{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T07:21:32Z","timestamp":1787728892950,"version":"build-2784847793"},"reference-count":44,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82073946"],"award-info":[{"award-number":["82073946"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82471715"],"award-info":[{"award-number":["82471715"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Renal cell carcinoma (RCC) is known as one of the three major malignant tumors of the urinary system, and clear\u2010cell RCC (ccRCC) is the most frequent and aggressive pathological subtype and is correlated with high mortality. Despite diverse treatments, the clinical prognosis of patients with RCC remains poor. Therefore, further characterization of the mechanisms underlying ccRCC progression is urgently required.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Different RCC celllines were used to study cell malignancies in vitro and to elucidate mechanisms. Nude mice were used for validating results in vivo. Sequencing, database and bioinformatic analysis were applied for screening candidate genes and signalings. Clinical samples were used to verify the expression pattern of key genes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      ETS1 expression is significantly higher in clinical ccRCC tissue samples, and consistent withthese findings, ETS1 overexpression increases RCC cell malignancies in cultured cell models in vitro as well as tumor growth in nude mice in vivo. Mechanistically, ETS1 binds to EGR2 and destabilizes the EGR2 protein, and the decreased EGR2 levels mitigate its inhibitory effect on NOTCH signaling through\n                      <jats:italic>RBP\u2010J<\/jats:italic>\n                      , resulting in activation of the NOTCH signaling pathway, ultimately leading to RCC development.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Therefore, targeting the ETS1\u2012EGR2\u2012NOTCH signaling axis may be a promising therapeutic strategy for ccRCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>ETS1 expression is significantly higher in ccRCC samples, and ETS1\u2010overexpression increases RCC cell malignancies in vitro and tumour growth in nude mice.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>ETS1 binds to EGR2 and destabilises EGR2 protein, which relieves EGR2's inhibitory effect on NOTCH signalling.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>NOTCH signalling activation promotes RCC development.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The ETS1\u2012EGR2\u2012NOTCH axis would potentially be a promising therapeutic strategy in ccRCC.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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