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We validated the reduction of <jats:italic>LHFPL3-AS2<\/jats:italic> in adult CD and noted a further reduction in patients with more severe CD from the RISK cohort. <jats:italic>LHFPL3-AS2<\/jats:italic> knockdown in Caco-2 cells robustly affected epithelial monolayer morphogenesis with markedly reduced confluency and spreading, showing atypical rounding, and clumping. mRNA-seq analysis of <jats:italic>LHFPL3-AS2<\/jats:italic> knockdown cells highlighted the reduction of genes and pathways linked with apical polarity, actin bundles, morphogenesis, and the b-catenin-TCF4 complex. <jats:italic>LHFPL3-AS2<\/jats:italic> knockdown significantly reduced the ability of cells to form an internal lumen within the 3-dimensional (3D) cyst model, with mislocalization of actin and adherent and tight junction proteins, affecting epithelial polarity. <jats:italic>LHFPL3-AS2<\/jats:italic> knockdown also resulted in defective mitotic spindle formation and consequent reduction in epithelial proliferation. Altogether, we show that <jats:italic>LHFPL3-AS2<\/jats:italic> reduction affects epithelial morphogenesis, polarity, mitotic spindle formation, and proliferation, which are key processes in maintaining epithelial homeostasis in CD. Reduced expression of <jats:italic>LHFPL3-AS2<\/jats:italic> in CD patients and its further reduction with ileal ulceration outcome, emphasizes its significance in this context.<\/jats:p>","DOI":"10.1038\/s41598-023-47997-7","type":"journal-article","created":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T17:02:08Z","timestamp":1700672528000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Reduced LHFPL3-AS2 lncRNA expression is linked to altered epithelial polarity and proliferation, and to ileal ulceration in Crohn disease"],"prefix":"10.1038","volume":"13","author":[{"given":"Katya E.","family":"Sosnovski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzipi","family":"Braun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amnon","family":"Amir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"BenShoshan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haya","family":"Abbas-Egbariya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakefet","family":"Ben-Yishay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liat","family":"Anafi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Avivi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Barshack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee A.","family":"Denson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yael","family":"Haberman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,22]]},"reference":[{"key":"47997_CR1","doi-asserted-by":"publisher","first-page":"218","DOI":"10.2307\/25470665","volume":"214","author":"CR Magie","year":"2008","unstructured":"Magie, C. 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