Gene expression levels of the glycolytic enzymes lactate dehydrogenase A (LDHA) and phosphofructokinase platelet (PFKP) are good predictors of survival time, recurrence and risk of death in cervical cancer

Background Up to 74% of patients with cervical cancer (CC) may experience recurrence after their treatment, and most of them are identified late when only the clinical parameters are used, which decreases their chances of recovery. Molecular markers can improve the prediction of clinical outcome and identify therapeutic targets in CC. Glycolysis is altered in 70% of CCs, so it could be a metabolic pathway in which molecular markers associated with the aggressiveness of CC can be identified. Methods The expression of 14 glycolytic genes was analyzed in 118 CC samples by microarrays, and only LDHA and PFKP were validated by qRT–PCR (n=58) and in second and third replicates by Western blotting (n=69) and immunohistochemistry (n=18). Results LDHA and PFKP were associated with poor overall survival [OS: LDHA HR=3.0 (95% CI= 1.1-8.2); p=2 . 9 × 10 -2 ; PFKP HR=3.4 (95% CI= 1.1-10.5); p= 3 . 5 × 10 -2 ] and disease-free survival [DFS: LDHA HR=2.7 (95% CI= 1.6-6.3); p=2 . 6 × 10 -2 ] independent of FIGO clinical stage. The risk of death was greater when both biomarkers were overexpressed than when using only FIGO stage [HR =7 (95% CI 1.6-31.1, p=1 . 0 × 10 -2 ) versus HR=8.1 (95% CI=2.6-26.1; p=4 . 3 × 10 -4 )] and increased exponentially as the expression of LDHA and PFKP increased. Conclusions LDHA and PFKP at the mRNA and protein levels were associated with poor overall survival, disease-free survival and increased risk of death of patients with CC regardless of FIGO stage. The measurement of expression of these two markers could be very useful to evaluate the clinical evolution and the risk of death from CC and to make better therapeutic decisions at the beginning of treatment. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by National Council on Science and Technology (Conacyt) under grant numbers 8135/A1, 24341 (to JB) and Laboratory Huella Genica ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of the General Hospital of Mexico (HGM) gave ethical approval for this work (approval number DIC/03/311/04/051). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript. ; * ADPGK : ADP-dependent glucokinase ALDOA : aldolase AUC : area under the curve CC : cervical cancer DFS : disease-free survival EDARADD : EDAR-associated death domain ENO1 : enolase 1 FIGO : International Federation of Gynecology and Obstetrics FC : fold change GPI : glucose-6-phosphate isomerase GAPDH : glyceraldehyde-3-phosphate dehydrogenase HG-CIN : high-grade cervical intraepithelial neoplasia HK2 : hexokinase 2 HR : hazard ratio IH : immunohistochemistry LDHA : lactate dehydrogenase A OS : overall survival PFKP : phosphofructokinase platelet PGK1 : phosphoglycerate kinase PKM : pyruvate kinase M qRT–PCR : quantitative real-time-polymerase chain reaction SLC2A1 : solute carrier family 2 member 1 SLC9A1 : solute carrier family 9 member A1 TP1P1 : triosephosphate isomerase 1 pseudogene 1 WB : Western blotting