Glycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma: a systematic review with meta-analysis
Molecular changes that affect mitochondrial glycolysis have been associated with the maintenance of tumor cells. Some metabolic factors have already been described as predictors of disease severity and outcomes. This systematic review was conducted to answer the question: Is the glycolytic pathway c...
- Autores:
-
Mattos, Sergio
Diel, Leonardo Francisco
Bittencourt, Leonardo
Schnorr, C.E.
Gonçalves, F.A.
Bernardi, L.
Lamers, M.L.
- Tipo de recurso:
- Article of journal
- Fecha de publicación:
- 2021
- Institución:
- Corporación Universidad de la Costa
- Repositorio:
- REDICUC - Repositorio CUC
- Idioma:
- eng
- OAI Identifier:
- oai:repositorio.cuc.edu.co:11323/8002
- Acceso en línea:
- https://hdl.handle.net/11323/8002
https://doi.org/10.1590/1414-431x202010504
https://repositorio.cuc.edu.co/
- Palabra clave:
- Oral cancer
Survival
Prognosis
Disease-free survival
Energy metabolism
- Rights
- openAccess
- License
- CC0 1.0 Universal
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dc.title.spa.fl_str_mv |
Glycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma: a systematic review with meta-analysis |
title |
Glycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma: a systematic review with meta-analysis |
spellingShingle |
Glycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma: a systematic review with meta-analysis Oral cancer Survival Prognosis Disease-free survival Energy metabolism |
title_short |
Glycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma: a systematic review with meta-analysis |
title_full |
Glycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma: a systematic review with meta-analysis |
title_fullStr |
Glycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma: a systematic review with meta-analysis |
title_full_unstemmed |
Glycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma: a systematic review with meta-analysis |
title_sort |
Glycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma: a systematic review with meta-analysis |
dc.creator.fl_str_mv |
Mattos, Sergio Diel, Leonardo Francisco Bittencourt, Leonardo Schnorr, C.E. Gonçalves, F.A. Bernardi, L. Lamers, M.L. |
dc.contributor.author.spa.fl_str_mv |
Mattos, Sergio Diel, Leonardo Francisco Bittencourt, Leonardo Schnorr, C.E. Gonçalves, F.A. Bernardi, L. Lamers, M.L. |
dc.subject.spa.fl_str_mv |
Oral cancer Survival Prognosis Disease-free survival Energy metabolism |
topic |
Oral cancer Survival Prognosis Disease-free survival Energy metabolism |
description |
Molecular changes that affect mitochondrial glycolysis have been associated with the maintenance of tumor cells. Some metabolic factors have already been described as predictors of disease severity and outcomes. This systematic review was conducted to answer the question: Is the glycolytic pathway correlated with the prognosis of oral squamous cell carcinoma (OSCC)? A search strategy was developed to retrieve studies in English from PubMed, Scopus, and ISI Web of Science using keywords related to squamous cell carcinoma, survival, and glycolytic pathway, with no restriction of publication date. The search retrieved 1273 publications. After the titles and abstracts were analyzed, 27 studies met inclusion criteria. Studies were divided into groups according to two subtopics, glycolytic pathways and diagnosis, which describe the glycolytic profile of OSCC tumors. Several components of tumor energy metabolism found in this review are important predictors of survival of patients with OSCC. |
publishDate |
2021 |
dc.date.accessioned.none.fl_str_mv |
2021-03-12T20:24:13Z |
dc.date.available.none.fl_str_mv |
2021-03-12T20:24:13Z |
dc.date.issued.none.fl_str_mv |
2021-01-25 |
dc.type.spa.fl_str_mv |
Artículo de revista |
dc.type.coar.fl_str_mv |
http://purl.org/coar/resource_type/c_2df8fbb1 |
dc.type.coar.spa.fl_str_mv |
http://purl.org/coar/resource_type/c_6501 |
dc.type.content.spa.fl_str_mv |
Text |
dc.type.driver.spa.fl_str_mv |
info:eu-repo/semantics/article |
dc.type.redcol.spa.fl_str_mv |
http://purl.org/redcol/resource_type/ART |
dc.type.version.spa.fl_str_mv |
info:eu-repo/semantics/acceptedVersion |
format |
http://purl.org/coar/resource_type/c_6501 |
status_str |
acceptedVersion |
dc.identifier.issn.spa.fl_str_mv |
0100-879X 1414-431X |
dc.identifier.uri.spa.fl_str_mv |
https://hdl.handle.net/11323/8002 |
dc.identifier.doi.spa.fl_str_mv |
https://doi.org/10.1590/1414-431x202010504 |
