{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T05:18:31Z","timestamp":1787635111134,"version":"build-2736575974"},"reference-count":194,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020917","name":"Mohammed bin Rashid University of Medicine and Health Sciences","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100020917","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/01xfzxq83","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Protease-activated receptor-2 (PAR-2; encoded by F2RL1) is emerging as a context-dependent driver of gastrointestinal cancer. Activated by irreversible N-terminal cleavage, its signalling output is not fixed but is calibrated by the identity and source of the activating protease, the receptor cleavage state, cellular context and biased coupling to G-protein \u03b1q (G\u03b1q), G-protein \u03b112\/13 (G\u03b112\/13) and \u03b2-arrestin. PAR-2 is best understood not as a simple inflammatory receptor but as a proteolytic rheostat that converts diverse coagulation, inflammatory, microbial and stromal protease inputs into distinct oncogenic programmes. Colorectal cancer and pancreatic ductal adenocarcinoma provide complementary models: in colorectal cancer, PAR-2 links mucosal inflammation and coagulation to proliferation, metastatic competence and resistance to epidermal growth factor receptor (EGFR)-targeted therapy, whereas in pancreatic cancer, it is embedded in a tissue-factor-rich desmoplastic microenvironment that promotes invasion, immune exclusion and chemoresistance. Therapeutic strategies suggested by this framework include direct and biased PAR-2 modulators, upstream protease and factor Xa (FXa) inhibition, statin repurposing and activated-fragment biomarkers such as the PAR-2 activation neoepitope (PRO-PAR2). These strategies must be applied under biomarker guidance, since PAR-2 blockade may benefit inflammation-dominant tumours yet prove counterproductive where PAR-2 sustains antitumour immunity.<\/jats:p>","DOI":"10.3390\/ijms27177526","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T11:47:19Z","timestamp":1787572039000},"page":"7526","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Protease-Activated Receptor-2 as a Proteolytic Rheostat in Colorectal and Pancreatic Cancer: From Mechanism to Biomarker-Guided Therapy"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8744-0941","authenticated-orcid":false,"given":"Hodasadat Tabatabaei","family":"Yeganeh","sequence":"first","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6412-3611","authenticated-orcid":false,"given":"Malak","family":"Sellat","sequence":"additional","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2340-0790","authenticated-orcid":false,"given":"Zayd","family":"Anis","sequence":"additional","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0168-1616","authenticated-orcid":false,"given":"Reine","family":"Chiri","sequence":"additional","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajashree","family":"Patnaik","sequence":"additional","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4459-1666","authenticated-orcid":false,"given":"Shloka","family":"Gambhir","sequence":"additional","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7546-8893","authenticated-orcid":false,"given":"Yajnavalka","family":"Banerjee","sequence":"additional","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1002\/bjs.1800820831","article-title":"Tissue factor expression correlates with histological grade in human pancreatic cancer","volume":"82","author":"Kakkar","year":"1995","journal-title":"Br. 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