{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T05:50:42Z","timestamp":1777009842438,"version":"3.51.4"},"reference-count":38,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Colorectal cancer (CRC) is a major global health problem, ranking as the third most commonly diagnosed cancer and the second leading cause of cancer\u2010related deaths. This study aimed to elucidate the role and underlying molecular mechanism of the Regenerating Islet\u2010Derived Protein 1 Alpha (REG I\u03b1)\/Endothelin Receptor B (EDNRB) axis in CRC malignant progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A nude mouse xenograft model and human CRC cell lines were used to investigate the REG I\u03b1\/EDNRB axis. RNA\u2010sequencing (RNA\u2010seq) was employed to identify downstream targets following REG I\u03b1 knockdown. Interventions included siRNA\u2010mediated knockdown of REG I\u03b1, overexpression of EDNRB, and pharmacological inhibition with the Ca\n                      <jats:sup>2+<\/jats:sup>\n                      chelator BAPTA\u2010AM. Cell proliferation, apoptosis, migration, invasion, and epithelial\u2010mesenchymal transition (EMT) were assessed using Western blotting, RT\u2010qPCR, and Transwell assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      REG I\u03b1 was significantly upregulated in CRC tissues. Downregulation of REG I\u03b1 suppressed CRC cell proliferation, migration, and invasion while promoting apoptosis. Mechanistically, REG I\u03b1 silencing downregulated the expression of its target EDNRB and subsequently inhibited the Ca\n                      <jats:sup>2+<\/jats:sup>\n                      \/CaMKII signaling pathway, triggering endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) accumulation to induce apoptosis. Importantly, overexpression of EDNRB rescued the malignant phenotypes suppressed by REG I\u03b1 knockdown, whereas BAPTA\u2010AM treatment abolished this rescue effect. The REG I\u03b1\/EDNRB axis was further demonstrated to drive the EMT process, and these findings were validated in\u00a0vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The REG I\u03b1\/EDNRB axis promotes the malignant progression of CRC by activating Ca\n                      <jats:sup>2+<\/jats:sup>\n                      \u2010dependent epithelial\u2010mesenchymal transition, suggesting that targeting this axis is a promising therapeutic strategy to inhibit CRC metastasis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.71754","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T12:11:41Z","timestamp":1776082301000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Role of Ca\n                    <sup>2+<\/sup>\n                    \u2010Dependent Epithelial\u2010Mesenchymal Transition in Malignant Progression of Colorectal Cancer: Special Focus on\n                    <scp>REG<\/scp>\n                    I\u03b1\/\n                    <scp>EDNRB<\/scp>"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2512-6111","authenticated-orcid":false,"given":"Xiao","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery The First Affiliated Hospital of Chongqing Medical University  Chongqing China"},{"name":"Department of General Surgery Renji Hospital, School of Medicine, Chongqing University (The Fifth People\u2019s Hospital of Chongqing)  Chongqing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shunyuan","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of General Surgery Renji Hospital, School of Medicine, Chongqing University (The Fifth People\u2019s Hospital of Chongqing)  Chongqing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Jian","sequence":"additional","affiliation":[{"name":"Department of General Surgery Renji Hospital, School of Medicine, Chongqing University (The Fifth People\u2019s Hospital of Chongqing)  Chongqing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of General Surgery Renji Hospital, School of Medicine, Chongqing University (The Fifth People\u2019s Hospital of Chongqing)  Chongqing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiyi","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of General Surgery Renji Hospital, School of Medicine, Chongqing University (The Fifth People\u2019s Hospital of Chongqing)  Chongqing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziwei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery The First Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"e_1_2_13_2_1","first-page":"303","article-title":"Natural Chemicals, Synthetic Chemicals, Risk Assessment, and Cancer","volume":"21","author":"Ames B. 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