Skip to main content
Top
Published in: Journal of Translational Medicine 1/2022

Open Access 01-12-2022 | Biomarkers | Research

Identification of ENO1 as a prognostic biomarker and molecular target among ENOs in bladder cancer

Authors: Zhengnan Huang, Yilin Yan, Tengjiao Wang, Zeyi Wang, Jinming Cai, Xiangqian Cao, Chenkai Yang, Fang Zhang, Gang Wu, Bing Shen

Published in: Journal of Translational Medicine | Issue 1/2022

Login to get access

Abstract

Background

Enolase is an essential enzyme in the process of glycolysis and has been implicated in cancer progression. Though dysregulation of ENOs has been reported in multiple cancers, their prognostic value and specific role in bladder cancer (BLCA) remain unclear.

Methods

Multiple databases were employed to examine the expression of ENOs in BLCA. The expression of ENO1 was also validated in BLCA cell lines and tissue samples by western blotting and immunohistochemistry. Kaplan–Meier analysis, ROC curve, univariate and multivariate Cox regression were performed to evaluate the predictive capability of the ENO1. Gene ontology (GO) and Gene Set Enrichment Analyses (GSEA) analysis were employed to perform the biological processes enrichment. Function experiments were performed to explore the biological role of ENO1 in BLCA. The correlation of ENO1 with immune cell infiltration was explored by CIBERSORT.

Results

By analyzing three ENO isoforms in multiple databases, we identified that ENO1 was the only significantly upregulated gene in BLCA. High expression level of ENO1 was further confirmed in BLCA tissue samples. Aberrant ENO1 overexpression was associated with clinicopathological characteristics and unfavorable prognosis. Functional studies demonstrated that ENO1 depletion inhibited cancer cell aggressiveness. Furthermore, the expression level of ENO1 was correlated with the infiltration levels of immune cells and immune-related functions.