dc.identifier.instname.spa.fl_str_mv |
Corporación Universidad de la Costa |
dc.identifier.reponame.spa.fl_str_mv |
REDICUC - Repositorio CUC |
dc.identifier.repourl.spa.fl_str_mv |
https://repositorio.cuc.edu.co/ |
identifier_str_mv |
0100-879X 1414-431X Corporación Universidad de la Costa REDICUC - Repositorio CUC |
url |
https://hdl.handle.net/11323/8002 https://doi.org/10.1590/1414-431x202010504 https://repositorio.cuc.edu.co/ |
dc.language.iso.none.fl_str_mv |
eng |
language |
eng |
dc.relation.references.spa.fl_str_mv |
1 Hay N. Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? Nat Rev Cancer2016; 16: 635–649, doi: 10.1038/nrc.2016.77. [ Links ] 2 Ishikawa S, Sugimoto M, Kitabatake K, Sugano A, Nakamura M, Kaneko M, et al. Identification of salivary metabolomic biomarkers for oral cancer screening. Sci Rep2016; 6: 31520, doi: 10.1038/srep31520. [ Links ] 3 Scully C, Bagan J. Oral squamous cell carcinoma overview. Oral Oncol2009; 45: 301–308, doi: 10.1016/j.oraloncology.2009.01.004. [ Links ] 4 Chen L, Yang Y, Liu S, Piao L, Zhang Y, Lin Z, et al. High expression of leucine zipper-EF-hand containing transmembrane protein 1 predicts poor prognosis in head and neck squamous cell carcinoma. BioMed Res Int2014; 2014: 850316, doi: 10.1155/2014/850316. [ Links ] 5 Baffy G, Derdak Z, Robson SC. Mitochondrial recoupling: a novel therapeutic strategy for cancer? Br J Cancer2011; 105: 469–474, doi: 10.1038/bjc.2011.245. [ Links ] 6 Martinez-Outschoorn UE, Peiris-Pagés M, Pestell RG, Sotgia F, Lisanti MP. Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol2017; 14: 11–31, doi: 10.1038/nrclinonc.2016.60. [ Links ] 7 Kurhanewicz J, Vigneron DB, Brindle K, Chekmenev EY, Comment A, Cunningham CH, et al. Analysis of cancer metabolism by imaging hyperpolarized nuclei: prospects for translation to clinical research. Neoplasia2011; 13: 81–97, doi: 10.1593/neo.101102. [ Links ] 8 Tanaka T, Ishigamori R. Understanding carcinogenesis for fighting oral cancer. J Oncol2011; 2011: 603740. [ Links ] 9 Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov2011; 10: 671–684, doi: 10.1038/nrd3504. [ Links ] 10 Cochran WG. The combination of estimates from different experiments. Biometrics1954; 10: 101–129, doi: 10.2307/3001666. [ Links ] 11 Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ2003; 327: 557–560, doi: 10.1136/bmj.327.7414.557. [ Links ] 12 Chen SW, Chou CT, Chang CC, Li YJ, Chen ST, Lin IC, et al. HMGCS2 enhances invasion and metastasis via direct interaction with PPARalpha to activate Src signaling in colorectal cancer and oral cancer. Oncotarget2017; 8: 22460–22476, doi: 10.18632/oncotarget.13006. [ Links ] 13 Grimm M, Alexander D, Munz A, Hoffmann J, Reinert S. Increased LDH5 expression is associated with lymph node metastasis and outcome in oral squamous cell carcinoma. Clin Exp Metastasis2013; 30: 529–540, doi: 10.1007/s10585-012-9557-2. [ Links ] 14 Grimm M, Munz A, Teriete P, Nadtotschi T, Reinert S. GLUT-1(+)/TKTL1(+) coexpression predicts poor outcome in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol2014; 117: 743–753, doi: 10.1016/j.oooo.2014.02.007. [ Links ] 15 Kondo Y, Yoshikawa K, Omura Y, Shinohara A, Kazaoka Y, Sano J, et al. Clinicopathological significance of carbonic anhydrase 9, glucose transporter-1, Ki-67 and p53 expression in oral squamous cell carcinoma. Oncol Rep2011; 25: 1227–1233, doi: 10.3892/or.2011.1216. [ Links ] 16 Kunkel M, Reichert TE, Benz P, Lehr HA, Jeong JH, Wieand S, et al. Overexpression of Glut-1 and increased glucose metabolism in tumors are associated with a poor prognosis in patients with oral squamous cell carcinoma. Cancer2003; 97: 1015–1024, doi: 10.1002/cncr.11159. [ Links ] 17 Li YJ, Huang TH, Hsiao M, Lin BR, Cheng SJ, Yang CN, et al. Suppression of fructose-bisphosphate aldolase C expression as a predictor of advanced oral squamous cell carcinoma. Head Neck2016; 38: E1075–E1085, doi: 10.1002/hed.24161. [ Links ] 18 Ohba S, Fujii H, Ito S, Fujimaki M, Matsumoto F, Furukawa M, et al. Overexpression of GLUT-1 in the invasion front is associated with depth of oral squamous cell carcinoma and prognosis. J Oral Pathol Med2009; 39: 74–78, doi: 10.1111/j.1600-0714.2009.00814.x. [ Links ] 19 Sun W, Zhang X, Ding X, Li H, Geng M, Xie Z, et al. Lactate dehydrogenase B is associated with the response to neoadjuvant chemotherapy in oral squamous cell carcinoma. PloS One2015; 10: e0125976, doi: 10.1371/journal.pone.0125976. [ Links ] 20 Wang Y, Zhang X, Zhang Y, Zhu Y, Yuan C, Qi B, et al. Overexpression of pyruvate kinase M2 associates