Zeineldin Maged, Larman Tatianna C
Department of Pathology, Division of Gastrointestinal/Liver Pathology, and Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
bioRxiv. 2023 Feb 3:2023.02.01.526729. doi: 10.1101/2023.02.01.526729.
Epithelial metaplasia is a common adaptation to chronic inflammatory processes and can be associated with increased risk of dysplasia and cancer. The distal colon of patients with inflammatory bowel disease (IBD) commonly shows crypt architectural distortion and Paneth cell metaplasia (PCM), and IBD patients also carry increased risk of colitis-associated dysplasia and cancer (CAC). Loss of SATB2 expression (Special AT-rich binding 2 protein, a colon-restricted chromatin remodeler) has recently been shown to distinguish colitis-associated dysplasia and CAC from sporadic disease. Here we report non-diffuse heterogeneous patterns of SATB2 loss across non-dysplastic distal colon biopsies from IBD patients (n=20). This cohort was specifically curated to include biopsies with well-developed histologic features of villiform growth and PCM. Notably, CDX2 was strongly expressed and P53 showed a wild-type immunolabeling pattern across our non-dysplastic cohort, regardless of SATB2 immunolabeling pattern. Our findings fit with recent murine studies in which colon-specific deletion resulted in histologic conversion of colonic mucosa to small intestinal-like mucosa, including emergence of villi and Paneth cells. Taken together, we show that SATB2 loss is associated with a pre-neoplastic metaplastic response to chronic injury in human IBD and chronic colitis, reframing PCM more broadly as small intestinal metaplasia. We propose that inflammation-associated SATB2 loss mediates a remodeled chromatin landscape permissive for dysplasia and CAC.
上皮化生是对慢性炎症过程的一种常见适应性变化，可能与发育异常和癌症风险增加有关。炎症性肠病（IBD）患者的远端结肠通常表现为隐窝结构扭曲和潘氏细胞化生（PCM），IBD患者患结肠炎相关发育异常和癌症（CAC）的风险也会增加。最近研究表明，SATB2表达缺失（特殊富含AT序列结合蛋白2，一种结肠特异性染色质重塑因子）可将结肠炎相关发育异常和CAC与散发性疾病区分开来。在此，我们报告了IBD患者（n = 20）非发育异常的远端结肠活检组织中SATB2缺失的非弥漫性异质性模式。该队列特意选取了具有典型绒毛状生长和PCM组织学特征的活检组织。值得注意的是，在我们的非发育异常队列中，无论SATB2免疫标记模式如何，CDX2均强烈表达，P53呈现野生型免疫标记模式。我们的研究结果与最近的小鼠研究结果相符，在这些研究中，结肠特异性缺失导致结肠黏膜组织学转变为小肠样黏膜，包括绒毛和潘氏细胞的出现。综上所述，我们表明SATB2缺失与人类IBD和慢性结肠炎中对慢性损伤的肿瘤前化生反应相关，将PCM更广泛地重新定义为小肠化生。我们提出，炎症相关的SATB2缺失介导了一种允许发育异常和CAC发生的染色质重塑景观。
