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The miR-424(322)\n                    <jats:sup>~<\/jats:sup>\n                    503 cluster, comprising miR-424 and miR-503, has been implicated in various malignancies, exhibiting dual roles as tumor suppressors or oncogenes depending on the context. However, its function in CRC remains poorly understood. This study investigates the role of the miR-424(322)\n                    <jats:sup>~<\/jats:sup>\n                    503 cluster in CRC driven by PTEN deficiency using genetically modified mouse models. Our findings reveal that the loss of miR-424(322)\n                    <jats:sup>~<\/jats:sup>\n                    503 significantly exacerbates CRC progression in PTEN-deficient mice. Double knockout (dKO) mice lacking both PTEN and miR-424(322)\n                    <jats:sup>~<\/jats:sup>\n                    503 exhibited a higher number and larger size of colorectal lesions compared to PTEN-deficient counterparts. Histological analysis demonstrated increased severity of dysplasia and adenocarcinoma development in dKO mice. Mechanistically, while Wnt\/\u03b2-catenin signaling remained unaltered, transcriptomic analyses highlighted dysregulation of MAPK and TGF\u03b2 pathways, alongside epithelial-to-mesenchymal transition (EMT)-related gene signatures. Protein-level validation confirmed hyperactivation of MAPK (ERK1\/2 and p38) and TGF\u03b2 signaling, as well as elevated cyclin D1 expression in dKO colonic tissues. These results underscore the tumor-suppressive role of the miR-424(322)\n                    <jats:sup>~<\/jats:sup>\n                    503 cluster in CRC by modulating key oncogenic pathways such as MAPK and TGF\u03b2. Our study provides novel insights into the interplay between PTEN loss and miRNA regulation in CRC pathogenesis.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-08504-8","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T01:13:03Z","timestamp":1771895583000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["miR-424(322)~503 impairs colon cancer progression driven by PTEN deficiency"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4154-6061","authenticated-orcid":false,"given":"Maria","family":"Vidal-Saban\u00e9s","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00faria","family":"Bonifaci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1622-5311","authenticated-orcid":false,"given":"Ra\u00fal","family":"Navaridas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaquim","family":"EGEA","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Encinas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4925-8865","authenticated-orcid":false,"given":"Ruth","family":"Rodriguez-Barrueco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose M.","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Matias-Guiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Tarragona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1443-7003","authenticated-orcid":false,"given":"David","family":"Llobet-Navas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1921-0449","authenticated-orcid":false,"given":"Xavier","family":"Dolcet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,24]]},"reference":[{"key":"8504_CR1","first-page":"229","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. 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All authors of this manuscript have participated in the execution and analysis of the study, are aware of and agree to the content of the manuscript. They have approved the final version submitted, being listed as authors on the manuscript. The contents of this manuscript have not been copyrighted or published previously. There are no directly related manuscripts or abstracts, published or unpublished, by one or more authors of this manuscript. The contents of this manuscript are not under consideration for publication elsewhere. The submitted manuscript or any similar script, in whole or in part, will not be copyrighted, submitted, or published elsewhere while it is under consideration.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"254"}}