Retrotransposition of long interspersed nucleotide element-1 is associated with colitis but not tumors in a murine colitic cancer model.
Retrotransposition of long interspersed nucleotide element-1 is associated with colitis but not tumors in a murine colitic cancer model.
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DOI：
10.1371/journal.pone.0116072
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Kawamura YI
中科院分区：
文献类型：
--
作者：
Otsubo T;Okamura T;Hagiwara T;Ishizaka Y;Dohi T;Kawamura YI
长散布元件-1（L1）是一种可以在基因组内移动的转座元件，可能导致基因组多样性和基因功能的改变。尽管体细胞中的L1活性通常通过DNA甲基化被抑制，但一些L1在包括结直肠癌在内的肿瘤中被激活。然而，如何L1-逆转录转座（L1-RTP）参与胃肠道疾病仍有待阐明。我们假设体细胞中的L1-RTP可能有助于结肠炎相关癌症（CAC）。为了解决这个问题，我们采用了CAC的实验模型，使用转基因L1-报告小鼠携带人类L1-EGFP报告基因。通过注射致癌物氧化偶氮甲烷（AOM），在饮用水中给予葡聚糖硫酸钠（DSS）诱导小鼠结肠炎的重复循环。L1-RTP水平通过定量聚合酶链反应在各种组织和细胞类型中靶向新插入的报告基因EGFP来测量，包括通过激光显微切割和流式细胞术细胞分选获得的样品。通过亚硫酸氢盐焦磷酸测序分析人L1启动子的DNA甲基化水平。AOM+ DSS处理的小鼠在结肠炎急性期的整个结肠组织中表现出显著更高水平的L1-RTP，与对照组相比。整个结肠组织中的L1-RTP水平与结肠炎的组织学严重程度和中性粒细胞浸润到固有层（LP）的程度呈正相关，但与结肠中的肿瘤发展无关。L1-RTP富含LP间充质细胞，而不是上皮细胞（EC），髓样细胞或淋巴样细胞。人L1启动子区DNA甲基化水平与L1-RTP水平呈负相关。在22周龄小鼠中发现的大多数肿瘤中不存在L1-RTP。总之，我们证明，L1-RTP诱导小鼠CAC粘膜根据急性炎症反应，然而，逆转录转座似乎没有直接相关性结肠炎诱导的癌症的启动。
Long interspersed element-1 (L1) is a transposable element that can move within the genome, potentially leading to genome diversity and modified gene function. Although L1 activity in somatic cells is normally suppressed through DNA methylation, some L1s are activated in tumors including colorectal carcinoma. However, how L1-retrotransposition (L1-RTP) is involved in gastrointestinal disorders remains to be elucidated. We hypothesized that L1-RTP in somatic cells might contribute to colitis-associated cancer (CAC). To address this, we employed an experimental model of CAC using transgenic L1-reporter mice carrying a human L1-EGFP reporter gene. Mice were subjected to repeated cycles of colitis induced by administration of dextran sodium sulfate (DSS) in drinking water with injection of carcinogen azoxymethane (AOM). L1-RTP levels were measured by a quantitative polymerase chain reaction targeting the newly inserted reporter EGFP in various tissues and cell types, including samples obtained by laser microdissection and cell sorting with flow cytometry. DNA methylation levels of the human L1 promoter were analyzed by bisulfite pyrosequencing. AOM+DSS-treated mice exhibited significantly higher levels of L1-RTP in whole colon tissue during the acute phase of colitis when compared with control naïve mice. L1-RTP levels in whole colon tissue were positively correlated with the histological severity of colitis and degree of neutrophil infiltration into the lamina propria (LP), but not with tumor development in the colon. L1-RTP was enriched in LP mesenchymal cells rather than epithelial cells (ECs), myeloid, or lymphoid cells. DNA methylation levels of the human L1 promoter region showed a negative correlation with L1-RTP levels. L1-RTP was absent from most tumors found in 22-week-old mice. In conclusion, we demonstrated that L1-RTP was induced in the mouse CAC mucosa in accordance with the acute inflammatory response; however, retrotransposition appears not to have direct relevance to colitis-induced cancer initiation.
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影响因子：
64.5
作者：
Shukla R;Upton KR;Muñoz-Lopez M;Gerhardt DJ;Fisher ME;Nguyen T;Brennan PM;Baillie JK;Collino A;Ghisletti S;Sinha S;Iannelli F;Radaelli E;Dos Santos A;Rapoud D;Guettier C;Samuel D;Natoli G;Carninci P;Ciccarelli FD;Garcia-Perez JL;Faivre J;Faulkner GJ
通讯作者：
Faulkner GJ
影响因子：
3.5
作者：
Nakkuntod, Jeerawat;Sukkapan, Pattadon;Hirankarn, Nattiya
通讯作者：
Hirankarn, Nattiya
影响因子：
64.5
作者：
Symer, DE;Connelly, C;Boeke, JD
通讯作者：
Boeke, JD
影响因子：
64.5
作者：
Gilbert, N;Lutz-Prigge, S;Moran, JV
通讯作者：
Moran, JV
影响因子：
50.3
作者：
Bollrath, Julia;Phesse, Toby J.;Greten, Florian R.
通讯作者：
Greten, Florian R.