Conclusions

Taken together, our results indicated that ENO1 might serve as a promising prognostic biomarker for prognosticating prognosis associated with the tumor immune microenvironment, suggesting that ENO1 could be a potential immune-related target against BLCA.
Appendix
Available only for authorised users
Literature
2.
go back to reference Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33.PubMedCrossRef Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33.PubMedCrossRef
3.
4.
go back to reference Patel VG, Oh WK, Galsky MD. Treatment of muscle-invasive and advanced bladder cancer in 2020. CA Cancer J Clin. 2020;70(5):404–23.PubMedCrossRef Patel VG, Oh WK, Galsky MD. Treatment of muscle-invasive and advanced bladder cancer in 2020. CA Cancer J Clin. 2020;70(5):404–23.PubMedCrossRef
5.
go back to reference Lunt SY, Vander Heiden MG. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. 2011;27:441–64.PubMedCrossRef Lunt SY, Vander Heiden MG. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. 2011;27:441–64.PubMedCrossRef
6.
go back to reference DeBerardinis RJ, Chandel NS. We need to talk about the Warburg effect. Nat Metab. 2020;2(2):127–9.PubMedCrossRef DeBerardinis RJ, Chandel NS. We need to talk about the Warburg effect. Nat Metab. 2020;2(2):127–9.PubMedCrossRef
7.
go back to reference Yang YF, Chuang HW, Kuo WT, Lin BS, Chang YC. Current development and application of anaerobic glycolytic enzymes in urothelial cancer. Int J Mol Sci. 2021;22:19. Yang YF, Chuang HW, Kuo WT, Lin BS, Chang YC. Current development and application of anaerobic glycolytic enzymes in urothelial cancer. Int J Mol Sci. 2021;22:19.
8.
go back to reference Yu X, Li S. Non-metabolic functions of glycolytic enzymes in tumorigenesis. Oncogene. 2017;36(19):2629–36.PubMedCrossRef Yu X, Li S. Non-metabolic functions of glycolytic enzymes in tumorigenesis. Oncogene. 2017;36(19):2629–36.PubMedCrossRef
9.
go back to reference Baig MH, Adil M, Khan R, Dhadi S, Ahmad K, Rabbani G, et al. Enzyme targeting strategies for prevention and treatment of cancer: Implications for cancer therapy. Semin Cancer Biol. 2019;56:1–11.PubMedCrossRef Baig MH, Adil M, Khan R, Dhadi S, Ahmad K, Rabbani G, et al. Enzyme targeting strategies for prevention and treatment of cancer: Implications for cancer therapy. Semin Cancer Biol. 2019;56:1–11.PubMedCrossRef
10.
go back to reference Piast M, Kustrzeba-Wójcicka I, Matusiewicz M, Banaś T. Molecular evolution of enolase. Acta Biochim Pol. 2005;52(2):507–13.PubMedCrossRef Piast M, Kustrzeba-Wójcicka I, Matusiewicz M, Banaś T. Molecular evolution of enolase. Acta Biochim Pol. 2005;52(2):507–13.PubMedCrossRef
11.
go back to reference Poyner RR, Reed GH. Structure of the bis divalent cation complex with phosphonoacetohydroxamate at the active site of enolase. Biochemistry. 1992;31(31):7166–73.PubMedCrossRef Poyner RR, Reed GH. Structure of the bis divalent cation complex with phosphonoacetohydroxamate at the active site of enolase. Biochemistry. 1992;31(31):7166–73.PubMedCrossRef
12.
go back to reference Joseph J, Cruz-Sánchez FF, Carreras J. Enolase activity and isoenzyme distribution in human brain regions and tumors. J Neurochem. 1996;66(6):2484–90.PubMedCrossRef Joseph J, Cruz-Sánchez FF, Carreras J. Enolase activity and isoenzyme distribution in human brain regions and tumors. J Neurochem. 1996;66(6):2484–90.PubMedCrossRef
13.
go back to reference Qiao G, Wu A, Chen X, Tian Y, Lin X. Enolase 1, a moonlighting protein, as a potential target for cancer treatment. Int J Biol Sci. 2021;17(14):3981–92.PubMedPubMedCentralCrossRef Qiao G, Wu A, Chen X, Tian Y, Lin X. Enolase 1, a moonlighting protein, as a potential target for cancer treatment. Int J Biol Sci. 2021;17(14):3981–92.PubMedPubMedCentralCrossRef
14.
go back to reference Marangos PJ, Schmechel DE. Neuron specific enolase, a clinically useful marker for neurons and neuroendocrine cells. Annu Rev Neurosci. 1987;10:269–95.PubMedCrossRef Marangos PJ, Schmechel DE. Neuron specific enolase, a clinically useful marker for neurons and neuroendocrine cells. Annu Rev Neurosci. 1987;10:269–95.PubMedCrossRef
16.
