{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T02:57:37Z","timestamp":1784170657949,"version":"3.55.0"},"reference-count":38,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T00:00:00Z","timestamp":1756771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of South Australia President\u2019s Scholarship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Effective treatment of ovarian cancer is limited by late-stage detection and chemotherapy resistance. There is a clinical need for the discovery of novel molecular targets to enable the development of innovative theranostic approaches. We investigated the coagulation factor II receptor\/protease-activated receptor 1 (F2R\/PAR1) as a potential diagnostic\/prognostic biomarker and therapeutic target for ovarian cancer treatment. Public RNA sequence and DNA microarray data were used to analyze F2R gene expression in ovarian cancers, with protein expression confirmed in tumor samples by flow cytometry, immunofluorescence, and immunohistochemistry (IHC). Functional assays were conducted to study effects of F2R suppression on tumor progression. Our analysis confirmed elevated F2R mRNA and protein expression in ovarian cancers, notably in patients with metastatic and chemotherapy-resistant disease. Kaplan\u2013Meier survival analysis demonstrated an association between high F2R protein detection and reduced progression-free survival. F2R suppression in ovarian cancer cell lines reduced tumor cell motility, invasion, spheroid formation, and metabolism and enhanced carboplatin sensitivity. F2R is a compelling diagnostic\/prognostic and therapeutic target that could be used to treat chemotherapy-resistant and metastatic disease. The evaluation of novel F2R targeting strategies, using antibody-conjugated drugs or F2R ligand-decorated drug carriers, could lead to the development of effective therapeutics for patients with ovarian cancer.<\/jats:p>","DOI":"10.3390\/ijms26178529","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T15:02:57Z","timestamp":1756825377000},"page":"8529","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Protease-Activated Receptor F2R Is a Potential Target for New Diagnostic\/Prognostic and Treatment Applications for Patients with Ovarian Cancer"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5166-8930","authenticated-orcid":false,"given":"Riya","family":"Khetan","sequence":"first","affiliation":[{"name":"Centre of Pharmaceutical Innovation, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2071-5308","authenticated-orcid":false,"given":"Noor A.","family":"Lokman","sequence":"additional","affiliation":[{"name":"Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preethi","family":"Eldi","sequence":"additional","affiliation":[{"name":"UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5306-3468","authenticated-orcid":false,"given":"Zoe K.","family":"Price","sequence":"additional","affiliation":[{"name":"Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin K.","family":"Oehler","sequence":"additional","affiliation":[{"name":"Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia"},{"name":"Department of Gynaecological Oncology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9098-3626","authenticated-orcid":false,"given":"Doug A.","family":"Brooks","sequence":"additional","affiliation":[{"name":"UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7630-4874","authenticated-orcid":false,"given":"Anton","family":"Blencowe","sequence":"additional","affiliation":[{"name":"Centre of Pharmaceutical Innovation, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia"},{"name":"Applied Chemistry and Translational Biomaterials Group, Centre of Pharmaceutical Innovation, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7253-2629","authenticated-orcid":false,"given":"Sanjay","family":"Garg","sequence":"additional","affiliation":[{"name":"Centre of Pharmaceutical Innovation, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7415-1854","authenticated-orcid":false,"given":"Carmela","family":"Ricciardelli","sequence":"additional","affiliation":[{"name":"Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3951-1866","authenticated-orcid":false,"given":"Hugo","family":"Albrecht","sequence":"additional","affiliation":[{"name":"Centre of Pharmaceutical Innovation, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Khetan, R., Dharmayanti, C., Gillam, T.A., Kubler, E., Klingler-Hoffmann, M., Ricciardelli, C., Oehler, M.K., Blencowe, A., Garg, S., and Albrecht, H. (2022). Using GPCRs as Molecular Beacons to Target Ovarian Cancer with Nanomedicines. Cancers, 14.","DOI":"10.3390\/cancers14102362"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16061","DOI":"10.1038\/nrdp.2016.61","article-title":"Ovarian cancer","volume":"2","author":"Matulonis","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1186\/s13048-024-01479-0","article-title":"Unveiling G-protein coupled receptors as potential targets for ovarian cancer nanomedicines: From RNA sequencing data analysis to in vitro validation","volume":"17","author":"Khetan","year":"2024","journal-title":"J. Ovarian Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.cell.2004.12.018","article-title":"PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells","volume":"120","author":"Boire","year":"2005","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"565","DOI":"10.3892\/ijo.2012.1738","article-title":"The activation of proteinase-activated receptor-1 (PAR1) promotes gastric cancer cell alteration of cellular morphology related to cell motility and invasion","volume":"42","author":"Fujimoto","year":"2013","journal-title":"Int. J. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1158\/1541-7786.395.2.7","article-title":"Protease-activated receptors (PAR1 and PAR2) contribute to tumor cell motility and metastasis","volume":"2","author":"Shi","year":"2004","journal-title":"Mol. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1242\/jcs.03409","article-title":"Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer","volume":"120","author":"Arora","year":"2007","journal-title":"J. Cell Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1111\/pcmr.12217","article-title":"miR-20b regulates expression of proteinase-activated receptor-1 (PAR-1) thrombin receptor in melanoma cells","volume":"27","author":"Saleiban","year":"2014","journal-title":"Pigment. Cell Melanoma Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11977","DOI":"10.3748\/wjg.v20.i34.11977","article-title":"Proteinase activated-receptors-associated signaling in the control of gastric cancer","volume":"20","author":"Sedda","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1007\/s12032-015-0614-y","article-title":"Endothelial cell protein C receptor promotes MGC803 gastric cancer cells proliferation and migration by activating ERK1\/2","volume":"32","author":"Wang","year":"2015","journal-title":"Med. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6561","DOI":"10.1158\/0008-5472.CAN-11-1432","article-title":"PAR-1 and thrombin: The ties that bind the microenvironment to melanoma metastasis","volume":"71","author":"Zigler","year":"2011","journal-title":"Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s10549-022-06514-6","article-title":"Exosomal MMP-1 transfers metastasis potential in triple-negative breast cancer through PAR1-mediated EMT","volume":"193","author":"Zhu","year":"2022","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ma, J., Shi, Y., Lu, Q., and Huang, D. (2024). F2RL3 Regulates Epithelial-Mesenchymal Transition and Angiogenesis in Gastric Cancer through the Rap1\/MAPK Signaling Pathway. Front. Biosci. (Landmark Ed.), 29.","DOI":"10.31083\/j.fbl2905177"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Rabinovitch, E., Mihara, K., Sananes, A., Zaretsky, M., Heyne, M., Shifman, J., Aharoni, A., Hollenberg, M.D., and Papo, N. (2021). A KLK4 proteinase substrate capture approach to antagonize PAR1. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-95666-4"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.1158\/1535-7163.MCT-08-0177","article-title":"Targeting a metalloprotease-PAR1 signaling system with cell-penetrating pepducins inhibits angiogenesis, ascites, and progression of ovarian cancer","volume":"7","author":"Agarwal","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1007\/s10528-022-10232-5","article-title":"A prognostic risk model for ovarian cancer based on gene expression profiles from gene expression omnibus database","volume":"61","author":"Fan","year":"2023","journal-title":"Biochem. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1002\/ijc.20607","article-title":"Differential expression of protease activated receptor 1 (Par1) and pY397FAK in benign and malignant human ovarian tissue samples","volume":"113","author":"Salah","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3619","DOI":"10.21873\/anticanres.12636","article-title":"The Role of PAR1 Autoantibodies in Patients with Primary Epithelial Ovarian Cancer","volume":"38","author":"Kreienbring","year":"2018","journal-title":"Anticancer. Res."},{"key":"ref_19","first-page":"5375","article-title":"Identifying miRNA-mRNA regulation network of major depressive disorder in ovarian cancer patients","volume":"16","author":"Wu","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Park, S.J., Yoon, B.H., Kim, S.K., and Kim, S.Y. (2019). GENT2: An updated gene expression database for normal and tumor tissues. BMC Med. Genom., 12.","DOI":"10.1186\/s12920-019-0514-7"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Bartha, A., and Gyorffy, B. (2021). TNMplot.com: A Web Tool for the Comparison of Gene Expression in Normal, Tumor and Metastatic Tissues. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052622"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kosti, I., Jain, N., Aran, D., Butte, A.J., and Sirota, M. (2016). Cross-tissue Analysis of Gene and Protein Expression in Normal and Cancer Tissues. Sci. Rep., 6.","DOI":"10.1038\/srep24799"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zhang, R., Siu, M.K.Y., Ngan, H.Y.S., and Chan, K.K.L. (2022). Molecular Biomarkers for the Early Detection of Ovarian Cancer. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231912041"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/1479-5876-7-47","article-title":"PAR1 is selectively over expressed in high grade breast cancer patients: A cohort study","volume":"7","author":"Hernandez","year":"2009","journal-title":"J. Transl. Med."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Witte, D., Zeeh, F., Gadeken, T., Gieseler, F., Rauch, B.H., Settmacher, U., Kaufmann, R., Lehnert, H., and Ungefroren, H. (2016). Proteinase-Activated Receptor 2 Is a Novel Regulator of TGF-beta Signaling in Pancreatic Cancer. J. Clin. Med., 5.","DOI":"10.3390\/jcm5120111"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6223","DOI":"10.1158\/0008-5472.CAN-09-0187","article-title":"Blockade of PAR1 signaling with cell-penetrating pepducins inhibits Akt survival pathways in breast cancer cells and suppresses tumor survival and metastasis","volume":"69","author":"Yang","year":"2009","journal-title":"Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Deng, Y., Tan, Y., Zhou, D., Bai, Y., Cao, T., Zhong, C., Huang, W., Ou, Y., Guo, L., and Liu, Q. (2022). Single-Cell RNA-Sequencing Atlas Reveals the Tumor Microenvironment of Metastatic High-Grade Serous Ovarian Carcinoma. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.923194"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2974","DOI":"10.1097\/CM9.0000000000002328","article-title":"Characterization of candidate factors associated with the metastasis and progression of high-grade serous ovarian cancer","volume":"136","author":"Liu","year":"2023","journal-title":"Chin. Med. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1182\/blood-2012-09-355958","article-title":"Matrix metalloproteases and PAR1 activation","volume":"121","author":"Austin","year":"2013","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Gallyas, F., Sumegi, B., and Szabo, C. (2020). Role of Akt Activation in PARP Inhibitor Resistance in Cancer. Cancers, 12.","DOI":"10.3390\/cancers12030532"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.molcel.2005.08.016","article-title":"Binding and phosphorylation of par-4 by akt is essential for cancer cell survival","volume":"20","author":"Goswami","year":"2005","journal-title":"Mol. Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/j.bbamcr.2018.10.011","article-title":"Protease-activated receptor 2 induces migration and promotes Slug-mediated epithelial-mesenchymal transition in lung adenocarcinoma cells","volume":"1866","author":"Tsai","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1038\/onc.2015.217","article-title":"Dysregulated protease activated receptor 1 (PAR1) promotes metastatic phenotype in breast cancer through HMGA2","volume":"35","author":"Yang","year":"2016","journal-title":"Oncogene"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1007\/s10555-015-9599-4","article-title":"Protease-activated receptors (PARs)\u2014biology and role in cancer invasion and metastasis","volume":"34","author":"Wojtukiewicz","year":"2015","journal-title":"Cancer Metastasis Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"17819","DOI":"10.18632\/oncotarget.14867","article-title":"Keratin 5 overexpression is associated with serous ovarian cancer recurrence and chemotherapy resistance","volume":"8","author":"Ricciardelli","year":"2017","journal-title":"Oncotarget"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Lokman, N.A., Price, Z.K., Hawkins, E.K., Macpherson, A.M., Oehler, M.K., and Ricciardelli, C. (2019). 4-Methylumbelliferone Inhibits Cancer Stem Cell Activation and Overcomes Chemoresistance in Ovarian Cancer. Cancers, 11.","DOI":"10.3390\/cancers11081187"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bankhead, P., Loughrey, M.B., Fernandez, J.A., Dombrowski, Y., McArt, D.G., Dunne, P.D., McQuaid, S., Gray, R.T., Murray, L.J., and Coleman, H.G. (2017). QuPath: Open source software for digital pathology image analysis. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-17204-5"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s00011-010-0268-3","article-title":"MnTMPyP, a superoxide dismutase\/catalase mimetic, decreases inflammatory indices in ischemic acute kidney injury","volume":"60","author":"Mortensen","year":"2011","journal-title":"Inflamm. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8529\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:38:03Z","timestamp":1760035083000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8529"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,2]]},"references-count":38,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26178529"],"URL":"https:\/\/doi.org\/10.3390\/ijms26178529","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,2]]}}}