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Previous work has shown that the PIWI pathway is crucial for TE suppression in the germline. However, the status and function of this pathway is not well characterized in differentiated somatic cells and there is lack of consensus on the role of the pathway in somatic tumorigenesis. To shed light on this conundrum, we examined the PIWI pathway in colon cancer through combining bioinformatic analyses and cell-based assays. Shifted Weighted Annotation Network (SWAN) analysis revealed that the pathway experiences significant allelic losses in colon cancer and that PIWIL2, the main catalytic component of the pathway responsible for TE silencing, experiences the highest percent deletions. PIWIL2 is downregulated in colon tumors of advanced stage, nodal metastasis, and in certain subtypes, correlating with poor survival, while it is also downregulated in ulcerative colitis, an inflammatory bowel disease that predisposes to colon cancer. PIWIL2 depletion in colon epithelial Caco2 cells leads to increased anchorage-independent growth, loss of transposon-targeting - non-canonical - piRNAs, increased LINE-1 levels and activity, and in DNA damage, altogether highlighting a tumor-suppressing role of PIWIL2 in the colon.<\/jats:p>\n                <jats:sec>\n                  <jats:title>SUMMARY STATEMENT<\/jats:title>\n                  <jats:p>This study investigates the PIWI-piRNA pathway in colon cancer using a nuanced bioinformatic and cell-based approach, linking the downregulation of PIWIL2 to disease progression, transposable element activation and DNA damage.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.20.655197","type":"posted-content","created":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T10:15:12Z","timestamp":1748081712000},"source":"Crossref","is-referenced-by-count":0,"title":["PIWIL2 downregulation in colon cancer promotes transposon activity and pro-tumorigenic phenotypes"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4171-4320","authenticated-orcid":false,"given":"Alyssa","family":"Risner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce","family":"Nair-Menon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6701-0606","authenticated-orcid":false,"given":"Abhinav","family":"Cheedipudi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8978-5961","authenticated-orcid":false,"given":"Joe 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