{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:15:36Z","timestamp":1792178136248,"version":"4.4.0"},"reference-count":35,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Background\/Objectives: To evaluate the immunohistochemical expression of hexokinase-2 (HK2), glutaminase-1 (GLS1), and fatty acid synthase (FASN) and its prognostic significance in diffuse gastric adenocarcinoma. Materials and Methods: Formalin-fixed paraffin-embedded tissue samples from 92 patients with diffuse gastric adenocarcinoma were analyzed. Immunohistochemistry (IHC) was performed to assess the expression of HK2, GLS1 and FASN. Expression levels were evaluated semi-quantitatively based on staining intensity and the percentage of positive cells. Associations between enzyme expression and clinicopathological features were assessed using the Chi-square test. Kaplan\u2013Meier survival analysis was employed to evaluate progression-free survival (PFS) and overall survival (OS) and the log-rank test and Cox proportional hazards models were used for statistical analysis. Results: HK2 and FASN were overexpressed in 20.7% and 22.8% of patients, respectively, and were significantly associated with advanced tumor stage. In contrast, GLS1 expression, found in 30.4% of patients, did not independently correlate with clinicopathological characteristics. Furthermore, HK2 expression and co-expression of HK2\/FASN (10.9%) and HK2\/GLS1\/FASN (8.7%) were associated with progressive disease. In the univariate analysis, stage, HK2 overexpression, and co-expression of HK2\/FASN and HK2\/GLS1\/FASN were associated with shorter survival. However, only stage retained prognostic value in the multivariate analysis. Conclusions: Co-expression of these key metabolic enzymes remains a promising candidate as prognostic markers and therapeutic targets. Concurrent targeting of these metabolic pathways may offer novel therapeutic opportunities for patients with advanced-stage gastric cancer.<\/jats:p>","DOI":"10.3390\/medsci14010148","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T12:49:24Z","timestamp":1773924564000},"page":"148","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Expression of Hexokinase-2 (HK2), Glutaminase-1 (GLS1) and Fatty Acid Synthase (FASN) in Gastric Cancer and Their Prognostic Significance"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3372-741X","authenticated-orcid":false,"given":"Elisa","family":"Garc\u00eda-Mart\u00ednez","sequence":"first","affiliation":[{"name":"Basic Research Subdirection, National Cancer Institute of Mexico (INCan), Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7394-5123","authenticated-orcid":false,"given":"Leonardo S.","family":"Lino-Silva","sequence":"additional","affiliation":[{"name":"Department of Pathology, National Cancer Institute of Mexico (INCan), Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3985-0101","authenticated-orcid":false,"given":"Adriana","family":"Romo-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia","family":"Bornstein-Quevedo","sequence":"additional","affiliation":[{"name":"InmunoQ, Laboratorio de Patolog\u00eda, Inmunohistoqu\u00edmica y Biolog\u00eda Molecular, Mexico City 03100, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4201-5935","authenticated-orcid":false,"given":"Alma","family":"Chavez-Blanco","sequence":"additional","affiliation":[{"name":"Basic Research Subdirection, National Cancer Institute of Mexico (INCan), Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guadalupe","family":"Dominguez-Gomez","sequence":"additional","affiliation":[{"name":"Basic Research Subdirection, National Cancer Institute of Mexico (INCan), Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horacio N.","family":"Lopez-Basave","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, National Cancer Institute of Mexico (INCan), Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Padilla-Rosciano","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, National Cancer Institute of Mexico (INCan), Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Consuelo","family":"Diaz-Romero","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, National Cancer Institute of Mexico (INCan), Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurora","family":"Gonzalez-Fierro","sequence":"additional","affiliation":[{"name":"Basic Research Subdirection, National Cancer Institute of Mexico (INCan), Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2956-645X","authenticated-orcid":false,"given":"Alfonso","family":"Duenas-Gonzalez","sequence":"additional","affiliation":[{"name":"Direction of Teaching and Research, Maternal and Child Institute of the State of Mexico (IMIEM), Toluca 50170, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"ref_1","unstructured":"Global Cancer Observatory, GLOBOCAN 2022 (2026, March 15). International Agency for Research on Cancer. Available online: https:\/\/gco.iarc.fr\/1."