Nterma Pinelopi, Panopoulou Eleni, Papadaki-Petrou Eleni, Assimakopoulou Martha
Department of Anatomy, Histology and Embryology, School of Medicine, University of Patras, Biomedical Sciences Research Building, 1 Asklipiou, Gr-26504, Rion, Greece.
Department of Pathology, General Hospital Agios Andreas, Patras, Greece.
Pathol Oncol Res. 2020 Jan;26(1):567-574. doi: 10.1007/s12253-018-00575-z. Epub 2019 Jan 2.
The intestinal neoplastic transformation is a possible risk of chronic inflammatory bowel disease (IBD). Previous evidence in mice IBD provides a role for the RAS-association domain family tumor suppressor protein 1 A (RASSF1A), in the repairing process following mucosa epithelium damage, through cooperation with the HIPPO-signaling molecules p73, and YAP. HIPPO pathway which has been implicated in stem cell activity includes as key components for signal transduction the large tumor suppressor homology Ser/Thr kinases LATS1/2. The aim of this study was to assess immunohistochemically, using specific antibodies, the RASSF1A and LATS1/2 expression patterns in a cohort of patients with IBD including 52 ulcerative colitis (UC), 24 Crohn's disease (CD) and 24 IBD unclassified (IBD-U), compared with normal intestine from non-IBD patients (control group). The relationship between subtypes of IBD and RASSF1A and LATS1/2 expression, both individually and related to p73 and YAP/pYAP(Ser127) proteins was also investigated. Quantitative analyses of the immunohistochemical findings in mucosa cells revealed a significantly decreased expression in UC and IBD-U for RASSF1A expression and a significantly elevated expression in UC, IBD-U, and CD for LATS1/2 expression compared with normal mucosa (P < 0.05). However, ROC curve analysis showed that only LATS1/2 could differentiate IBD from control group. RASSF1A expression was significantly correlated with LATS1/2 in UC with dysplasia (P < 0.0001), and p73 in UC (P < 0.001), and IBD-U (P < 0.02). The expression of all proteins did not differ significantly between subtypes of IBD (P ≥ 0.05). RASSF1A-LATS1/2 co-expression was mainly observed in IBD samples. These findings suggest that tumor suppression proteins RASSF1A and LATS1/2 may be involved in the pathogenesis of human IBD and imply a potential cooperation of RASSF1A, and HIPPO signaling pathways in human bowel inflammation.
肠道肿瘤转化是慢性炎症性肠病（IBD）的一种潜在风险。先前在小鼠IBD中的证据表明，RAS关联结构域家族肿瘤抑制蛋白1A（RASSF1A）通过与HIPPO信号分子p73和YAP合作，在黏膜上皮损伤后的修复过程中发挥作用。涉及干细胞活性的HIPPO通路包括大肿瘤抑制同源性丝氨酸/苏氨酸激酶LATS1/2作为信号转导的关键成分。本研究的目的是使用特异性抗体，通过免疫组织化学评估一组IBD患者（包括52例溃疡性结肠炎（UC）、24例克罗恩病（CD）和24例未分类IBD（IBD-U））中RASSF1A和LATS1/2的表达模式，并与非IBD患者的正常肠道组织（对照组）进行比较。还研究了IBD亚型与RASSF1A和LATS1/2表达之间的关系，包括单独的关系以及与p73和YAP/pYAP（Ser127）蛋白的关系。对黏膜细胞免疫组织化学结果的定量分析显示，与正常黏膜相比，UC和IBD-U中RASSF1A表达显著降低，UC、IBD-U和CD中LATS1/2表达显著升高（P < 0.05）。然而，ROC曲线分析表明，只有LATS1/2能够区分IBD与对照组。在有发育异常的UC中，RASSF1A表达与LATS1/2显著相关（P < 0.0001），在UC（P < 0.001）和IBD-U（P < 0.02）中与p73显著相关。IBD各亚型之间所有蛋白的表达无显著差异（P≥0.05）。RASSF1A-LATS1/2共表达主要在IBD样本中观察到。这些发现表明，肿瘤抑制蛋白RASSF1A和LATS
