Top

Journal of Translational Medicine

Published in:

01-12-2021 | Ovarian Cancer | Research

Establishment of a novel glycolysis-related prognostic gene signature for ovarian cancer and its relationships with immune infiltration of the tumor microenvironment

Authors: Jianlei Bi, Fangfang Bi, Xue Pan, Qing Yang

Published in: Journal of Translational Medicine | Issue 1/2021

Abstract

Background

Glycolysis affects tumor growth, invasion, chemotherapy resistance, and the tumor microenvironment. In this study, we aimed to construct a glycolysis-related prognostic model for ovarian cancer and analyze its relationship with the tumor microenvironment’s immune cell infiltration.

Methods

We obtained six glycolysis-related gene sets for gene set enrichment analysis (GSEA). Ovarian cancer data from The Cancer Genome Atlas (TCGA) database and two Gene Expression Omnibus (GEO) datasets were divided into two groups after removing batch effects. We compared the tumor environments' immune components in high-risk and low-risk groups and analyzed the correlation between glycolysis- and immune-related genes. Then, we generated and validated a predictive model for the prognosis of ovarian cancer using the glycolysis-related genes.

Results

Overall, 27/329 glycolytic genes were associated with survival in ovarian cancer, 8 of which showed predictive value. The tumor cell components in the tumor microenvironment did not differ between the high-risk and low-risk groups; however, the immune score differed significantly between groups. In total, 13/24 immune cell types differed between groups, including 10 T cell types and three other immune cell types. Eight glycolysis-related prognostic genes were related to the expression of multiple immune-related genes at varying degrees, suggesting a relationship between glycolysis and immune response.

Conclusions

We identified eight glycolysis-related prognostic genes that effectively predicted survival in ovarian cancer. To a certain extent, the newly identified gene signature was related to the tumor microenvironment, especially immune cell infiltration and immune-related gene expression. These findings provide potential biomarkers and therapeutic targets for ovarian cancer.

Available only for authorised users

Maringe C, Walters S, Butler J, Coleman MP, Hacker N, Hanna L, Mosgaard BJ, Nordin A, Rosen B, Engholm G, Gjerstorff ML, Hatcher J, Johannesen TB, McGahan CE, Meechan D, Middleton R, Tracey E, Turner D, Richards MA, Rachet B, ICBP Module 1 Working Group. Stage at diagnosis and ovarian cancer survival: evidence from the International Cancer Benchmarking Partnership. Gynecol Oncol. 2012;127:75–82. https://doi.org/10.1016/j.ygyno.2012.06.033.CrossRefPubMed

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74. https://doi.org/10.1016/j.cell.2011.02.013.CrossRefPubMed

Warburg O. On the origin of cancer cells. Science. 1956;123:309–14. https://doi.org/10.1126/science.123.3191.309.CrossRefPubMed

Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33. https://doi.org/10.1126/science.1160809.CrossRefPubMedPubMedCentral

Chen B, Tang H, Liu X, Liu P, Yang L, Xie X, Ye F, Song C, Xie X, Wei W. miR-22 as a prognostic factor targets glucose transporter protein type 1 in breast cancer. Cancer Lett. 2015;356:410–7. https://doi.org/10.1016/j.canlet.2014.09.028.CrossRefPubMed

Goos JA, de Cuba EM, Coupé VM, Diosdado B, Delis-Van Diemen PM, Karga C, Beliën JA, van Menke-Van der HouvenOordt CW, Geldof AA, Meijer GA, Hoekstra OS, Fijneman RJ, DeCoDe PET Group. Glucose transporter 1 (SLC2A1) and vascular endothelial growth factor A (VEGFA) predict survival after resection of colorectal cancer liver metastasis. Ann Surg. 2016;263:138–45. https://doi.org/10.1097/SLA.0000000000001109.CrossRefPubMed

Du S, Guan Z, Hao L, Song Y, Wang L, Gong L, Liu L, Qi X, Hou Z, Shao S. Fructose-bisphosphate aldolase a is a potential metastasis-associated marker of lung squamous cell carcinoma and promotes lung cell tumorigenesis and migration. PLoS ONE. 2014;9: e85804. https://doi.org/10.1371/journal.pone.0085804.CrossRefPubMedPubMedCentral

Chang CH, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, Chen Q, Gindin M, Gubin MM, van der Windt GJ, Tonc E, Schreiber RD, Pearce EJ, Pearce EL. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015;162:1229–41. https://doi.org/10.1016/j.cell.2015.08.016.CrossRefPubMedPubMedCentral

Ganapathy V, Thangaraju M, Prasad PD. Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. Pharmacol Ther. 2009;121:29–40. https://doi.org/10.1016/j.pharmthera.2008.09.005.CrossRefPubMed

10.