go back to reference Comi GP, Fortunato F, Lucchiari S, Bordoni A, Prelle A, Jann S, et al. Beta-enolase deficiency, a new metabolic myopathy of distal glycolysis. Ann Neurol. 2001;50(2):202–7.PubMedCrossRef Comi GP, Fortunato F, Lucchiari S, Bordoni A, Prelle A, Jann S, et al. Beta-enolase deficiency, a new metabolic myopathy of distal glycolysis. Ann Neurol. 2001;50(2):202–7.PubMedCrossRef
17.
go back to reference Muller FL, Colla S, Aquilanti E, Manzo VE, Genovese G, Lee J, et al. Passenger deletions generate therapeutic vulnerabilities in cancer. Nature. 2012;488(7411):337–42.PubMedPubMedCentralCrossRef Muller FL, Colla S, Aquilanti E, Manzo VE, Genovese G, Lee J, et al. Passenger deletions generate therapeutic vulnerabilities in cancer. Nature. 2012;488(7411):337–42.PubMedPubMedCentralCrossRef
18.
go back to reference Zhu X, Miao X, Wu Y, Li C, Guo Y, Liu Y, et al. ENO1 promotes tumor proliferation and cell adhesion mediated drug resistance (CAM-DR) in Non-Hodgkin’s Lymphomas. Exp Cell Res. 2015;335(2):216–23.PubMedCrossRef Zhu X, Miao X, Wu Y, Li C, Guo Y, Liu Y, et al. ENO1 promotes tumor proliferation and cell adhesion mediated drug resistance (CAM-DR) in Non-Hodgkin’s Lymphomas. Exp Cell Res. 2015;335(2):216–23.PubMedCrossRef
19.
go back to reference Tsai ST, Chien IH, Shen WH, Kuo YZ, Jin YT, Wong TY, et al. ENO1, a potential prognostic head and neck cancer marker, promotes transformation partly via chemokine CCL20 induction. Eur J Cancer. 2010;46(9):1712–23.PubMedCrossRef Tsai ST, Chien IH, Shen WH, Kuo YZ, Jin YT, Wong TY, et al. ENO1, a potential prognostic head and neck cancer marker, promotes transformation partly via chemokine CCL20 induction. Eur J Cancer. 2010;46(9):1712–23.PubMedCrossRef
20.
go back to reference Fu QF, Liu Y, Fan Y, Hua SN, Qu HY, Dong SW, et al. Alpha-enolase promotes cell glycolysis, growth, migration, and invasion in non-small cell lung cancer through FAK-mediated PI3K/AKT pathway. J Hematol Oncol. 2015;8:22.PubMedPubMedCentralCrossRef Fu QF, Liu Y, Fan Y, Hua SN, Qu HY, Dong SW, et al. Alpha-enolase promotes cell glycolysis, growth, migration, and invasion in non-small cell lung cancer through FAK-mediated PI3K/AKT pathway. J Hematol Oncol. 2015;8:22.PubMedPubMedCentralCrossRef
21.
go back to reference Yang T, Shu X, Zhang HW, Sun LX, Yu L, Liu J, et al. Enolase 1 regulates stem cell-like properties in gastric cancer cells by stimulating glycolysis. Cell Death Dis. 2020;11(10):870.PubMedPubMedCentralCrossRef Yang T, Shu X, Zhang HW, Sun LX, Yu L, Liu J, et al. Enolase 1 regulates stem cell-like properties in gastric cancer cells by stimulating glycolysis. Cell Death Dis. 2020;11(10):870.PubMedPubMedCentralCrossRef
22.
go back to reference Zhou J, Zhang S, Chen Z, He Z, Xu Y, Li Z. CircRNA-ENO1 promoted glycolysis and tumor progression in lung adenocarcinoma through upregulating its host gene ENO1. Cell Death Dis. 2019;10(12):885.PubMedPubMedCentralCrossRef Zhou J, Zhang S, Chen Z, He Z, Xu Y, Li Z. CircRNA-ENO1 promoted glycolysis and tumor progression in lung adenocarcinoma through upregulating its host gene ENO1. Cell Death Dis. 2019;10(12):885.PubMedPubMedCentralCrossRef
23.
go back to reference Sun L, Lu T, Tian K, Zhou D, Yuan J, Wang X, et al. Alpha-enolase promotes gastric cancer cell proliferation and metastasis via regulating AKT signaling pathway. Eur J Pharmacol. 2019;845:8–15.PubMedCrossRef Sun L, Lu T, Tian K, Zhou D, Yuan J, Wang X, et al. Alpha-enolase promotes gastric cancer cell proliferation and metastasis via regulating AKT signaling pathway. Eur J Pharmacol. 2019;845:8–15.PubMedCrossRef
24.
go back to reference Yukimoto R, Nishida N, Hata T, Fujino S, Ogino T, Miyoshi N, et al. Specific activation of glycolytic enzyme enolase 2 in BRAF V600E-mutated colorectal cancer. Cancer Sci. 2021;112(7):2884–94.PubMedPubMedCentralCrossRef Yukimoto R, Nishida N, Hata T, Fujino S, Ogino T, Miyoshi N, et al. Specific activation of glycolytic enzyme enolase 2 in BRAF V600E-mutated colorectal cancer. Cancer Sci. 2021;112(7):2884–94.PubMedPubMedCentralCrossRef
25.
go back to reference Park C, Lee Y, Je S, Chang S, Kim N, Jeong E, et al. Overexpression and Selective Anticancer Efficacy of ENO3 in STK11 Mutant Lung Cancers. Mol Cells. 2019;42(11):804–9.PubMedPubMedCentral Park C, Lee Y, Je S, Chang S, Kim N, Jeong E, et al. Overexpression and Selective Anticancer Efficacy of ENO3 in STK11 Mutant Lung Cancers. Mol Cells. 2019;42(11):804–9.PubMedPubMedCentral
