{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:08:53Z","timestamp":1769558933271,"version":"3.49.0"},"reference-count":21,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":15,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"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 Reports"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chemotherapy resistance in colorectal cancer (CRC) is often mediated by enhanced DNA damage repair (DDR). Transmembrane protein TMEM59L is implicated in cancer progression, but its role in CRC chemoresistance is unclear. We investigated whether TMEM59L regulates 5\u2010fluorouracil (5\u2010FU) sensitivity through PTPRN\u2010mediated DDR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>This study aimed to investigate the role of TMEM59L in regulating PTPRN\u2010mediated DNA damage repair and its impact on 5\u2010FU sensitivity in colorectal cancer, with the goal of identifying potential therapeutic targets to overcome chemoresistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p>Bioinformatics analyses assessed TMEM59L\/PTPRN expression and prognosis in CRC cohorts. Gain\u2010 and loss\u2010of\u2010function experiments were conducted in CRC cell lines (HCT116, SW480) and their 5\u2010FU\u2010resistant derivatives. Cell proliferation, migration, invasion, apoptosis, DNA damage, and reactive oxygen species (ROS) were measured. Protein interactions were examined by Western blot and immunofluorescence. A xenograft model in nude mice validated the TMEM59L\/PTPRN axis on tumor growth, stemness, and EMT markers. TMEM59L expression was elevated in metastatic lesions and associated with poor CRC patient survival. Functionally, TMEM59L promoted malignant behaviors and epithelial\u2013mesenchymal transition. It was upregulated in 5\u2010FU\u2010resistant cells and non\u2010responsive patients. TMEM59L knockdown sensitized cells to 5\u2010FU, increasing ROS, DNA damage, and apoptosis, while its overexpression induced resistance. Mechanistically, TMEM59L regulated 5\u2010FU\u2010induced DNA damage and ROS through PTPRN. PTPRN overexpression reversed the sensitization caused by TMEM59L silencing. In\u00a0vivo, TMEM59L knockdown enhanced 5\u2010FU's antitumor effect, which was counteracted by PTPRN overexpression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The TMEM59L\/PTPRN axis is a key regulator of DDR and 5\u2010FU resistance in CRC. TMEM59L promotes chemoresistance via PTPRN by enhancing DNA repair and reducing ROS\u2010mediated apoptosis. Targeting this pathway may offer a novel strategy to overcome 5\u2010FU resistance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cnr2.70448","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:40:31Z","timestamp":1768567231000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transmembrane Protein\n                    <scp>TMEM59L<\/scp>\n                    Modulates 5\u2010\n                    <scp>FU<\/scp>\n                    Resistance via\n                    <scp>PTPRN<\/scp>\n                    \u2010Mediated\n                    <scp>DNA<\/scp>\n                    Damage Repair in Colorectal Cancer"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1282-5142","authenticated-orcid":false,"given":"Wenzhi","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery Pudong Hospital Affiliated to Fudan University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of General Surgery The People's Hospital of Wuhai Inner Mongolia  Wuhai Inner Mongolia China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zenghui","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Children's Hospital of Fudan University, National Children's Medical Center  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhua","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of General Surgery The People's Hospital of Wuhai Inner Mongolia  Wuhai Inner Mongolia China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fenming","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of General Surgery The People's Hospital of Wuhai Inner Mongolia  Wuhai Inner Mongolia China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiqing","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of General Surgery The People's Hospital of Wuhai Inner Mongolia  Wuhai Inner Mongolia China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of General Surgery The People's Hospital of Wuhai Inner Mongolia  Wuhai Inner Mongolia China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9851-0436","authenticated-orcid":false,"given":"Xiaoliang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery Pudong Hospital Affiliated to Fudan University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of General Surgery The People's Hospital of Wuhai Inner Mongolia  Wuhai Inner Mongolia China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1155\/2023\/8881715"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/cbdd.13947"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2023.5296"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2023.115741"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1054157"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/jrr\/rrad053"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1155\/2023\/9942663"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.667884"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci12060763"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.676287"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.2337\/db20-1206"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111233"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2019.100645"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.13224"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2021.100770"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.03.076"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-016-9997-9"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.19048"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/mc.22526"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.622018"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-017-0089-8"}],"container-title":["Cancer 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