with aggressive clinicopathological features and unfavorable prognosis in oral squamous cell carcinoma. Cancer Biol Ther2015; 16: 839–845, doi: 10.1080/15384047.2015.1030551. [ Links ] 21 Eckert A, Lautner M, Schütze A, Taubert H, Schubert J, Bilkenroth U. Coexpression of hypoxia-inducible factor-1 alpha and glucose transporter-1 is associated with poor prognosis in oral squamous cell carcinoma patients. Histopathology2011; 58: 1136–1147, doi: 10.1111/j.1365-2559.2011.03806.x. [ Links ] 22 Grimm M, Schmitt S, Teriete P, Biegner T, Stenzl A, Hennenlotter J, et al. A biomarker based detection and characterization of carcinomas exploiting two fundamental biophysical mechanisms in mammalian cells. BMC Cancer2013; 13: 569, doi: 10.1186/1471-2407-13-569. [ Links ] 23 Kunkel M, Förster GJ, Reichert TE, Kutzner J, Benz P, Bartenstein P, et al. Radiation response non-invasively imaged by [18F]FDG-PET predicts local tumor control and survival in advanced oral squamous cell carcinoma. Oral Oncol2003; 39: 170–177, doi: 10.1016/S1368-8375(02)00087-8. [ Links ] 24 Abd El-Hafez YG, Moustafa HM, Khalil HF, Liao CT, Yen TC. Total lesion glycolysis: a possible new prognostic parameter in oral cavity squamous cell carcinoma. Oral Oncol2013; 49: 261–268, doi: 10.1016/j.oraloncology.2012.09.005. [ Links ] 25 Cho JK, Hyun SH, Choi N, Kim MJ, Padera TP, Choi JY, et al. Significance of lymph node metastasis in cancer dissemination of head and neck cancer. Transl Oncol2015; 8: 119–125, doi: 10.1016/j.tranon.2015.03.001. [ Links ] 26 Hasegawa O, Satomi T, Kono M, Watanabe M, Ikehata N, Chikazu D. Correlation between the malignancy and prognosis of oral squamous cell carcinoma in the maximum standardized uptake value. Odontology2019; 107: 237–243, doi: 10.1007/s10266-018-0379-9. [ Links ] 27 Hofele C, Freier K, Thiele OC, Haberkorn U, Buchmann I. High 2-[18F]fluoro-2-deoxy-d-glucose (18FDG) uptake measured by positron emission tomography is associated with reduced overall survival in patients with oral squamous cell carcinoma. Oral Oncol2009; 45: 963–967, doi: 10.1016/j.oraloncology.2009.06.008. [ Links ] 28 Joo YH, Yoo IR, Cho KJ, Park JO, Nam IC, Kim MS. Extracapsular spread and FDG PET/CT correlations in oral squamous cell carcinoma. Int J Oral Maxillofac Surg2013; 42: 158–163, doi: 10.1016/j.ijom.2012.11.006. [ Links ] 29 Kunkel M, Helisch A, Reichert TE, Jeong JH, Buchholz HG, Benz P, et al. Clinical and prognostic value of [18F]FDG-PET for surveillance of oral squamous cell carcinoma after surgical salvage therapy. Oral Oncol2006; 42: 297–305, doi: 10.1016/j.oraloncology.2005.08.004. [ Links ] 30 Morand GB, Vital DG, Kudura K, Werner J, Stoeckli SJ, Huber GF, et al. Maximum standardized uptake value (SUVmax) of primary tumor predicts occult neck metastasis in oral cancer. Sci Rep2018; 8: 11817, doi: 10.1038/s41598-018-30111-7. [ Links ] 31 Shimizu M, Mitsudo K, Koike I, Taguri M, Iwai T, Koizumi T, et al. Prognostic value of 2-[18 F]fluoro-2-deoxy-D-glucose positron emission tomography for patients with oral squamous cell carcinoma treated with retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy. Oral Surg Oral Med Oral Pathol Oral Radiol2016; 121: 239–247, doi: 10.1016/j.oooo.2015.10.018. [ Links ] 32 Suzuki H, Hasegawa Y, Terada A, Hyodo I, Nakashima T, Nishio M, et al. FDG-PET predicts survival and distant metastasis in oral squamous cell carcinoma. Oral Oncol2009; 45: 569–573, doi: 10.1016/j.oraloncology.2008.07.009. [ Links ] 33 Suzuki H, Fukuyama R, Hasegawa Y, Tamaki T, Nishio M, Nakashima T, et al. Tumor thickness, depth of invasion, and Bcl-2 expression are correlated with FDG-uptake in oral squamous cell carcinomas. Oral Oncol2009; 45: 891–897, doi: 10.1016/j.oraloncology.2009.03.009. [ Links ] 34 Suzuki H, Tamaki T, Nishio M, Beppu S, Mukoyama N, Hanai N, et al. Peak of standardized uptake value in oral cancer predicts survival adjusting for pathological stage. In Vivo2018; 32: 1193–1198, doi: 10.21873/invivo.11363. [ Links ] 35 Yamaga E, Toriihara A, Nakamura S, Asai S, Fujioka T, Yoshimura R, et al. Clinical usefulness of 2-deoxy-2-[18F] fluoro-d-glucose-positron emission tomography/computed tomography for assessing early oral squamous cell carcinoma (cT1-2N0M0). Jpn J Clin Oncol2018; 48: 633–639, doi: 10.1093/jjco/hyy065. [ Links ] 36 Zhang H, Seikaly H, Abele JT, Jeffery DT, Harris JR, O’Connell DA. Metabolic tumour volume as a prognostic factor for oral cavity squamous cell carcinoma treated with primary surgery. J Otolaryngol Head Neck Surg2014; 43: 33. [ Links ] 37 Kim M, Higuchi T, Nakajima T, Andriana P, Hirasawa H, Tokue A, et al. 18F-FDG and 18F-FAMT PET-derived metabolic parameters predict outcome of oral squamous cell carcinoma. Oral Radiol2019; 35: 308–314, doi: 10.1007/s11282-019-00377-2. [ Links ] 38 Kimura M, Kato I, Ishibashi K, Shibata A, Nishiwaki S, Fukumura M, et al. The prognostic significance of intratumoral heterogeneity of 18F-FDG uptake in patients with oral cavity squamous cell carcinoma. Eur J Radiol2019; 114: 99–104, doi: 10.1016/j.ejrad.2019.03.004. [ Links ] 39 Genden EM, Ferlito A, Silver CE, Takes RP, Suarez C, Owen RP, et al. Contemporary management of cancer of the oral cavity. Eur Arch Otorhinolaryngol2010; 267: 1001–1017, doi: 10.1007/s00405-010-1206-2. [ Links ] 40 Ram H, Sarkar J, Kumar H, Konwar R, Bhatt ML, Mohammad S. Oral cancer: risk factors and molecular pathogenesis. J Maxillofac Oral Surg2011; 10: 132–137, doi: 10.1007/s12663-011-0195-z. [ Links ] 41 Li CX, Sun JL, Gong ZC, Lin ZQ, Liu H. Prognostic value of GLUT-1 expression in oral squamous cell carcinoma. A prisma-compliant meta-analysis. Medicine (Baltimore)2016; 95: e5324, doi: 10.1097/MD.0000000000005324. [ Links ] 42 Denko NC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer2008; 8: 705–713, doi: 10.1038/nrc2468. [ Links ] 43 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell2011; 144: 646–674, doi: 10.1016/j.cell.2011.02.013. [ Links ] 44 Koukourakis MI, Giatromanolaki A, Simopoulos C, Polychronidis A, Sivridis E. Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer. Clin Exp Metastasis2005; 22: 25–30, doi: 10.1007/s10585-005-2343-7. [ Links ] 45 Kato Y, Ozawa S, Miyamoto C, Maehata Y, Suzuki A, Maeda T, et al. Acidic extracellular microenvironment and cancer. Cancer Cell Int2013; 13: 89, doi: 10.1186/1475-2867-13-89. [ Links ] 46 Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell2008; 13: 472–482, doi: 10.1016/j.ccr.2008.05.005. [ Links ] 47 Xu Q, Tu J, Dou C, Zhang J, Yang L, Liu X, et al. HSP90 promotes cell glycolysis, proliferation and inhibits apoptosis by regulating PKM2 abundance via Thr-328 phosphorylation in hepatocellular carcinoma. Mol Cancer2017; 16: 178, doi: 10.1186/s12943-017-0748-y. [ Links ] 48 Hamabe A, Konno M, Tanuma N, Shima H, Tsunekuni K, Kawamoto K, et al. Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial-mesenchymal transition. Proc Natl Acad Sci USA2014; 111: 15526–15531, doi: 10.1073/pnas.1407717111. [ Links ] 49 Huang C, Huang Z, Bai P, Luo G, Zhao X, Wang X. Expression of pyruvate kinase M2 in human bladder cancer and its correlation with clinical parameters and prognosis. Onco Targets Ther2018; 11: 2075–2082, doi: 10.2147/OTT.S152999. [ Links ] 50 Wang C, Jiang J, Ji J, Cai Q, Chen X, Yu Y, et al. PKM2 promotes cell migration and inhibits autophagy by mediating PI3K/AKT activation and contributes to the malignant development of gastric cancer. Sci Rep2017; 7: 2886, doi: 10.1038/s41598-017-03031-1. [ Links ] 51 Turner DM, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta2014; 1843: 2563–2582, doi: 10.1016/j.bbamcr.2014.05.014. [ Links ] 52 Lau AN, Vander Heiden GM. Metabolism in the tumor microenvironment. Ann Rev Cancer Biol2019; 4: 17–40, doi: 10.1146/annurev-cancerbio-030419-033333. [ Links ] 53 Palsson-McDermott EM, Curtis AM, Goel G, Lauterbach MAR, Sheedy FJ, Gleeson LE, et al. Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages. Cell Metab2015; 21: 65–80, doi: 10.1016/j.cmet.2014.12.005. [ Links ] 54 Shirai T, Nazarewicz RR, Wallis BB, Yanes RE, Watanabe R, Hilhorst M, et al. The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. J Exp Med2016; 213: 337–354, doi: 10.1084/jem.20150900. [ Links ] 55 Yang P, Li Z, Li H, Lu Y, Wu H, Li Z. Pyruvate kinase M2 accelerates pro-inflammatory cytokine secretion and cell proliferation induced by lipopolysaccharide in colorectal cancer. Cell Signal2015; 27: 1525–1532, doi: 10.1016/j.cellsig.2015.02.032. [ Links ] 56 Krockenberger M, Honig A, Rieger L, Coy JF, Sutterlin M, Kapp M, et al. Transketolase-like 1 expression correlates with subtypes of ovarian cancer and the presence of distant metastases. Int J Gynecol Cancer2007; 17: 101–106, doi: 10.1111/j.1525-1438.2007.00799.x. [ Links ] 57 Coy JF. EDIM-TKTL1/Apo10 blood test: an innate immune system based liquid biopsy for the early detection, characterization and targeted treatment of cancer. Int J Mol Sci2017; 18: 878, doi: 10.3390/ijms18040878. [ Links ] 58 Song Y, Liu D, He G. TKTL1 and p63 are biomarkers for the poor prognosis of gastric cancer patients. Cancer Biomark2015; 15: 591–597, doi: 10.3233/CBM-150499. [ Links ] 59 Su SG, Yang M, Zhang MF, Peng QZ, Li MY, Liu LP, et al. miR-107-mediated decrease of HMGCS2 indicates poor outcomes and promotes cell migration in hepatocellular carcinoma. Int J Biochem Cell Biol2017; 91: 53–59, doi: 10.1016/j.biocel.2017.08.016. [ Links ] 60 Ross JS, Tse T, Zarin DA, Xu H, Zhou L, Krumholz HM. Publication of NIH funded trials registered in ClinicalTrials.gov: cross sectional analysis. BMJ2012; 344: d7292, doi: 10.1136/bmj.d7292. [ Links ] |