26.
go back to reference Huang Z, Yan Y, Zhu Z, Liu J, He X, Dalangood S, et al. CBX7 suppresses urinary bladder cancer progression via modulating AKR1B10-ERK signaling. Cell Death Dis. 2021;12(6):537.PubMedPubMedCentralCrossRef Huang Z, Yan Y, Zhu Z, Liu J, He X, Dalangood S, et al. CBX7 suppresses urinary bladder cancer progression via modulating AKR1B10-ERK signaling. Cell Death Dis. 2021;12(6):537.PubMedPubMedCentralCrossRef
27.
go back to reference Yan YL, Huang ZN, Zhu Z, Cui YY, Li MQ, Huang RM, et al. Downregulation of TET1 Promotes Bladder Cancer Cell Proliferation and Invasion by Reducing DNA Hydroxymethylation of AJAP1. Front Oncol. 2020;10:667.PubMedPubMedCentralCrossRef Yan YL, Huang ZN, Zhu Z, Cui YY, Li MQ, Huang RM, et al. Downregulation of TET1 Promotes Bladder Cancer Cell Proliferation and Invasion by Reducing DNA Hydroxymethylation of AJAP1. Front Oncol. 2020;10:667.PubMedPubMedCentralCrossRef
28.
go back to reference Beckner ME, Fellows-Mayle W, Zhang Z, Agostino NR, Kant JA, Day BW, et al. Identification of ATP citrate lyase as a positive regulator of glycolytic function in glioblastomas. Int J Cancer. 2010;126(10):2282–95.PubMedPubMedCentral Beckner ME, Fellows-Mayle W, Zhang Z, Agostino NR, Kant JA, Day BW, et al. Identification of ATP citrate lyase as a positive regulator of glycolytic function in glioblastomas. Int J Cancer. 2010;126(10):2282–95.PubMedPubMedCentral
29.
go back to reference Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21(3):309–22.PubMedCrossRef Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21(3):309–22.PubMedCrossRef
30.
go back to reference Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature. 2013;501(7467):346–54.PubMedCrossRef Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature. 2013;501(7467):346–54.PubMedCrossRef
32.
go back to reference Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer. 2015;15(1):25–41.PubMedCrossRef Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer. 2015;15(1):25–41.PubMedCrossRef
33.
go back to reference Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.PubMedPubMedCentralCrossRef Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.PubMedPubMedCentralCrossRef
34.
go back to reference Yin H, Wang L, Liu HL. ENO1 overexpression in pancreatic cancer patients and its clinical and diagnostic significance. Gastroenterol Res Practice. 2018;2018:3842198. Yin H, Wang L, Liu HL. ENO1 overexpression in pancreatic cancer patients and its clinical and diagnostic significance. Gastroenterol Res Practice. 2018;2018:3842198.
35.
go back to reference Zhang Y, Li M, Liu Y, Han N, Zhang K, Xiao T, et al. ENO1 protein levels in the tumor tissues and circulating plasma samples of non-small cell lung cancer patients. Chin J Lung Cancer. 2010;13(12):1089–93. Zhang Y, Li M, Liu Y, Han N, Zhang K, Xiao T, et al. ENO1 protein levels in the tumor tissues and circulating plasma samples of non-small cell lung cancer patients. Chin J Lung Cancer. 2010;13(12):1089–93.
36.
go back to reference Hoang AT, Vizio B, Chiusa L, Cimino A, Solerio D, Do NH, et al. Impact of tissue enolase 1 protein overexpression in esophageal cancer progression. Int J Med Sci. 2021;18(6):1406–14.PubMedPubMedCentralCrossRef Hoang AT, Vizio B, Chiusa L, Cimino A, Solerio D, Do NH, et al. Impact of tissue enolase 1 protein overexpression in esophageal cancer progression. Int J Med Sci. 2021;18(6):1406–14.PubMedPubMedCentralCrossRef
37.
go back to reference Liu P, Sun SJ, Ai YJ, Feng X, Zheng YM, Gao Y, et al. Elevated nuclear localization of glycolytic enzyme TPI1 promotes lung adenocarcinoma and enhances chemoresistance. Cell Death Dis. 2022;13(3):205.PubMedPubMedCentralCrossRef Liu P, Sun SJ, Ai YJ, Feng X, Zheng YM, Gao Y, et al. Elevated nuclear localization of glycolytic enzyme TPI1 promotes lung adenocarcinoma and enhances chemoresistance. Cell Death Dis. 2022;13(3):205.PubMedPubMedCentralCrossRef
38.
go back to reference Yu WL, Yu G, Dong H, Chen K, Xie J, Yu H, et al. Proteomics analysis identified TPI1 as a novel biomarker for predicting recurrence of intrahepatic cholangiocarcinoma. J Gastroenterol. 2020;55(12):1171–82.PubMedCrossRef Yu WL, Yu G, Dong H, Chen K, Xie J, Yu H, et al. Proteomics analysis identified TPI1 as a novel biomarker for predicting recurrence of intrahepatic cholangiocarcinoma. J Gastroenterol. 2020;55(12):1171–82.PubMedCrossRef
