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LHFPL3-AS2 lncRNA 表达降低与克罗恩病中肠上皮细胞极性和增殖改变以及回肠溃疡有关。

Reduced LHFPL3-AS2 lncRNA expression is linked to altered epithelial polarity and proliferation, and to ileal ulceration in Crohn disease.

机构信息

Sheba Medical Center, Tel-Hashomer, Affiliated with the Tel Aviv University, Tel Aviv, Israel.

Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

出版信息

Sci Rep. 2023 Nov 22;13(1):20513. doi: 10.1038/s41598-023-47997-7.

DOI:10.1038/s41598-023-47997-7
PMID:37993670
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10665440/
Abstract

Disruption of intestinal epithelial functions is linked to Crohn disease (CD) pathogenesis. We identified a widespread reduction in the expression of long non-coding RNAs (lncRNAs) including LHFPL3-AS2 in the treatment-naïve CD ileum of the RISK pediatric cohort. We validated the reduction of LHFPL3-AS2 in adult CD and noted a further reduction in patients with more severe CD from the RISK cohort. LHFPL3-AS2 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 LHFPL3-AS2 knockdown cells highlighted the reduction of genes and pathways linked with apical polarity, actin bundles, morphogenesis, and the b-catenin-TCF4 complex. LHFPL3-AS2 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. LHFPL3-AS2 knockdown also resulted in defective mitotic spindle formation and consequent reduction in epithelial proliferation. Altogether, we show that LHFPL3-AS2 reduction affects epithelial morphogenesis, polarity, mitotic spindle formation, and proliferation, which are key processes in maintaining epithelial homeostasis in CD. Reduced expression of LHFPL3-AS2 in CD patients and its further reduction with ileal ulceration outcome, emphasizes its significance in this context.

摘要

肠道上皮功能障碍与克罗恩病（CD）的发病机制有关。我们在 RISK 儿科队列未经治疗的 CD 回肠中发现大量长非编码 RNA（lncRNA）包括 LHFPL3-AS2 的表达减少。我们验证了成人 CD 中 LHFPL3-AS2 的减少，并注意到来自 RISK 队列的更严重 CD 患者的减少进一步增加。LHFPL3-AS2 在 Caco-2 细胞中的敲低显著影响上皮单层形态发生，导致细胞融合和扩散明显减少，细胞呈现非典型圆形和聚集。LHFPL3-AS2 敲低细胞的 mRNA-seq 分析突出了与顶极极性、肌动蛋白束、形态发生和 b-catenin-TCF4 复合物相关的基因和途径的减少。LHFPL3-AS2 敲低显著降低了细胞在 3 维（3D）囊肿模型中形成内部腔的能力，导致肌动蛋白和黏附及紧密连接蛋白定位错误，影响上皮极性。LHFPL3-AS2 敲低还导致有丝分裂纺锤体形成缺陷，进而导致上皮增殖减少。总的来说，我们表明 LHFPL3-AS2 的减少会影响上皮形态发生、极性、有丝分裂纺锤体形成和增殖，这是维持 CD 上皮细胞内稳态的关键过程。CD 患者中 LHFPL3-AS2 表达减少及其在回肠溃疡结局中的进一步减少，强调了其在这种情况下的重要性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b272/10665440/c50096beca00/41598_2023_47997_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b272/10665440/cb5e8c560875/41598_2023_47997_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b272/10665440/721d8c1c3053/41598_2023_47997_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b272/10665440/d14645ddf6b4/41598_2023_47997_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b272/10665440/aa6dafb11ff6/41598_2023_47997_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b272/10665440/c50096beca00/41598_2023_47997_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b272/10665440/cb5e8c560875/41598_2023_47997_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b272/10665440/721d8c1c3053/41598_2023_47997_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b272/10665440/d14645ddf6b4/41598_2023_47997_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b272/10665440/aa6dafb11ff6/41598_2023_47997_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b272/10665440/c50096beca00/41598_2023_47997_Fig5_HTML.jpg

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