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Mattos, SergioDiel, Leonardo FranciscoBittencourt, LeonardoSchnorr, C.E.Gonçalves, F.A.Bernardi, L.Lamers, M.L.2021-03-12T20:24:13Z2021-03-12T20:24:13Z2021-01-250100-879X1414-431Xhttps://hdl.handle.net/11323/8002https://doi.org/10.1590/1414-431x202010504Corporación Universidad de la CostaREDICUC - Repositorio CUChttps://repositorio.cuc.edu.co/Molecular changes that affect mitochondrial glycolysis have been associated with the maintenance of tumor cells. Some metabolic factors have already been described as predictors of disease severity and outcomes. This systematic review was conducted to answer the question: Is the glycolytic pathway correlated with the prognosis of oral squamous cell carcinoma (OSCC)? A search strategy was developed to retrieve studies in English from PubMed, Scopus, and ISI Web of Science using keywords related to squamous cell carcinoma, survival, and glycolytic pathway, with no restriction of publication date. The search retrieved 1273 publications. After the titles and abstracts were analyzed, 27 studies met inclusion criteria. Studies were divided into groups according to two subtopics, glycolytic pathways and diagnosis, which describe the glycolytic profile of OSCC tumors. Several components of tumor energy metabolism found in this review are important predictors of survival of patients with OSCC.Mattos, Sergio-will be generated-orcid-0000-0001-6628-8797-600Diel, Leonardo Francisco-will be generated-orcid-0000-0003-1526-2575-600Bittencourt, Leonardo-will be generated-orcid-0000-0001-9649-556X-600Schnorr, C.E.Gonçalves, F.A.Bernardi, L.Lamers, M.L.application/pdfengCorporación Universidad de la CostaCC0 1.0 Universalhttp://creativecommons.org/publicdomain/zero/1.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Brazilian Journal of Medical and Biological Researchhttps://www.scielo.br/scielo.php?pid=S0100-879X2021000300301&script=sci_arttext&tlng=enOral cancerSurvivalPrognosisDisease-free survivalEnergy metabolismGlycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma: a systematic review with meta-analysisArtículo de revistahttp://purl.org/coar/resource_type/c_6501http://purl.org/coar/resource_type/c_2df8fbb1Textinfo:eu-repo/semantics/articlehttp://purl.org/redcol/resource_type/ARTinfo:eu-repo/semantics/acceptedVersion1 Hay N. Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? Nat Rev Cancer2016; 16: 635–649, doi: 10.1038/nrc.2016.77. [ Links ]2 Ishikawa S, Sugimoto M, Kitabatake K, Sugano A, Nakamura M, Kaneko M, et al. Identification of salivary metabolomic biomarkers for oral cancer screening. Sci Rep2016; 6: 31520, doi: 10.1038/srep31520. [ Links ]3 Scully C, Bagan J. Oral squamous cell carcinoma overview. Oral Oncol2009; 45: 301–308, doi: 10.1016/j.oraloncology.2009.01.004. [ Links ]4 Chen L, Yang Y, Liu S, Piao L, Zhang Y, Lin Z, et al. High expression of leucine zipper-EF-hand containing transmembrane protein 1 predicts poor prognosis in head and neck squamous cell carcinoma. BioMed Res Int2014; 2014: 850316, doi: 10.1155/2014/850316. [ Links ]5 Baffy G, Derdak Z, Robson SC. Mitochondrial recoupling: a novel therapeutic strategy for cancer? Br J Cancer2011; 105: 469–474, doi: 10.1038/bjc.2011.245. [ Links ]6 Martinez-Outschoorn UE, Peiris-Pagés M, Pestell RG, Sotgia F, Lisanti MP. Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol2017; 14: 11–31, doi: 10.1038/nrclinonc.2016.60. [ Links ]7 Kurhanewicz J, Vigneron DB, Brindle K, Chekmenev EY, Comment A, Cunningham CH, et al. Analysis of cancer metabolism by imaging hyperpolarized nuclei: prospects for translation to clinical research. Neoplasia2011; 13: 81–97, doi: 10.1593/neo.101102. [ Links ]8 Tanaka T, Ishigamori R. Understanding carcinogenesis for fighting oral cancer. J Oncol2011; 2011: 603740. [ Links ]9 Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov2011; 10: 671–684, doi: 10.1038/nrd3504. [ Links ]10 Cochran WG. The combination of estimates from different experiments. Biometrics1954; 10: 101–129, doi: 10.2307/3001666. [ Links ]11 Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ2003; 327: 557–560, doi: 10.1136/bmj.327.7414.557. [ Links ]12 Chen SW, Chou CT, Chang CC, Li YJ, Chen ST, Lin IC, et al. HMGCS2 enhances invasion and metastasis via direct interaction with PPARalpha to activate Src signaling in colorectal cancer and oral cancer. Oncotarget2017; 8: 22460–22476, doi: 10.18632/oncotarget.13006. [ Links ]13 Grimm M, Alexander D, Munz A, Hoffmann J, Reinert S. Increased LDH5 expression is associated with lymph node metastasis and outcome in oral squamous cell carcinoma. Clin Exp Metastasis2013; 30: 529–540, doi: 10.1007/s10585-012-9557-2. [ Links ]14 Grimm M, Munz A, Teriete P, Nadtotschi T, Reinert S. GLUT-1(+)/TKTL1(+) coexpression predicts poor outcome in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol2014; 117: 743–753, doi: 10.1016/j.oooo.2014.02.007. [ Links ]15 Kondo Y, Yoshikawa K, Omura Y, Shinohara A, Kazaoka Y, Sano J, et al. Clinicopathological significance of carbonic anhydrase 9, glucose transporter-1, Ki-67 and p53 expression in oral squamous cell carcinoma. Oncol Rep2011; 25: 1227–1233, doi: 10.3892/or.2011.1216. [ Links ]16 Kunkel M, Reichert TE, Benz P, Lehr HA, Jeong JH, Wieand S, et al. Overexpression of Glut-1 and increased glucose metabolism in tumors are associated with a poor prognosis in patients with oral squamous cell carcinoma. Cancer2003; 97: 1015–1024, doi: 10.1002/cncr.11159. [ Links ]17 Li YJ, Huang TH, Hsiao M, Lin BR, Cheng SJ, Yang CN, et al. Suppression of fructose-bisphosphate aldolase C expression as a predictor of advanced oral squamous cell carcinoma. Head Neck2016; 38: E1075–E1085, doi: 10.1002/hed.24161. [ Links ]18 Ohba S, Fujii H, Ito S, Fujimaki M, Matsumoto F, Furukawa M, et al. Overexpression of GLUT-1 in the invasion front is associated with depth of oral squamous cell carcinoma and prognosis. J Oral Pathol Med2009; 39: 74–78, doi: 10.1111/j.1600-0714.2009.00814.x. [ Links ]19 Sun W, Zhang X, Ding X, Li H, Geng M, Xie Z, et al. Lactate dehydrogenase B is associated with the response to neoadjuvant chemotherapy in oral squamous cell carcinoma. PloS One2015; 10: e0125976, doi: 10.1371/journal.pone.0125976. [ Links ]20 Wang Y, Zhang X, Zhang Y, Zhu Y, Yuan C, Qi B, et al. Overexpression of pyruvate kinase M2 associates with aggressive clinicopathological features and unfavorable prognosis in oral squamous cell carcinoma. Cancer Biol Ther2015; 16: 839–845, doi: 10.1080/15384047.2015.1030551. [ Links ]21 Eckert A, Lautner M, Schütze A, Taubert H, Schubert J, Bilkenroth U. Coexpression of hypoxia-inducible factor-1 alpha and glucose transporter-1 is associated with poor prognosis in oral squamous cell carcinoma patients. Histopathology2011; 58: 1136–1147, doi: 10.1111/j.1365-2559.2011.03806.x. [ Links ]22 Grimm M, Schmitt S, Teriete P, Biegner T, Stenzl A, Hennenlotter J, et al. A biomarker based detection and characterization of carcinomas exploiting two fundamental biophysical mechanisms in mammalian cells. BMC Cancer2013; 13: 569, doi: 10.1186/1471-2407-13-569. [ Links ]23 Kunkel M, Förster GJ, Reichert TE, Kutzner J, Benz P, Bartenstein P, et al. Radiation response non-invasively imaged by [18F]FDG-PET predicts local tumor control and survival in advanced oral squamous cell carcinoma. Oral Oncol2003; 39: 170–177, doi: 10.1016/S1368-8375(02)00087-8. [ Links ]24 Abd El-Hafez YG, Moustafa HM, Khalil HF, Liao CT, Yen TC. Total lesion glycolysis: a possible new prognostic parameter in oral cavity squamous cell carcinoma. Oral Oncol2013; 49: 261–268, doi: 10.1016/j.oraloncology.2012.09.005. [ Links ]25 Cho JK, Hyun SH, Choi N, Kim MJ, Padera TP, Choi JY, et al. Significance of lymph node metastasis in cancer dissemination of head and neck cancer. Transl Oncol2015; 8: 119–125, doi: 10.1016/j.tranon.2015.03.001. [ Links ]26 Hasegawa O, Satomi T, Kono M, Watanabe M, Ikehata N, Chikazu D. Correlation between the malignancy and prognosis of oral squamous cell carcinoma in the maximum standardized uptake value. Odontology2019; 107: 237–243, doi: 10.1007/s10266-018-0379-9. [ Links ]27 Hofele C, Freier K, Thiele OC, Haberkorn U, Buchmann I. High 2-[18F]fluoro-2-deoxy-d-glucose (18FDG) uptake measured by positron emission tomography is associated with reduced overall survival in patients with oral squamous cell carcinoma. Oral Oncol2009; 45: 963–967, doi: 10.1016/j.oraloncology.2009.06.008. [ Links ]28 Joo YH, Yoo IR, Cho KJ, Park JO, Nam IC, Kim MS. Extracapsular spread and FDG PET/CT correlations