantly poorer prognosis in high-risk group than in low-risk group (P < 0.001). Both internal validation and external dataset validation demonstrate good predictive ability of the model (AUC = 0.805, P < 0.001; AUC = 0.763, P < 0.001). Gene aggregation analysis showed that DEGs highly expressed in high-risk group were mainly concentrated in the glycolysis level, immune status, and tumor cell proliferation, etc. In addition, the samples in high-risk group showed immunosuppressed status and infiltrated by relatively more macrophages and less CD8+T cell.Conclusions: These findings suggested that the gene signature based on glycolysis-related genes had potential diagnostic, therapeutic, and prognostic value for PDAC.

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“…Phosphofructokinase (PFK) is a major rate-limiting enzyme in glycometabolism process and catalyzes fructose-6-phosphate to convert to fructose-1,6-diphosphate irreversibly [10,11]. PFK has three types of isoforms and among them PFKP is known as the phosphofructokinase's platelet-specific isoform, which plays vital roles in various types of cancer, including breast cancer [12], glioblastoma [13], renal clear cell carcinoma [14], pancreatic cancer [15], and oral squamous cell carcinoma [16] through metabolic reprogramming. Previous studies have shown that PFKP was closely related with invasion and migration ability of breast cancer cells [17,18].…”

Section: Introductionmentioning

confidence: 99%

PFKP is transcriptionally repressed by BRCA1/ZBRK1 and predicts prognosis in breast cancer

et al. 2020

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ObjectivesThe present study aims to elucidate the underlying mechanism how PFKP is regulated by BRCA1 and the clinical significance of PFKP in breast cancer. MethodsMEF-BRCA1 4/4 and the wild type counterpart MEF-BRCA1 +/+ cell lines were used to test the sensitivity of glucose depletion in culture medium. Glucose Assay Kit was used to quantify glucose levels in cultural supernatant and cell lysate. Real time PCR was used to measure the mRNA expression levels of genes. Western blot was used to detect protein levels. Chromatin immunoprecipitation was used to verify the bindings between transcription factors and DNA elements. Luciferase reporter assay was performed to determine the transcriptional activity. Histochemistry assay was performed on tissue microarray. ResultsWe found that MEF-BRCA1 4/4 cells consumed more glucose and were more vulnerable to glucose-deprived culture medium. The mRNA profiles and qPCR assay of MEF-BRCA1 4/4 and MEF-BRCA1 +/+ cells revealed that PFKP, the rate-limiting enzyme of glycolysis, was significantly upregulated in MEF-BRCA1 4/4 cells. Consistently, the repressive effects of BRCA1 on PFKP were confirmed by overexpression or knockdown of BRCA1. Moreover, we also demonstrated that PFKP was suppressed by ZBRK1 as well, which was the corepression partner of BRCA1. Mechanistically, we figured out that BRCA1 formed a transcriptional repression complex with ZBRK1 on the promoter of PFKP and consequently restrained its expression. Importantly, the expression levels of PFKP were demonstrated to associate with poor survival of patients with breast cancer.

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Hypoxia-inducible Factor-1α Mediates Hyperglycemia-induced Pancreatic Cancer Glycolysis

Cited by 23 publications

References 39 publications

Hyperglycemia promotes Snail-induced epithelial–mesenchymal transition of gastric cancer via activating ENO1 expression

Hyperglycemia promotes Snail-induced epithelial–mesenchymal transition of gastric cancer via activating ENO1 expression

Glycolysis-Related Gene Expression Profiling Screen for Prognostic Risk Signature of Pancreatic Ductal Adenocarcinoma

PFKP is transcriptionally repressed by BRCA1/ZBRK1 and predicts prognosis in breast cancer

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