39.
go back to reference Yuen HF, Chan KK, Grills C, Murray JT, Platt-Higgins A, Eldin OS, et al. Ran is a potential therapeutic target for cancer cells with molecular changes associated with activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways. Clin Cancer Res. 2012;18(2):380–91.PubMedCrossRef Yuen HF, Chan KK, Grills C, Murray JT, Platt-Higgins A, Eldin OS, et al. Ran is a potential therapeutic target for cancer cells with molecular changes associated with activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways. Clin Cancer Res. 2012;18(2):380–91.PubMedCrossRef
40.
go back to reference Zhang C, Zhao X, Du W, Shen J, Li S, Li Z, et al. Ran promotes the proliferation and migration ability of head and neck squamous cell carcinoma cells. Pathol Res Pract. 2020;216(6): 152951.PubMedCrossRef Zhang C, Zhao X, Du W, Shen J, Li S, Li Z, et al. Ran promotes the proliferation and migration ability of head and neck squamous cell carcinoma cells. Pathol Res Pract. 2020;216(6): 152951.PubMedCrossRef
41.
go back to reference Liu BHM, Tey SK, Mao X, Ma APY, Yeung CLS, Wong SWK, et al. TPI1-reduced extracellular vesicles mediated by Rab20 downregulation promotes aerobic glycolysis to drive hepatocarcinogenesis. J Extracell Vesicles. 2021;10(10): e12135.PubMedPubMedCentralCrossRef Liu BHM, Tey SK, Mao X, Ma APY, Yeung CLS, Wong SWK, et al. TPI1-reduced extracellular vesicles mediated by Rab20 downregulation promotes aerobic glycolysis to drive hepatocarcinogenesis. J Extracell Vesicles. 2021;10(10): e12135.PubMedPubMedCentralCrossRef
42.
go back to reference Zaoui K, Boudhraa Z, Khalifé P, Carmona E, Provencher D, Mes-Masson AM. Ran promotes membrane targeting and stabilization of RhoA to orchestrate ovarian cancer cell invasion. Nat Commun. 2019;10(1):2666.PubMedPubMedCentralCrossRef Zaoui K, Boudhraa Z, Khalifé P, Carmona E, Provencher D, Mes-Masson AM. Ran promotes membrane targeting and stabilization of RhoA to orchestrate ovarian cancer cell invasion. Nat Commun. 2019;10(1):2666.PubMedPubMedCentralCrossRef
44.
go back to reference Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med. 2015;21(8):938–45.PubMedPubMedCentralCrossRef Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med. 2015;21(8):938–45.PubMedPubMedCentralCrossRef
45.
go back to reference Wouters MCA, Nelson BH. Prognostic Significance of Tumor-Infiltrating B Cells and Plasma Cells in Human Cancer. Clin Cancer Res. 2018;24(24):6125–35.PubMedCrossRef Wouters MCA, Nelson BH. Prognostic Significance of Tumor-Infiltrating B Cells and Plasma Cells in Human Cancer. Clin Cancer Res. 2018;24(24):6125–35.PubMedCrossRef
46.
go back to reference Gomes Dias SM, Mello LV, da SilvGiotto MT, Gavalda S, Blonski C, et al. Structural flexibility in Trypanosoma brucei enolase revealed by X-ray crystallography and molecular dynamics. FEBS J. 2007;274(19):5077–89.PubMedCrossRef Gomes Dias SM, Mello LV, da SilvGiotto MT, Gavalda S, Blonski C, et al. Structural flexibility in Trypanosoma brucei enolase revealed by X-ray crystallography and molecular dynamics. FEBS J. 2007;274(19):5077–89.PubMedCrossRef
47.
go back to reference Gao J, Zhao R, Xue Y, Niu Z, Cui K, Yu F, et al. Role of enolase-1 in response to hypoxia in breast cancer: exploring the mechanisms of action. Oncol Rep. 2013;29(4):1322–32.PubMedCrossRef Gao J, Zhao R, Xue Y, Niu Z, Cui K, Yu F, et al. Role of enolase-1 in response to hypoxia in breast cancer: exploring the mechanisms of action. Oncol Rep. 2013;29(4):1322–32.PubMedCrossRef
Metadata
Title
Identification of ENO1 as a prognostic biomarker and molecular target among ENOs in bladder cancer
Authors
Zhengnan Huang
Yilin Yan
Tengjiao Wang
Zeyi Wang
Jinming Cai
Xiangqian Cao
Chenkai Yang
Fang Zhang
Gang Wu
Bing Shen
Publication date
01-12-2022
Publisher
BioMed Central
Keyword
Biomarkers
Published in
Journal of Translational Medicine / Issue 1/2022
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-022-03509-1

Other articles of this Issue 1/2022

Journal of Translational Medicine 1/2022 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine