{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T13:45:11Z","timestamp":1774532711869,"version":"3.50.1"},"reference-count":51,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100024211","name":"Acibadem Mehmet Ali Aydinlar University","doi-asserted-by":"crossref","award":["THD-2024-2213"],"award-info":[{"award-number":["THD-2024-2213"]}],"id":[{"id":"10.13039\/100024211","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gastric cancer is one of the leading causes of cancer-related deaths worldwide, and due to its late-stage diagnosis, the prognosis is poor. Therefore, researching biomarkers that can be used in early diagnosis and prognostic processes is crucial. Insulin-like growth factor (IGF) signaling pathways play critical roles in cellular proliferation, apoptosis, differentiation, and tumor progression. This study investigated the biomarker potential of IGF-1, IGFBP-4, IGFBP-5, and PAPP-A in gastric cancer. Forty gastric cancer patients and forty healthy individuals were included, and protein levels in serum samples were measured using the ELISA method. The findings showed that IGF-1 levels were significantly decreased in the gastric cancer group, while IGFBP-4 levels were significantly increased. IGFBP-5 levels were also lower in gastric cancer patients. In contrast, PAPP-A levels did not differ significantly between the two groups. ROC analyses revealed that IGF-1, IGFBP-4, and IGFBP-5 have good discriminatory properties in the diagnosis of gastric cancer, while PAPP-A offers low diagnostic value. In conclusion, this study suggests that IGF pathway components, particularly IGF-1, IGFBP-4, and IGFBP-5, might be promising biomarker candidates for gastric cancer.<\/jats:p>","DOI":"10.3390\/ijms262210880","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T08:57:55Z","timestamp":1762765075000},"page":"10880","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["IGF Pathway Components as Potential Biomarkers in Gastric Cancer"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8768-6452","authenticated-orcid":false,"given":"Betul","family":"Ceylaner","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, T\u00fcrkiye"},{"name":"Department of Biochemistry and Molecular Biology, Institute of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1296-9711","authenticated-orcid":false,"given":"Furkan","family":"Sahin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Institute of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, T\u00fcrkiye"},{"name":"Acibadem Labmed Clinical Laboratories, Istanbul 34752, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anil","family":"Yildiz","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, Institute of Oncology, Istanbul University, Istanbul 34116, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Didem","family":"Tastekin","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, Institute of Oncology, Istanbul University, Istanbul 34116, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali Fuat Kaan","family":"Gok","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Surgical Sciences, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34116, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8814-7351","authenticated-orcid":false,"given":"Ahmet Tarik","family":"Baykal","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Institute of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, T\u00fcrkiye"},{"name":"Acibadem Labmed Clinical Laboratories, Istanbul 34752, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","first-page":"251","article-title":"Gastric cancer: Classification, histology and application of molecular pathology","volume":"3","author":"Hu","year":"2012","journal-title":"J. Gastrointest. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1111\/apm.1965.64.1.31","article-title":"The Two Histological Main Types of Gastric Carcinoma: Diffuse and So-Called Intestinal-Type Carcinoma. An Attempt at a Histo-Clinical Classification","volume":"64","year":"1965","journal-title":"Acta Pathol. Microbiol. Scand."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Machlowska, J., Baj, J., Sitarz, M., Maciejewski, R., and Sitarz, R. (2020). Gastric cancer: Epidemiology, risk factors, classification, genomic characteristics and treatment strategies. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21114012"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wang, Z. (2021). Regulation of cell cycle progression by growth factor-induced cell signaling. Cells, 10.","DOI":"10.3390\/cells10123327"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.ecl.2012.04.014","article-title":"IGF signaling in cancer","volume":"41","author":"Weroha","year":"2012","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1007\/s12291-014-0421-9","article-title":"Pregnancy Associated Plasma Protein-A (PAPP-A) Levels in Acute Coronary Syndrome: A Case Control Study in a Tertiary Care Centre","volume":"30","author":"Parveen","year":"2015","journal-title":"Indian J. Clin. Biochem. IJCB"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s13045-020-00904-3","article-title":"Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: A challenge for cancer therapy","volume":"13","author":"Hua","year":"2020","journal-title":"J. Hematol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.cell.2017.07.029","article-title":"The PI3K Pathway in Human Disease","volume":"170","author":"Fruman","year":"2017","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/S0960-9776(02)00214-X","article-title":"Significance of serum vascular endothelial growth factor, insulin-like growth factor-I levels and nitric oxide activity in breast cancer patients","volume":"12","author":"Sancak","year":"2003","journal-title":"Breast"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.maturitas.2016.08.012","article-title":"Insulin growth factor (IGF) 1, IGF-binding proteins and ovarian cancer risk: A systematic review and meta-analysis","volume":"94","author":"Gianuzzi","year":"2016","journal-title":"Maturitas"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1097\/MPA.0b013e3182550d9d","article-title":"Clinical value of circulating lipocalins and insulin-like growth factor axis in pancreatic cancer diagnosis","volume":"42","author":"Hamdy","year":"2013","journal-title":"Pancreas"},{"key":"ref_13","first-page":"1458","article-title":"Circulating levels of IGF-I and IGFBP-3 in gastric cancer","volume":"42","author":"Altinkaynak","year":"2012","journal-title":"Turkish J. Med. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ghir.2018.05.002","article-title":"IGFBP-4 and PAPP-A in normal physiology and disease","volume":"41","author":"Hjortebjerg","year":"2018","journal-title":"Growth Horm. IGF Res."},{"key":"ref_15","first-page":"6876","article-title":"IGFBP-4 expression is adversely associated with lung cancer prognosis","volume":"14","author":"Xiao","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/1757-2215-5-3","article-title":"IGFBP-4 tumor and serum levels are increased across all stages of epithelial ovarian cancer","volume":"5","author":"Mosig","year":"2012","journal-title":"J. Ovarian Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1593\/neo.13212","article-title":"IGFBP-4 anti-angiogenic and anti-tumorigenic effects are associated with anti-cathepsin B activity","volume":"15","author":"Moreno","year":"2013","journal-title":"Neoplasia"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Liu, Q., Jiang, J., Zhang, X., Zhang, M., and Fu, Y. (2021). Comprehensive Analysis of IGFBPs as Biomarkers in Gastric Cancer. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.723131"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"29676","DOI":"10.1074\/jbc.M301965200","article-title":"Insulin-like growth factor-binding protein-5 inhibits the growth of human breast cancer cells in vitro and in vivo","volume":"278","author":"Butt","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1002\/(SICI)1097-4652(200006)183:3<330::AID-JCP5>3.0.CO;2-N","article-title":"Tumor necrosis factor-\u03b1-induced apoptosis is associated with suppression of insulin-like growth factor binding protein-5 secretion in differentiating murine skeletal myoblasts","volume":"183","author":"Meadows","year":"2000","journal-title":"J. Cell. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Waters, J.A., Urbano, I., Robinson, M., and House, C.D. (2022). Insulin-like growth factor binding protein 5: Diverse roles in cancer. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1052457"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"T1","DOI":"10.1530\/JME-17-0236","article-title":"PAPP-A and cancer","volume":"61","author":"Conover","year":"2018","journal-title":"J. Mol. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.ghir.2006.11.003","article-title":"Pregnancy-associated plasma protein-A (PAPP-A): A local regulator of IGF bioavailability through cleavage of IGFBPs","volume":"17","author":"Boldt","year":"2007","journal-title":"Growth Horm. IGF Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.ghir.2014.10.007","article-title":"Pregnancy-associated plasma protein-A expression in human breast cancer","volume":"24","author":"Mansfield","year":"2014","journal-title":"Growth Horm. IGF Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Pan, H., Hanada, S., Zhao, J., Mao, L., and Ma, M.Z.-Q. (2012). Protein Secretion Is Required for Pregnancy-Associated Plasma Protein-A to Promote Lung Cancer Growth In Vivo. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0048799"},{"key":"ref_26","first-page":"973","article-title":"A Novel Neutralizing Antibody Targeting Pregnancy-Associated Plasma Protein-A Inhibits Ovarian Cancer Growth and Ascites Accumulation in Patient Mouse Tumorgrafts","volume":"14","author":"Becker","year":"2015","journal-title":"Mayo Clin."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ghir.2017.11.007","article-title":"The IGF-p53 connection in cancer","volume":"39","author":"Conover","year":"2018","journal-title":"Growth Horm. IGF Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s12935-025-03650-z","article-title":"Overexpression of metalloproteinase PAPPA accelerates cancer progression and correlates with immune cell infiltration in gastric cancer: Insights from bioinformatics and in vitro investigations","volume":"25","author":"Yu","year":"2025","journal-title":"Cancer Cell Int."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Brahmkhatri, V.P., Prasanna, C., and Atreya, H.S. (2015). Insulin-like growth factor system in cancer: Novel targeted therapies. BioMed Res. Int., 2015.","DOI":"10.1155\/2015\/538019"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"32","DOI":"10.3346\/jkms.1997.12.1.32","article-title":"Serum insulin-like growth factors (IGFs) and IGF binding protein (IGFBP)-3 in patients with gastric cancer: IGFBP-3 protease activity induced by surgery","volume":"12","author":"Lee","year":"1997","journal-title":"J. Korean Med Sci."