PGK1 is a Potential Survival Biomarker and Invasion Promoter by Regulating the HIF-1α–Mediated Epithelial-Mesenchymal Transition Process in Breast Cancer

Fu, Deyuan; He, Chunyan; Wei, Jinli; Zhang, Zhengquan; Luo, Yumin; H, Tan; Ren, Chuanli

doi:10.1159/000495900

Cited by 74 publications

(51 citation statements)

References 29 publications

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“…The results indicated that HIF‐2α co–immunoprecipitated with proteins, including PGK1 (Appendix ), ALDOC, and ENO2, etc. Evidence suggested that PGK1, which was considered as a vital kinase in cellular activity and a target gene of HIF‐1α, could form a positive feed‐forward loop with HIF‐1α and, thus, stimulated breast cancer progression and metastases . However, we discovered that PGK1 could form a complex with HIF‐2α using silver staining and mass spectrometry, which seemed interesting.…”

Section: Resultsmentioning

confidence: 89%

Extracellular ATP promotes breast cancer invasion and epithelial‐mesenchymal transition via hypoxia‐inducible factor 2α signaling

et al. 2019

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Extracellular ATP has been shown to play an important role in invasion and the epithelial‐mesenchymal transition (EMT) process in breast cancer; however, the mechanism is unclear. Here, by using a cDNA microarray, we demonstrated that extracellular ATP could stimulate hypoxia‐inducible factor (HIF) signaling and upregulate hypoxia‐inducible factor 1/2α (HIF‐1/2α) expression. After knocking down HIF‐1/2α using siRNA, we found that ATP‐driven invasion and EMT were significantly attenuated via HIF2A‐siRNA in breast cancer cells. By using ChIP assays, we revealed that the biological function of extracellular ATP in invasion and EMT process depended on HIF‐2α direct targets, among which lysyl oxidase‐like 2 (LOXL2) and matrix metalloproteinase‐9 (MMP‐9) mediated ATP‐driven invasion, and E‐cadherin and Snail mediated ATP‐driven EMT, respectively. In addition, using silver staining and mass spectrometry, we found that phosphoglycerate kinase 1 (PGK1) could interact with HIF‐2α and mediate ATP‐driven HIF‐2α upregulation. Furthermore, we demonstrated that expressions of HIF‐2α and its target proteins could be regulated via ATP by AKT‐PGK1 pathway. Using a Balb/c mice model, we illustrated the function of HIF‐2α in promoting tumor growth and metastasis in vivo. Moreover, by exploring online databases, we found that molecules involved in ATP‐HIF‐2α signaling were highly expressed in human breast carcinoma tissues and were associated with poor prognosis. Altogether, these findings suggest that extracellular ATP could promote breast carcinoma invasion and EMT via HIF‐2α signaling, which may be a potential target for future anti–metastasis therapy.

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Section: Resultsmentioning

confidence: 89%

Extracellular ATP promotes breast cancer invasion and epithelial‐mesenchymal transition via hypoxia‐inducible factor 2α signaling

et al. 2019

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“…To measure the performance and determine the reliability of OSbrca, we have collected previously published prognostic biomarkers of breast cancer (Table S1) and tested their prognostic potency in OSbrca. Fu et al have demonstrated that PGK1 was overexpressed in tumor tissue and was an indication of worse survival biomarker in breast cancer (13). Using OSbrca, we showed that PGK1 gene was indeed a poor survival biomarker in breast cancer cohorts (Figure 1).…”

Section: Evaluation Of the Previously Reported Prognostic Biomarkers mentioning

confidence: 68%

OSbrca: A Web Server for Breast Cancer Prognostic Biomarker Investigation With Massive Data From Tens of Cohorts

et al. 2019

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Potential prognostic mRNA biomarkers are exploited to assist in the clinical management and treatment of breast cancer, which is the first life-threatening tumor in women worldwide. However, it is technically challenging for untrained researchers to process high dimensional profiling data to screen and validate the potential prognostic values of genes of interests in multiple cohorts. Our aim is to develop an easy-to-use web server to facilitate the screening, developing, and evaluating of prognostic biomarkers in breast cancers. Herein, we collected more than 7,400 cases of breast cancer with gene expression profiles and clinical follow-up information from The Cancer Genome Atlas and Gene Expression Omnibus data, and built an Online consensus Survival analysis web server for Breast Cancers, abbreviated OSbrca, to generate the Kaplan-Meier survival plot with a hazard ratio and log rank P-value for given genes in an interactive way. To examine the performance of OSbrca, the prognostic potency of 128 previously published biomarkers of breast cancer was reassessed in OSbrca. In conclusion, it is highly valuable for biologists and clinicians to perform the preliminary assessment and validation of novel or putative prognostic biomarkers for breast cancers. OSbrca could be accessed at

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“…This signature includes 44 metabolic genes that are essential for EMT but not cell proliferation, involving metabolism regulation of glucose, lipid, and nucleotide [48]. Noticeably, functional studies demonstrated that knockdown of PGK1 could reverse the EMT process to inhibit invasion of BC cells [21]. An investigation on hepatocellular carcinoma indicated that G6PD could activate the STAT3 pathway to promote EMT and further favor cancer metastasis [49].…”

Section: Discussionmentioning

confidence: 99%

“…Studies demonstrated that up-regulated PGK1 and G6PD in BC tissues is associated with a high risk of recurrent metastasis and poor survival of patients. The mechanisms include the enhancement of energy supply and activation of the HIF-1α pathway in cell migration and invasion [21,22]. Therefore, PGK1 and G6PD are potential markers to profile the metabolic activity of CTCs and further indicate the functional CTCs subtypes for BC patients.…”

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confidence: 99%

Metabolic classification of circulating tumor cells as a biomarker for metastasis and prognosis in breast cancer

Chen

Dong

et al. 2020

J Transl Med

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Background: Circulating tumor cells (CTCs) has been demonstrated as a promising liquid biopsy marker for breast cancer (BC). However, the intra-patient heterogeneity of CTCs remains a challenge to clinical application. We aim at profiling aggressive CTCs subpopulation in BC utilizing the distinctive metabolic reprogramming which is a hallmark of metastatic tumor cells. Methods: Oncomine, TCGA and Kaplan-Meier plotter databases were utilized to analyze expression and survival relevance of the previously screened metastasis-promoting metabolic markers (PGK1/G6PD) in BC patients. CTCs detection and metabolic classification were performed through micro-filtration and multiple RNA in situ hybridization using CD45 and PGK1/G6PD probes. Blood samples were collected from 64 BC patients before treatment for CTCs analysis. Patient characteristics were recorded to evaluate clinical applications of CTCs metabolic subtypes, as well as morphological EMT subtypes classified by epithelial (EpCAM/CKs) and mesenchymal (Vimentin/Twist) markers. Results: PGK1 and G6PD expressions were up-regulated in invasive BC tissues compared with normal mammary tissues. Increased tissue expressions of PGK1 or G6PD indicated shortened overall and relapse-free survival of BC patients (P < 0.001). Blood GM + CTCs (DAPI + CD45 − PGK1/G6PD +) was detectable (range 0-54 cells/5 mL) in 61.8% of tCTCs > 0 patients. Increased GM + CTCs number and positive rate were correlated with tumor metastasis and progression (P < 0.05). The GM + CTCs ≥ 2/5 mL level presented superior AUC of ROC at 0.854 (95% CI 0.741-0.968) in the diagnosis of BC metastasis (sensitivity/specificity: 66.7%/91.3%), compared with that of tCTCs (0.779) and CTCs-EMT subtypes (E-CTCs 0.645, H-CTCs 0.727 and M-CTCs 0.697). Moreover, GM + CTCs + group had inferior survival with decreased 2 years-PFS proportion (18.5%) than GM + CTCs − group (87.9%; P = 0.001). Conclusions: This work establishes a PGK1/G6PD-based method for CTCs metabolic classification to identify the aggressive CTCs subpopulation. Metabolically active GM + CTCs subtype is suggested a favorable biomarker of distant metastasis and prognosis in BC patients.

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PGK1 is a Potential Survival Biomarker and Invasion Promoter by Regulating the HIF-1α–Mediated Epithelial-Mesenchymal Transition Process in Breast Cancer

Cited by 74 publications

References 29 publications

Extracellular ATP promotes breast cancer invasion and epithelial‐mesenchymal transition via hypoxia‐inducible factor 2α signaling

Extracellular ATP promotes breast cancer invasion and epithelial‐mesenchymal transition via hypoxia‐inducible factor 2α signaling

OSbrca: A Web Server for Breast Cancer Prognostic Biomarker Investigation With Massive Data From Tens of Cohorts

Metabolic classification of circulating tumor cells as a biomarker for metastasis and prognosis in breast cancer

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