Zhao S, Zhang X, Shi Y, Cheng L, Song T, Wu B, Li J, Yang H. MIEF2 over-expression promotes tumor growth and metastasis through reprogramming of glucose metabolism in ovarian cancer. J Exp Clin Cancer Res. 2020;39:286. https://doi.org/10.1186/s13046-020-01802-9.CrossRefPubMedPubMedCentral

11.

Moskovich D, Alfandari A, Finkelshtein Y, Weisz A, Katzav A, Kidron D, Edelstein E, Veroslavski D, Perets R, Arbib N, Kadan Y, Fishman A, Lerer B, Ellis M, Ashur-Fabian O. DIO3, the thyroid hormone inactivating enzyme, promotes tumorigenesis and metabolic reprogramming in high grade serous ovarian cancer. Cancer Lett. 2021;31(501):224–33. https://doi.org/10.1016/j.canlet.2020.11.011.CrossRef

12.

Dong D, Dong Y, Fu J, Lu S, Yuan C, Xia M, Sun L. Bcl2 inhibitor ABT737 reverses the Warburg effect via the Sirt3-HIF1α axis to promote oxidative stress-induced apoptosis in ovarian cancer cells. Life Sci. 2020;255: 117846. https://doi.org/10.1016/j.lfs.2020.117846.CrossRefPubMed

13.

Sun H, Wang H, Wang X, Aoki Y, Wang X, Yang Y, Cheng X, Wang Z, Wang X. Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. Theranostics. 2020;10:6928–45. https://doi.org/10.7150/thno.43811.CrossRefPubMedPubMedCentral

14.

Tian M, Chen XS, Li LY, Wu HZ, Zeng D, Wang XL, Zhang Y, Xiao SS, Cheng Y. Inhibition of AXL enhances chemosensitivity of human ovarian cancer cells to cisplatin via decreasing glycolysis. Acta Pharmacol Sin. 2021;42(7):1180–9. https://doi.org/10.1038/s41401-020-00546-8.CrossRefPubMed

15.

Agarwal SK, Simonds WF, Marx SJ. The parafibromin tumor suppressor protein interacts with actin-binding proteins actinin-2 and actinin-3. Mol Cancer. 2008;7:65. https://doi.org/10.1186/1476-4598-7-65.CrossRefPubMedPubMedCentral

16.

Ceyhan GO, Giese NA, Erkan M, Kerscher AG, Wente MN, Giese T, Büchler MW, Friess H. The neurotrophic factor artemin promotes pancreatic cancer invasion. Ann Surg. 2006;244:274–81. https://doi.org/10.1097/01.sla.0000217642.68697.55.CrossRefPubMedPubMedCentral

17.

Li S, Li Z, Guo F, Qin X, Liu B, Lei Z, Song Z, Sun L, Zhang HT, You J, Zhou Q. miR-223 regulates migration and invasion by targeting Artemin in human esophageal carcinoma. J Biomed Sci. 2011;18:24. https://doi.org/10.1186/1423-0127-18-24.CrossRefPubMedPubMedCentral

18.

Han Y, Liu Q, Hou J, Gu Y, Zhang Y, Chen Z, Fan J, Zhou W, Qiu S, Zhang Y, Dong T, Li N, Jiang Z, Zhu H, Zhang Q, Ma Y, Zhang L, Wang Q, Yu Y, Li N, Cao X. Tumor-induced generation of splenic erythroblast-like ter-cells promotes tumor progression. Cell. 2018;173:634-648.e12. https://doi.org/10.1016/j.cell.2018.02.061.CrossRefPubMed

19.

Pandey V, Jung Y, Kang J, Steiner M, Qian PX, Banerjee A, Mitchell MD, Wu ZS, Zhu T, Liu DX, Lobie PE. Artemin reduces sensitivity to doxorubicin and paclitaxel in endometrial carcinoma cells through specific regulation of CD24. Transl Oncol. 2010;3:218–29. https://doi.org/10.1593/tlo.09325.CrossRefPubMedPubMedCentral

20.