},{"key":"ref_2","unstructured":"National Cancer Institute (2023, April 24). Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Stomach Cancer, Available online: https:\/\/seer.cancer.gov\/statfacts\/html\/stomach.html."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s00432-022-04408-0","article-title":"Predictive biomarkers in gastric cancer","volume":"149","year":"2023","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/S0140-6736(10)61121-X","article-title":"Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial","volume":"376","author":"Bang","year":"2010","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2419","DOI":"10.1056\/NEJMoa2004413","article-title":"Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer","volume":"25","author":"Shitara","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrclinonc.2016.60","article-title":"Cancer metabolism: A therapeutic perspective","volume":"14","author":"Pestell","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"494","DOI":"10.2174\/1568026618666180523111351","article-title":"Inhibition of Glycolysis and Glutaminolysis: An Emerging Drug Discovery Approach to Combat Cancer","volume":"18","author":"Akins","year":"2018","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/978-981-33-6785-2_4","article-title":"Lipid Metabolism in Cancer Cells","volume":"1316","author":"Zheng","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1159\/000335792","article-title":"Defining the Molecular Basis of Tumor Metabolism: A Continuing Challenge Since Warburg\u2019s Discovery","volume":"28","year":"2011","journal-title":"Cell Physiol. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"eaaw5473","DOI":"10.1126\/science.aaw5473","article-title":"Metabolic reprogramming and cancer progression","volume":"368","author":"Faubert","year":"2020","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Bin, Y.L., Hu, H.S., Tian, F., Wen, Z.H., Yang, M.F., Wu, B.H., Wang, L.S., Yao, J., and Li, D.F. (2022). Metabolic Reprogramming in Gastric Cancer: Trojan Horse Effect. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.745209"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.3892\/or.2015.4077","article-title":"Antitumor effects of a drug combination targeting glycolysis, glutaminolysis and de novo synthesis of fatty acids","volume":"34","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"703","DOI":"10.2174\/1568009622666220413083534","article-title":"Progress in Metabolic Studies of Gastric Cancer and Therapeutic Implications","volume":"22","year":"2022","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Dong, W., Qian, X., Liu, H., Huo, J., and Wang, W. (2026). Mechanisms of Metabolic Reprogramming Regulating Immunosuppression in the Gastric Cancer Tumor Microenvironment. Biomolecules, 16.","DOI":"10.3390\/biom16010160"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/imm.70045","article-title":"Molecular Mediators of Metabolic Reprogramming in Cancer: Mechanisms, Regulatory Networks, and Therapeutic Strategies","volume":"177","author":"Ahuja","year":"2026","journal-title":"Immunology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1517\/14728222.2013.833607","article-title":"Targeting VDAC-bound hexokinase II: A promising approach for concomitant anti-cancer therapy","volume":"17","author":"Krasnov","year":"2013","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_17","first-page":"251","article-title":"Expression of type 2 hexokinase and mitochondria-related genes in gastric carcinoma tissues and cell lines","volume":"27","author":"Rho","year":"2007","journal-title":"Anticancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s13277-010-0109-6","article-title":"Expressions of hypoxia-inducible factor-1\u03b1 and hexokinase-II in gastric adenocarcinoma: The impact on prognosis and correlation to clinicopathologic features","volume":"1","author":"Qiu","year":"2011","journal-title":"Tumor Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"44","DOI":"10.3892\/ijo.2012.1687","article-title":"Expression of pyruvate dehydrogenase kinase-1 in gastric cancer as a potential therapeutic target","volume":"1","author":"Hur","year":"2013","journal-title":"Int. J. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Fhu, C.W., and Ali, A. (2020). Fatty Acid Synthase: An Emerging Target in Cancer. Molecules, 25.","DOI":"10.3390\/molecules25173935"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"999","DOI":"10.3892\/etm.2012.727","article-title":"High overexpression of fatty acid synthase is associated with poor survival in Chinese patients with gastric carcinoma","volume":"4","author":"Hou","year":"2012","journal-title":"Exp. Ther. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3027","DOI":"10.3892\/mmr.2016.4902","article-title":"Overexpression of fatty acid synthase predicts a poor prognosis for human gastric cancer","volume":"13","author":"Duan","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6851","DOI":"10.7314\/APJCP.2015.16.16.6851","article-title":"Expression of Fatty Acid Synthase Negatively Correlates with PTEN and Predicts Peritoneal Dissemination of Human Gastric Cancer","volume":"16","author":"Xiang","year":"2015","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e1800038","DOI":"10.1002\/prca.201800038","article-title":"iTRAQ-Based Quantitative Proteomics Approach Identifies Novel Diagnostic Biomarkers That Were Essential for Glutamine Metabolism and Redox Homeostasis for Gastric Cancer","volume":"4","author":"Jiang","year":"2019","journal-title":"Proteom. Clin. Appl."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3233\/CBM-160619","article-title":"MicroRNA-181b inhibits glycolysis in gastric cancer cells via targeting hexokinase 2 gene","volume":"17","author":"Li","year":"2016","journal-title":"Cancer Biomark."},{"key":"ref_26","first-page":"1181","article-title":"Licochalcone A suppresses hexokinase 2-mediated tumor glycolysis in gastric cancer via downregulation of the Akt signaling pathway","volume":"3","author":"Wu","year":"2018","journal-title":"Oncol. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"143956","DOI":"10.1016\/j.gene.2019.143956","article-title":"Oleanolic acid reduces aerobic glycolysis-associated proliferation by inhibiting yes-associated protein in gastric cancer cells","volume":"712","author":"Li","year":"2019","journal-title":"Gene"},{"key":"ref_28","first-page":"594","article-title":"Small interfering RNA-mediated knockdown of fatty acid synthase attenuates the proliferation and metastasis of human gastric cancer cells via the mTOR\/Gli1 signaling pathway","volume":"1","author":"Sun","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6674204","DOI":"10.1155\/2021\/6674204","article-title":"FASN Knockdown Inhibited Anoikis Resistance of Gastric Cancer Cells via P-ERK1\/2\/Bcl-xL Pathway","volume":"2021","author":"Yu","year":"2021","journal-title":"Gastroenterol. Res. Pract."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2462","DOI":"10.1111\/cas.13421","article-title":"Pyruvate kinase isozyme M2 and glutaminase might be promising molecular targets for the treatment of gastric cancer","volume":"12","author":"Kitayama","year":"2017","journal-title":"Cancer Sci."},{"key":"ref_31","first-page":"1905","article-title":"Feasibility and antitumor efficacy in vivo, of simultaneously targeting glycolysis, glutaminolysis and fatty acid synthesis using lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat in colon cancer","volume":"3","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1186\/s12935-021-02193-3","article-title":"Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation","volume":"1","author":"Cao","year":"2021","journal-title":"Cancer Cell Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4780","DOI":"10.1080\/21655979.2021.1956247","article-title":"Identification of four gastric cancer subtypes based on genetic analysis of cholesterogenic and glycolytic pathways","volume":"1","author":"Zhu","year":"2021","journal-title":"Bioengineered"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s43556-026-00427-2","article-title":"Metabolic reprogramming in cancer: Dysregulation of glucose, lipid, and amino acid pathways and therapeutic opportunities","volume":"7","author":"Yu","year":"2026","journal-title":"Mol. Biomed."},{"key":"ref_35","first-page":"5222","article-title":"Pharmacological inhibition of tumor anabolism and host catabolism as a cancer therapy","volume":"1","author":"Juarez","year":"2021","journal-title":"Sci. Rep."}],"container-title":["Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/1\/148\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T12:58:40Z","timestamp":1773925120000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/1\/148"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,19]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["medsci14010148"],"URL":"https:\/\/doi.org\/10.3390\/medsci14010148","relation":{},"ISSN":["2076-3271"],"issn-type":[{"value":"2076-3271","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,19]]}}}