in oral squamous cell carcinoma. Int J Oral Maxillofac Surg2013; 42: 158–163, doi: 10.1016/j.ijom.2012.11.006. [ Links ]29 Kunkel M, Helisch A, Reichert TE, Jeong JH, Buchholz HG, Benz P, et al. Clinical and prognostic value of [18F]FDG-PET for surveillance of oral squamous cell carcinoma after surgical salvage therapy. Oral Oncol2006; 42: 297–305, doi: 10.1016/j.oraloncology.2005.08.004. [ Links ]30 Morand GB, Vital DG, Kudura K, Werner J, Stoeckli SJ, Huber GF, et al. Maximum standardized uptake value (SUVmax) of primary tumor predicts occult neck metastasis in oral cancer. Sci Rep2018; 8: 11817, doi: 10.1038/s41598-018-30111-7. [ Links ]31 Shimizu M, Mitsudo K, Koike I, Taguri M, Iwai T, Koizumi T, et al. Prognostic value of 2-[18 F]fluoro-2-deoxy-D-glucose positron emission tomography for patients with oral squamous cell carcinoma treated with retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy. Oral Surg Oral Med Oral Pathol Oral Radiol2016; 121: 239–247, doi: 10.1016/j.oooo.2015.10.018. [ Links ]32 Suzuki H, Hasegawa Y, Terada A, Hyodo I, Nakashima T, Nishio M, et al. FDG-PET predicts survival and distant metastasis in oral squamous cell carcinoma. Oral Oncol2009; 45: 569–573, doi: 10.1016/j.oraloncology.2008.07.009. [ Links ]33 Suzuki H, Fukuyama R, Hasegawa Y, Tamaki T, Nishio M, Nakashima T, et al. Tumor thickness, depth of invasion, and Bcl-2 expression are correlated with FDG-uptake in oral squamous cell carcinomas. Oral Oncol2009; 45: 891–897, doi: 10.1016/j.oraloncology.2009.03.009. [ Links ]34 Suzuki H, Tamaki T, Nishio M, Beppu S, Mukoyama N, Hanai N, et al. Peak of standardized uptake value in oral cancer predicts survival adjusting for pathological stage. In Vivo2018; 32: 1193–1198, doi: 10.21873/invivo.11363. [ Links ]35 Yamaga E, Toriihara A, Nakamura S, Asai S, Fujioka T, Yoshimura R, et al. Clinical usefulness of 2-deoxy-2-[18F] fluoro-d-glucose-positron emission tomography/computed tomography for assessing early oral squamous cell carcinoma (cT1-2N0M0). Jpn J Clin Oncol2018; 48: 633–639, doi: 10.1093/jjco/hyy065. [ Links ]36 Zhang H, Seikaly H, Abele JT, Jeffery DT, Harris JR, O’Connell DA. Metabolic tumour volume as a prognostic factor for oral cavity squamous cell carcinoma treated with primary surgery. J Otolaryngol Head Neck Surg2014; 43: 33. [ Links ]37 Kim M, Higuchi T, Nakajima T, Andriana P, Hirasawa H, Tokue A, et al. 18F-FDG and 18F-FAMT PET-derived metabolic parameters predict outcome of oral squamous cell carcinoma. Oral Radiol2019; 35: 308–314, doi: 10.1007/s11282-019-00377-2. [ Links ]38 Kimura M, Kato I, Ishibashi K, Shibata A, Nishiwaki S, Fukumura M, et al. The prognostic significance of intratumoral heterogeneity of 18F-FDG uptake in patients with oral cavity squamous cell carcinoma. Eur J Radiol2019; 114: 99–104, doi: 10.1016/j.ejrad.2019.03.004. [ Links ]39 Genden EM, Ferlito A, Silver CE, Takes RP, Suarez C, Owen RP, et al. Contemporary management of cancer of the oral cavity. Eur Arch Otorhinolaryngol2010; 267: 1001–1017, doi: 10.1007/s00405-010-1206-2. [ Links ]40 Ram H, Sarkar J, Kumar H, Konwar R, Bhatt ML, Mohammad S. Oral cancer: risk factors and molecular pathogenesis. J Maxillofac Oral Surg2011; 10: 132–137, doi: 10.1007/s12663-011-0195-z. [ Links ]41 Li CX, Sun JL, Gong ZC, Lin ZQ, Liu H. Prognostic value of GLUT-1 expression in oral squamous cell carcinoma. A prisma-compliant meta-analysis. Medicine (Baltimore)2016; 95: e5324, doi: 10.1097/MD.0000000000005324. [ Links ]42 Denko NC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer2008; 8: 705–713, doi: 10.1038/nrc2468. [ Links ]43 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell2011; 144: 646–674, doi: 10.1016/j.cell.2011.02.013. [ Links ]44 Koukourakis MI, Giatromanolaki A, Simopoulos C, Polychronidis A, Sivridis E. Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer. Clin Exp Metastasis2005; 22: 25–30, doi: 10.1007/s10585-005-2343-7. [ Links ]45 Kato Y, Ozawa S, Miyamoto C, Maehata Y, Suzuki A, Maeda T, et al. Acidic extracellular microenvironment and cancer. Cancer Cell Int2013; 13: 89, doi: 10.1186/1475-2867-13-89. [ Links ]46 Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell2008; 13: 472–482, doi: 10.1016/j.ccr.2008.05.005. [ Links ]47 Xu Q, Tu J, Dou C, Zhang J, Yang L, Liu X, et al. HSP90 promotes cell glycolysis, proliferation and inhibits apoptosis by regulating PKM2 abundance via Thr-328 phosphorylation in hepatocellular carcinoma. Mol Cancer2017; 16: 178, doi: 10.1186/s12943-017-0748-y. [ Links ]48 Hamabe A, Konno M, Tanuma N, Shima H, Tsunekuni K, Kawamoto K, et al. Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial-mesenchymal transition. Proc Natl Acad Sci USA2014; 111: 15526–15531, doi: 10.1073/pnas.1407717111. [ Links ]49 Huang C, Huang Z, Bai P, Luo G, Zhao X, Wang X. Expression of pyruvate kinase M2 in human bladder cancer and its correlation with clinical parameters and prognosis. Onco Targets Ther2018; 11: 2075–2082, doi: 10.2147/OTT.S152999. [ Links ]50 Wang C, Jiang J, Ji J, Cai Q, Chen X, Yu Y, et al. PKM2 promotes cell migration and inhibits autophagy by mediating PI3K/AKT activation and contributes to the malignant development of gastric cancer. Sci Rep2017; 7: 2886, doi: 10.1038/s41598-017-03031-1. [ Links ]51 Turner DM, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta2014; 1843: 2563–2582, doi: 10.1016/j.bbamcr.2014.05.014. [ Links ]52 Lau AN, Vander Heiden GM. Metabolism in the tumor microenvironment. Ann Rev Cancer Biol2019; 4: 17–40, doi: 10.1146/annurev-cancerbio-030419-033333. [ Links ]53 Palsson-McDermott EM, Curtis AM, Goel G, Lauterbach MAR, Sheedy FJ, Gleeson LE, et al. Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages. Cell Metab2015; 21: 65–80, doi: 10.1016/j.cmet.2014.12.005. [ Links ]54 Shirai T, Nazarewicz RR, Wallis BB, Yanes RE, Watanabe R, Hilhorst M, et al. The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. J Exp Med2016; 213: 337–354, doi: 10.1084/jem.20150900. [ Links ]55 Yang P, Li Z, Li H, Lu Y, Wu H, Li Z. Pyruvate kinase M2 accelerates pro-inflammatory cytokine secretion and cell proliferation induced by lipopolysaccharide in colorectal cancer. Cell Signal2015; 27: 1525–1532, doi: 10.1016/j.cellsig.2015.02.032. [ Links ]56 Krockenberger M, Honig A, Rieger L, Coy JF, Sutterlin M, Kapp M, et al. Transketolase-like 1 expression correlates with subtypes of ovarian cancer and the presence of distant metastases. Int J Gynecol Cancer2007; 17: 101–106, doi: 10.1111/j.1525-1438.2007.00799.x. [ Links ]57 Coy JF. EDIM-TKTL1/Apo10 blood test: an innate immune system based liquid biopsy for the early detection, characterization and targeted treatment of cancer. Int J Mol Sci2017; 18: 878, doi: 10.3390/ijms18040878. [ Links ]58 Song Y, Liu D, He G. TKTL1 and p63 are biomarkers for the poor prognosis of gastric cancer patients. Cancer Biomark2015; 15: 591–597, doi: 10.3233/CBM-150499. [ Links ]59 Su SG, Yang M, Zhang MF, Peng QZ, Li MY, Liu LP, et al. miR-107-mediated decrease of HMGCS2 indicates poor outcomes and promotes cell migration in hepatocellular carcinoma. Int J Biochem Cell Biol2017; 91: 53–59, doi: 10.1016/j.biocel.2017.08.016. [ Links ]60 Ross JS, Tse T, Zarin DA, Xu H, Zhou L, Krumholz HM. Publication of NIH funded trials registered in ClinicalTrials.gov: cross sectional analysis. BMJ2012; 344: d7292, doi: 10.1136/bmj.d7292. [ Links ]PublicationORIGINALGlycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma. a systematic review with meta-analysis.pdfGlycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma. a systematic review with meta-analysis.pdfapplication/pdf1022734https://repositorio.cuc.edu.co/bitstreams/30db965a-663c-4c61-b4a4-91f26a9b368e/download6dc8173b9849b0b6c1a867302539beaaMD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8701https://repositorio.cuc.edu.co/bitstreams/72fc5fd0-e40c-4d14-ba90-1e1226372dcb/download42fd4ad1e89814f5e4a476b409eb708cMD52LICENSElicense.txtlicense.txttext/plain; charset=utf-83196https://repositorio.cuc.edu.co/bitstreams/158cd303-c821-4455-a4ca-a670e1d0dc7f/downloade30e9215131d99561d40d6b0abbe9badMD53THUMBNAILGlycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma. a systematic review with meta-analysis.pdf.jpgGlycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma. a systematic review with meta-analysis.pdf.jpgimage/jpeg67011https://repositorio.cuc.edu.co/bitstreams/f4b3ac9f-7d07-4157-8f75-3be6ad3ee33f/downloadd305bb19b7ad4726c0d04710ea979759MD54TEXTGlycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma. a systematic review with meta-analysis.pdf.txtGlycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma. a systematic review with meta-analysis.pdf.txttext/plain40498https://repositorio.cuc.edu.co/bitstreams/c04dfe60-9f17-488f-a88e-700c7009207e/download1f54870168358f3cc204eabfd51f4f43MD5511323/8002oai:repositorio.cuc.edu.co:11323/80022024-09-17 14:23:34.257http://creativecommons.org/publicdomain/zero/1.0/CC0 1.0 Universalopen.accesshttps://repositorio.cuc.edu.coRepositorio de la Universidad de la Costa 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