疾病和物种差异对肠道CLCA4基因表达的影响

IF 4.8 3区 医学 Q1 GENETICS & HEREDITY
K Teske, N A Erickson, A Huck, M Dzamukova, M Fulde, T Heinbokel, D Horst, N Klymiuk, E Pastille, A Mekes-Adamczyk, M Löhning, A D Gruber, R Glauben, L Mundhenk
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引用次数: 0

摘要

人类氯离子通道调节剂钙活化(CLCA) 4作为上皮细胞向间质转化的驱动因素以及结直肠癌(CRC)和溃疡性结肠炎的生物标志物进行了讨论。与人类不同的是,Clca4基因在小鼠中是复制的,而小鼠是研究基因功能的常用模型物种。然而,功能性小鼠Clca4变异在健康和患病肠道中的相关性在很大程度上是未知的。本研究采用RT-qPCR和原位杂交技术,对小鼠Clca4a和Clca4b基因在健康肠道以及葡聚糖硫酸钠(DSS)诱导的结肠炎和结肠炎相关结肠癌(CAC)小鼠模型中的时空表达模式进行了表征。同样,我们在单细胞水平上分析了人类CLCA4在健康、炎症和癌变肠道中的表达。小鼠的小肠上皮细胞中检测到Clca4a和-4b,而人的未检测到CLCA4。相反,健康的结肠细胞表达人CLCA4及其小鼠同源Clca4a,但不表达小鼠Clca4b。在炎症条件下,观察到Clca4b的新生表达,两种小鼠同源物在溃疡附近的肠细胞中大量表达。在人和小鼠中,肿瘤结肠细胞不表达或仅表达极少量的CLCA4同源物,而邻近的非肿瘤结肠细胞分别强烈上调人类或小鼠的同源物。我们的研究结果表明,三种CLCA4同源物的表达模式存在明显的物种特异性和同源特异性差异。此外,这三种细胞似乎在溃疡和肿瘤病变附近的反应性、非肿瘤性结肠炎细胞中发挥作用。关键信息:人类CLCA4和小鼠Clca4a,而不是Clca4b,在健康的结肠细胞中表达。炎症导致小鼠结肠细胞中Clca4b的从头表达。人和小鼠的肿瘤肠细胞中没有CLCA4同源物。人和小鼠的CLCA4s在肿瘤邻近的活性结肠炎细胞中高度表达。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The impact of disease and species differences on the intestinal CLCA4 gene expression.

The human chloride channel regulator, calcium-activated (CLCA) 4 is discussed as a driver of epithelial-to-mesenchymal transition as well as a biomarker for colorectal cancer (CRC) and ulcerative colitis. In contrast to humans, the Clca4 gene is duplicated in the mouse, a common model species to study gene functions. However, the relevance of the functional murine Clca4 variants in healthy and diseased intestine is largely unknown. Here, we characterized the spatiotemporal expression patterns of the murine Clca4a and Clca4b genes in the healthy intestinal tract as well as in dextran sulfate sodium (DSS)-induced colitis and colitis-associated colon cancer (CAC) mouse model using RT-qPCR and in situ-hybridization. Similarly, we analyzed expression of the human CLCA4 in healthy, inflamed and cancerous intestinal tracts at single cell level. Murine Clca4a and -4b but not the human CLCA4 were detected in small intestine enterocytes of the respective species. Conversely, healthy colonocytes expressed the human CLCA4 and its murine ortholog Clca4a but not the murine Clca4b. Under inflammatory conditions, de novo expression of Clca4b was observed with both murine homologs abundantly expressed in enterocytes adjacent to ulcerations. Neoplastic colonocytes expressed none or only minimal amounts of the CLCA4 homologs both in humans and mice, whereas adjacent non-neoplastic colonocytes strongly up-regulated the human or both murine homologs, respectively. Our results suggest marked species- and homolog-specific differences in the expression patterns of the three CLCA4 homologs. Moreover, all three seem to play a role in reactive, non-neoplastic colonocytes adjacent to ulcerated and neoplastic lesions. KEY MESSAGES: Human CLCA4 and murine Clca4a, but not Clca4b, are expressed in healthy colonocytes. Inflammation leads to a de novo expression of the murine Clca4b in colonocytes. Human and murine CLCA4 homologs are absent from neoplastic enterocytes. Human and murine CLCA4s are highly expressed in tumor-adjacent, reactive colonocytes.

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来源期刊
Journal of Molecular Medicine-Jmm
Journal of Molecular Medicine-Jmm 医学-医学:研究与实验
CiteScore
9.30
自引率
0.00%
发文量
100
审稿时长
1.3 months
期刊介绍: The Journal of Molecular Medicine publishes original research articles and review articles that range from basic findings in mechanisms of disease pathogenesis to therapy. The focus includes all human diseases, including but not limited to: Aging, angiogenesis, autoimmune diseases as well as other inflammatory diseases, cancer, cardiovascular diseases, development and differentiation, endocrinology, gastrointestinal diseases and hepatology, genetics and epigenetics, hematology, hypoxia research, immunology, infectious diseases, metabolic disorders, neuroscience of diseases, -omics based disease research, regenerative medicine, and stem cell research. Studies solely based on cell lines will not be considered. Studies that are based on model organisms will be considered as long as they are directly relevant to human disease.
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