},{"key":"ref_31","first-page":"297","article-title":"IGF-1 and IGF-1BP3 in gastric adenocarcinoma. Preliminary study","volume":"50","author":"Franciosi","year":"2003","journal-title":"Hepatogastroenterology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e14764","DOI":"10.1111\/ijcp.14764","article-title":"Association of IGF-1 and IGFBP-3 levels with gastric cancer: A systematic review and meta-analysis","volume":"75","author":"Liu","year":"2021","journal-title":"Int. J. Clin. Pract."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s12079-015-0259-9","article-title":"The role of PAPP-A in the IGF system: Location, location, location","volume":"9","author":"Oxvig","year":"2015","journal-title":"J. Cell Commun. Signal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1007\/BF02303854","article-title":"Altered serum levels of insulin-like growth-factor binding proteins in breast cancer patients","volume":"5","author":"Ng","year":"1998","journal-title":"Ann. Surg. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"237","DOI":"10.5937\/jomb0-25629","article-title":"Igfbp-4: A promising biomarker for lung cancer","volume":"40","author":"Nur","year":"2021","journal-title":"J. Med. Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1016\/S0959-8049(01)00269-6","article-title":"Expression of the insulin-like growth factors (IGFs) and the IGF-binding proteins (IGFBPs) in human gastric cancer cells","volume":"37","author":"Yi","year":"2001","journal-title":"Eur. J. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1210\/endrev\/bnad008","article-title":"Signaling Pathways of the Insulin-like Growth Factor Binding Proteins","volume":"44","author":"Baxter","year":"2023","journal-title":"Endocr. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1002\/mc.20203","article-title":"Differential Expression of Insulin-like Growth Factor Binding Protein-5 in Pancreatic Adenocarcinomas: Identification Using DNA Microarray","volume":"45","author":"Johnson","year":"2006","journal-title":"Mol. Carcinog."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1111\/j.1524-4741.2008.00572.x","article-title":"IGFBP2 and IGFBP5 overexpression correlates with the lymph node metastasis in T1 breast carcinomas","volume":"14","author":"Wang","year":"2008","journal-title":"Breast J."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Wang, S., Hong, Q., Geng, X., Chi, K., Cai, G., and Wu, D. (2019). Insulin-Like Growth Factor Binding Protein 5\u2014A Probable Target of Kidney Renal Papillary Renal Cell Carcinoma. BioMed Res. Int., 2019.","DOI":"10.1155\/2019\/3210324"},{"key":"ref_41","first-page":"1981","article-title":"Gene expression and prognosis of insulin-like growth factor-binding protein family members in non-small cell lung cancer","volume":"42","author":"Wang","year":"2019","journal-title":"Oncol. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"20636","DOI":"10.18632\/oncotarget.4114","article-title":"Insulin-like growth factor binding protein 5 (IGFBP5) functions as a tumor suppressor in human melanoma cells","volume":"6","author":"Wang","year":"2015","journal-title":"Oncotarget"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1186\/bcr2116","article-title":"Multifunctional roles of insulin-like growth factor binding protein 5 in breast cancer","volume":"10","author":"Akkiprik","year":"2008","journal-title":"Breast Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4590","DOI":"10.1038\/s41388-019-0743-4","article-title":"PKNOX2 suppresses gastric cancer through the transcriptional activation of IGFBP5 and p53","volume":"38","author":"Zhang","year":"2019","journal-title":"Oncogene"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Liu, Y., Shen, S., Yan, Z., Yan, L., Ding, H., Wang, A., Xu, Q., Sun, L., and Yuan, Y. (2023). Expression characteristics and their functional role of IGFBP gene family in pan-cancer. BMC Cancer, 23.","DOI":"10.1186\/s12885-023-10832-3"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3661","DOI":"10.1158\/0008-5472.CAN-12-3839","article-title":"DOG1 regulates growth and IGFBP-5 in gastrointestinal stromal tumors","volume":"73","author":"Simon","year":"2013","journal-title":"Cancer Res."},{"key":"ref_47","first-page":"241","article-title":"Relationship Between Pregnancy-Associated Plasma Protein-A and Lung Cancer","volume":"337","author":"Bulut","year":"2009","journal-title":"Clin. Investig."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Hjortebjerg, R., H\u00f8gdall, C., Hansen, K.H., H\u00f8gdall, E., and Frystyk, J. (2024). The IGF\u2014PAPP-A\u2014Stanniocalcin Axis in Serum and Ascites Associates with Prognosis in Patients with Ovarian Cancer. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25042014"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1002\/2211-5463.13156","article-title":"PAPP-A functions as a tumor suppressor and is downregulated in renal cell carcinoma","volume":"11","author":"Lu","year":"2021","journal-title":"FEBS Open Bio"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Review Hallmarks of Cancer: The Next Generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1172\/JCI107794","article-title":"Measurement of pregnancy-associated plasma proteins during human gestation","volume":"54","author":"Lin","year":"1974","journal-title":"J. Clin. Investig."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/10880\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T05:20:23Z","timestamp":1762924823000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/10880"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,10]]},"references-count":51,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262210880"],"URL":"https:\/\/doi.org\/10.3390\/ijms262210880","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,10]]}}}