Gomez Christian L, Neufeld Kristi L
Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA.
Exp Physiol. 2020 Dec;105(12):2154-2167. doi: 10.1113/EP088970. Epub 2020 Nov 4.
What is the central question of this study? What is the localization and distribution pattern of adenomatous polyposis coli (APC) in intestinal epithelial cells? Does this distribution change in different regions of the colon or in the condition of inflammation? What is the main finding and its importance? Colonic epithelia from mice and humans contain a subset of goblet cells displaying high APC levels. The number of APC goblet cells increases in inflamed tissue, which also displays increased GRP78, indicating potential stress from mucin production. In cultured human colon cells, expression of interleukin 1 pathway components (inducers of MUC2 expression) is reduced upon APC depletion raising the potential for APC participation in an inflammatory response.
Adenomatous polyposis coli (APC) serves as a gatekeeper of intestinal homeostasis by promoting cellular differentiation and maintaining crypt architecture. Although appreciated as a critical colon tumour suppressor, roles for APC in disease states such as inflammation have yet to be fully delineated. This study aimed to characterize the localization of APC protein in gastrointestinal tissues from human patients with active inflammatory bowel disease and mice with dextran sodium sulfate (DSS)-induced colitis. Fluorescence immunohistochemistry revealed a subset of goblet cells with elevated Apc staining intensity in the small intestines and proximal/medial colons of mice. Upon induction of colitis with DSS, these 'APC ' goblet cells remained in the proximal and medial colon, but now were also observed in the distal colon. This phenotype was recapitulated in humans, with APC goblet cells observed only in the descending colons of patients with active ulcerative colitis. In cultured human colon cells derived from normal tissue, APC depletion reduced expression of mRNAs encoding the interleukin 1 (IL1) signalling pathway components IL1β and interleukin-1 receptor (IL1R), known regulators of Muc2 expression. Treating cancer cells lacking wild-type APC with IL1β, or induction of full-length APC in these cells led to increases in IL1R and MUC2 expression. Combining IL1β treatment with APC induction led to an increase of MUC2 expression greater than expected for additive affects, suggesting that APC sensitizes cells to IL1 signalling. These findings suggest that APC has novel roles in maintaining proper goblet cell function, thus providing further evidence for APC as an important factor in intestinal tissue homeostasis and disease.
本研究的核心问题是什么？腺瘤性结肠息肉病蛋白（APC）在肠道上皮细胞中的定位和分布模式是怎样的？这种分布在结肠的不同区域或炎症状态下会发生变化吗？主要发现及其重要性是什么？来自小鼠和人类的结肠上皮含有一部分杯状细胞，其APC水平较高。在炎症组织中，APC杯状细胞的数量增加，同时GRP78也增加，这表明粘蛋白产生可能带来潜在压力。在培养的人结肠细胞中，APC缺失会降低白细胞介素1信号通路成分（MUC2表达的诱导剂）的表达，这增加了APC参与炎症反应的可能性。
腺瘤性结肠息肉病蛋白（APC）通过促进细胞分化和维持隐窝结构，充当肠道内环境稳定的守护者。尽管APC被视为一种关键的结肠肿瘤抑制因子，但其在炎症等疾病状态中的作用尚未完全阐明。本研究旨在描述APC蛋白在患有活动性炎症性肠病的人类患者和葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠的胃肠道组织中的定位。荧光免疫组织化学显示，在小鼠的小肠和近端/中段结肠中，有一部分杯状细胞的Apc染色强度升高。在用DSS诱导结肠炎后，这些“APC”杯状细胞仍存在于近端和中段结肠，但现在在远端结肠也能观察到。这种表型在人类中也得到了重现，在患有活动性溃疡性结肠炎的患者的降结肠中观察到了APC杯状细胞。在源自正常组织的培养人结肠细胞中，APC缺失会降低编码白细胞介素1（IL1）信号通路成分IL1β和白细胞介素-1受体（IL1R）的mRNA的表达，IL1β和IL1R是已知的Muc2表达调节因子。用IL1β处理缺乏野生型APC的癌细胞，或在这些细胞中诱导全长APC的表达，会导致IL1R和MUC2表达增加。将IL1β处理与APC诱导相结合，导致MUC2表达的增加大于预期的相加效应，这表明APC使细胞对IL1信号敏感。这些发现表明，APC在维持杯状细胞的正常功能方面具有新的作用，从而为APC作为肠道组织内环境稳定和疾病中的重要因素提供了进一步的证据。