Liang GQ, Liu J, Zhou XX, Lin ZX, Chen T, Chen G, Wei H. Anti-CXCR4 single-chain variable fragment antibodies have anti-tumor activity. Front Oncol. 2020;10: 571194. https://doi.org/10.3389/fonc.2020.571194.CrossRefPubMedPubMedCentral

21.

Wu Z, Zhang Y, Chen X, Tan W, He L, Peng L. Characterization of the prognostic values of the CXCR1-7 in clear cell renal cell carcinoma (ccRCC) microenvironment. Front Mol Biosci. 2020;7: 601206. https://doi.org/10.3389/fmolb.2020.601206.CrossRefPubMedPubMedCentral

22.

Reszegi A, Horváth Z, Fehér H, Wichmann B, Tátrai P, Kovalszky I, Baghy K. Protective role of decorin in primary hepatocellular carcinoma. Front Oncol. 2020;10:645. https://doi.org/10.3389/fonc.2020.00645.CrossRefPubMedPubMedCentral

23.

Mao L, Yang J, Yue J, Chen Y, Zhou H, Fan D, Zhang Q, Buraschi S, Iozzo RV, Bi X. Decorin deficiency promotes epithelial–mesenchymal transition and colon cancer metastasis. Matrix Biol. 2021;95:1–14. https://doi.org/10.1016/j.matbio.2020.10.001.CrossRefPubMed

24.

Rezaie R, Falakian Z, Mazloomzadeh S, Ayati M, Morakabati A, Teimouri Dastjerdan MR, Zare M, Moghimi M, Shahani T, Biglari A. While urine and plasma decorin remain unchanged in prostate cancer, prostatic tissue decorin has a prognostic value. Iran Biomed J. 2020;24:229–35. https://doi.org/10.29252/ibj.24.4.229.CrossRefPubMedPubMedCentral

25.

Luo T, Du Y, Duan J, Liang C, Chen G, Jiang K, Chen Y, Chen Y. Development and validation of a scoring system based on 9 glycolysis-related genes for prognosis prediction in gastric cancer. Technol Cancer Res Treat. 2020;19:1533033820971670. https://doi.org/10.1177/1533033820971670.CrossRefPubMedPubMedCentral

26.

Wicker CA, Takiar V, Suganya R, Arnold SM, Brill YM, Chen L, Horbinski CM, Napier D, Valentino J, Kudrimoti MR, Yu G, Izumi T. Evaluation of antioxidant network proteins as novel prognostic biomarkers for head and neck cancer patients. Oral Oncol. 2020;111: 104949. https://doi.org/10.1016/j.oraloncology.2020.104949.CrossRefPubMedPubMedCentral

27.

Li P, Cao J, Li J, Yao Z, Han D, Ying L, Wang Z, Tian J. Identification of prognostic biomarkers associated with stromal cell infiltration in muscle-invasive bladder cancer by bioinformatics analyses. Cancer Med. 2020;9:7253–67. https://doi.org/10.1002/cam4.3372.CrossRefPubMedPubMedCentral

28.

Liu J, Li S, Feng G, Meng H, Nie S, Sun R, Yang J, Cheng W. Nine glycolysis-related gene signature predicting the survival of patients with endometrial adenocarcinoma. Cancer Cell Int. 2020;20:183. https://doi.org/10.1186/s12935-020-01264-1.CrossRefPubMedPubMedCentral

29.

Amini S, Fathi F, Mobalegi J, Sofimajidpour H, Ghadimi T. The expressions of stem cell markers: Oct4, Nanog, Sox2, nucleostemin, Bmi, Zfx, Tcl1, Tbx3, Dppa4, and Esrrb in bladder, colon, and prostate cancer, and certain cancer cell lines. Anat Cell Biol. 2014;47:1–11. https://doi.org/10.5115/acb.2014.47.1.1.CrossRefPubMedPubMedCentral

30.

Kumari K, Adhya AK, Rath AK, Reddy PB, Mishra SK. Estrogen-related receptors alpha, beta and gamma expression and function is associated with transcriptional repressor EZH2 in breast carcinoma. BMC Cancer. 2018;18:690. https://doi.org/10.1186/s12885-018-4586-0.CrossRefPubMedPubMedCentral

31.

