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Abstract：
BACKGROUND: Cronkhite-Canada syndrome (CCS) is a rare, nonhereditary disease characterized by diffuse gastrointestinal polyposis and ectodermal abnormalities. Although it has been proposed to be a chronic inflammatory condition, direct evidence of its pathogenesis is lacking. This study aims to investigate the pathophysiology of CCS by analyzing transcriptomic changes in the colonic microenvironment.
METHODS: Next-generation sequencing-based genome-wide transcriptional profiling was performed on colonic hamartomatous polyps from four CCS patients and normal colonic mucosa from four healthy volunteers. Analyses of differential expression and multiple enrichment analyses were conducted from the molecular level to the cellular level. Quantitative real-time PCR (qRT-PCR) was carried out to validate the sequencing accuracy in samples from six CCS patients and six healthy volunteers.
RESULTS: A total of 543 differentially expressed genes were identified, including an abundance of CC- and CXC-chemokines. Innate immune response-related pathways and processes, such as leukocyte chemotaxis, cytokine production, IL-17, TNF, IL-1 and NF-kB signaling pathways, were prominently enhanced in CCS colonic polyps. Upregulation of wound healing, epithelial-mesenchymal transition, Wnt, and PI3K-Akt signaling pathways were also observed. Enrichment analyses at different levels identified extracellular structure disorganization, dysfunction of the gut mucosal barrier, and increased angiogenesis. Validation by qRT-PCR confirmed increased expression of the LCN2, IL1B, CXCL1, and CXCL3 genes in CCS colonic polyps.
CONCLUSIONS: This case-control whole transcriptome analysis of active CCS colonic hamartomatous polyps revealed intricate molecular pathways, emphasizing the role of the innate immune response, extracellular matrix disorganization, inflammatory cell infiltration, increased angiogenesis, and potential epithelial to mesenchymal transition. These findings supports CCS as a chronic inflammatory condition and sheds light on potential therapeutic targets, paving the way for more effective and personalized management of CCS in the future.
METHODS: Next-generation sequencing-based genome-wide transcriptional profiling was performed on colonic hamartomatous polyps from four CCS patients and normal colonic mucosa from four healthy volunteers. Analyses of differential expression and multiple enrichment analyses were conducted from the molecular level to the cellular level. Quantitative real-time PCR (qRT-PCR) was carried out to validate the sequencing accuracy in samples from six CCS patients and six healthy volunteers.
RESULTS: A total of 543 differentially expressed genes were identified, including an abundance of CC- and CXC-chemokines. Innate immune response-related pathways and processes, such as leukocyte chemotaxis, cytokine production, IL-17, TNF, IL-1 and NF-kB signaling pathways, were prominently enhanced in CCS colonic polyps. Upregulation of wound healing, epithelial-mesenchymal transition, Wnt, and PI3K-Akt signaling pathways were also observed. Enrichment analyses at different levels identified extracellular structure disorganization, dysfunction of the gut mucosal barrier, and increased angiogenesis. Validation by qRT-PCR confirmed increased expression of the LCN2, IL1B, CXCL1, and CXCL3 genes in CCS colonic polyps.
CONCLUSIONS: This case-control whole transcriptome analysis of active CCS colonic hamartomatous polyps revealed intricate molecular pathways, emphasizing the role of the innate immune response, extracellular matrix disorganization, inflammatory cell infiltration, increased angiogenesis, and potential epithelial to mesenchymal transition. These findings supports CCS as a chronic inflammatory condition and sheds light on potential therapeutic targets, paving the way for more effective and personalized management of CCS in the future.
摘要：
背景：Cronkhite-Canada综合征（CCS）是一种罕见的，以弥漫性胃肠息肉病和外胚层异常为特征的非遗传性疾病。虽然它被认为是一种慢性炎症，其发病机制缺乏直接证据。本研究旨在通过分析结肠微环境中的转录组变化来研究CCS的病理生理学。
方法：对4名CCS患者的结肠错构瘤息肉和4名健康志愿者的正常结肠粘膜进行了基于下一代测序的全基因组转录分析。从分子水平到细胞水平进行差异表达分析和多重富集分析。进行定量实时PCR(qRT-PCR)以验证来自6名CCS患者和6名健康志愿者的样品中的测序准确性。
结果：共鉴定出543个差异表达基因，包括丰富的CC-和CXC-趋化因子。先天免疫反应相关的途径和过程，如白细胞趋化性，细胞因子产生，IL-17,TNF,IL-1和NF-kB信号通路,在CCS结肠息肉中显著增强。伤口愈合的上调，上皮-间质转化，Wnt,和PI3K-Akt信号通路也被观察到。不同水平的富集分析确定了细胞外结构的解体，肠粘膜屏障功能障碍，增加血管生成。通过qRT-PCR验证证实LCN2、IL1B、CCS结肠息肉中的CXCL1和CXCL3基因。
结论：对活跃的CCS结肠错构瘤息肉的病例对照全转录组分析揭示了复杂的分子途径，强调先天免疫反应的作用，细胞外基质解体，炎性细胞浸润，血管生成增加，和潜在的上皮向间充质转化。这些发现支持CCS作为一种慢性炎症性疾病，并揭示了潜在的治疗靶点。为未来更有效和个性化的CCS管理铺平了道路。
方法：对4名CCS患者的结肠错构瘤息肉和4名健康志愿者的正常结肠粘膜进行了基于下一代测序的全基因组转录分析。从分子水平到细胞水平进行差异表达分析和多重富集分析。进行定量实时PCR(qRT-PCR)以验证来自6名CCS患者和6名健康志愿者的样品中的测序准确性。
结果：共鉴定出543个差异表达基因，包括丰富的CC-和CXC-趋化因子。先天免疫反应相关的途径和过程，如白细胞趋化性，细胞因子产生，IL-17,TNF,IL-1和NF-kB信号通路,在CCS结肠息肉中显著增强。伤口愈合的上调，上皮-间质转化，Wnt,和PI3K-Akt信号通路也被观察到。不同水平的富集分析确定了细胞外结构的解体，肠粘膜屏障功能障碍，增加血管生成。通过qRT-PCR验证证实LCN2、IL1B、CCS结肠息肉中的CXCL1和CXCL3基因。
结论：对活跃的CCS结肠错构瘤息肉的病例对照全转录组分析揭示了复杂的分子途径，强调先天免疫反应的作用，细胞外基质解体，炎性细胞浸润，血管生成增加，和潜在的上皮向间充质转化。这些发现支持CCS作为一种慢性炎症性疾病，并揭示了潜在的治疗靶点。为未来更有效和个性化的CCS管理铺平了道路。