Tiek DM, Khatib SA, Trepicchio CJ, Heckler MM, Divekar SD, Sarkaria JN, Glasgow E, Riggins RB. Estrogen-related receptor β activation and isoform shifting by cdc2-like kinase inhibition restricts migration and intracranial tumor growth in glioblastoma. FASEB J. 2019;33:13476–91. https://doi.org/10.1096/fj.201901075R.CrossRefPubMedPubMedCentral

32.

Dong C, Yuan T, Wu Y, Wang Y, Fan TW, Miriyala S, Lin Y, Yao J, Shi J, Kang T, Lorkiewicz P, St Clair D, Hung MC, Evers BM, Zhou BP. Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell. 2013;23:316–31. https://doi.org/10.1016/j.ccr.2013.01.022.CrossRefPubMedPubMedCentral

33.

He Y, Hua R, Li B, Gu H, Sun Y, Li Z. Loss of FBP1 promotes proliferation, migration, and invasion by regulating fatty acid metabolism in esophageal squamous cell carcinoma. Aging. 2020;13(4):4986–98. https://doi.org/10.18632/aging.103916.CrossRefPubMedPubMedCentral

34.

Li F, Huangyang P, Burrows M, Guo K, Riscal R, Godfrey J, Lee KE, Lin N, Lee P, Blair IA, Keith B, Li B, Simon MC. FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome. Nat Cell Biol. 2020;22:728–39. https://doi.org/10.1038/s41556-020-0511-2.CrossRefPubMedPubMedCentral

35.

Long Q, Johnson BA, Osunkoya AO, Lai YH, Zhou W, Abramovitz M, Xia M, Bouzyk MB, Nam RK, Sugar L, Stanimirovic A, Williams DJ, Leyland-Jones BR, Seth AK, Petros JA, Moreno CS. Protein-coding and microRNA biomarkers of recurrence of prostate cancer following radical prostatectomy. Am J Pathol. 2011;179:46–54. https://doi.org/10.1016/j.ajpath.2011.03.008.CrossRefPubMedPubMedCentral

36.

Liu M, Pan Q, Xiao R, Yu Y, Lu W, Wang L. A cluster of metabolism-related genes predict prognosis and progression of clear cell renal cell carcinoma. Sci Rep. 2020;10:12949. https://doi.org/10.1038/s41598-020-67760-6.CrossRefPubMedPubMedCentral

37.

Ayakannu T, Taylor AH, Konje JC. Selection of endogenous control reference genes for studies on type 1 or type 2 endometrial cancer. Sci Rep. 2020;10:8468. https://doi.org/10.1038/s41598-020-64663-4.CrossRefPubMedPubMedCentral

38.

Sonveaux P, Sonveaux P, Végran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O, Dewhirst MW. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008;118:3930–42. https://doi.org/10.1172/JCI36843.CrossRefPubMedPubMedCentral

39.

Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4:891–9. https://doi.org/10.1038/nrc1478.CrossRefPubMed

40.

Husain Z, Seth P, Sukhatme VP. Tumor-derived lactate and myeloid-derived suppressor cells: linking metabolism to cancer immunology. Oncoimmunology. 2013;2: e26383. https://doi.org/10.4161/onci.26383.CrossRefPubMedPubMedCentral

Title: Establishment of a novel glycolysis-related prognostic gene signature for ovarian cancer and its relationships with immune infiltration of the tumor microenvironment
Authors: Jianlei Bi
Fangfang Bi
Xue Pan
Qing Yang
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Ovarian Cancer
Ovarian Cancer
Published in: Journal of Translational Medicine / Issue 1/2021
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-021-03057-0

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

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

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2021

Extrachromosomal circular DNA: a new potential role in cancer progression

Panaxydol attenuates ferroptosis against LPS-induced acute lung injury in mice by Keap1-Nrf2/HO-1 pathway

Radiomic signature of the FOWARC trial predicts pathological response to neoadjuvant treatment in rectal cancer

Expanding the phenotypic spectrum of mutations in LRP2: a novel candidate gene of non-syndromic familial comitant strabismus

Eleven immune-gene pairs signature associated with TP53 predicting the overall survival of gastric cancer: a retrospective analysis of large sample and multicenter from public database

Establishment and evaluation of a rat model of extracorporeal membrane oxygenation (ECMO) thrombosis using a 3D-printed mock-oxygenator

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

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage