Department of Biochemistry, Faculty of Medicine & Dentistry, University of Alberta, 113 Street 87 Avenue, Edmonton, AB T6G 2E1, Canada.
Department of Medicine, Faculty of Medicine & Dentistry, University of Alberta, 113 Street 87 Avenue, Edmonton, AB T6G 2E1, Canada.
Int J Mol Sci. 2023 Mar 22;24(6):5967. doi: 10.3390/ijms24065967.
Persistent inflammation can trigger altered epigenetic, inflammatory, and bioenergetic states. Inflammatory bowel disease (IBD) is an idiopathic disease characterized by chronic inflammation of the gastrointestinal tract, with evidence of subsequent metabolic syndrome disorder. Studies have demonstrated that as many as 42% of patients with ulcerative colitis (UC) who are found to have high-grade dysplasia, either already had colorectal cancer (CRC) or develop it within a short time. The presence of low-grade dysplasia is also predictive of CRC. Many signaling pathways are shared among IBD and CRC, including cell survival, cell proliferation, angiogenesis, and inflammatory signaling pathways. Current IBD therapeutics target a small subset of molecular drivers of IBD, with many focused on the inflammatory aspect of the pathways. Thus, there is a great need to identify biomarkers of both IBD and CRC, that can be predictive of therapeutic efficacy, disease severity, and predisposition to CRC. In this study, we explored the changes in biomarkers specific for inflammatory, metabolic, and proliferative pathways, to help determine the relevance to both IBD and CRC. Our analysis demonstrated, for the first time in IBD, the loss of the tumor suppressor protein Ras associated family protein 1A (RASSF1A), via epigenetic changes, the hyperactivation of the obligate kinase of the NOD2 pathogen recognition receptor (receptor interacting protein kinase 2 [RIPK2]), the loss of activation of the metabolic kinase, AMP activated protein kinase (AMPKα1), and, lastly, the activation of the transcription factor and kinase Yes associated protein (YAP) kinase, that is involved in proliferation of cells. The expression and activation status of these four elements are mirrored in IBD, CRC, and IBD-CRC patients and, importantly, in matched blood and biopsy samples. The latter would suggest that biomarker analysis can be performed non-invasively, to understand IBD and CRC, without the need for invasive and costly endoscopic analysis. This study, for the first time, illustrates the need to understand IBD or CRC beyond an inflammatory perspective and the value of therapeutics directed to reset altered proliferative and metabolic states within the colon. The use of such therapeutics may truly drive patients into remission.
持续的炎症会引发表观遗传、炎症和生物能量状态的改变。炎症性肠病（IBD）是一种特发性疾病，其特征为胃肠道慢性炎症，随后出现代谢综合征紊乱的证据。研究表明，多达 42%的溃疡性结肠炎（UC）患者发现存在高级别异型增生，要么已经患有结直肠癌（CRC），要么在短时间内发展为 CRC。低级别异型增生的存在也预示着 CRC。IBD 和 CRC 之间存在许多共同的信号通路，包括细胞存活、细胞增殖、血管生成和炎症信号通路。目前的 IBD 治疗方法针对的是 IBD 的一小部分分子驱动因素，其中许多方法侧重于通路的炎症方面。因此，非常有必要识别 IBD 和 CRC 的生物标志物，这些生物标志物可以预测治疗效果、疾病严重程度和 CRC 的易感性。在这项研究中，我们探讨了炎症、代谢和增殖途径的特定生物标志物的变化，以帮助确定它们与 IBD 和 CRC 的相关性。我们的分析首次表明，在 IBD 中，肿瘤抑制蛋白 Ras 相关家族蛋白 1A（RASSF1A）通过表观遗传变化丢失，NOD2 病原体识别受体（受体相互作用蛋白激酶 2 [RIPK2]）的必需激酶过度激活，代谢激酶 AMP 激活蛋白激酶（AMPKα1）的激活丢失，最后，转录因子和激酶 Yes 相关蛋白（YAP）激酶的激活，该激酶参与细胞增殖。这四个元素的表达和激活状态在 IBD、CRC 和 IBD-CRC 患者中得到了反映，重要的是，在匹配的血液和活检样本中也得到了反映。后者表明，生物标志物分析可以非侵入性地进行，以了解 IBD 和 CRC，而无需进行侵入性和昂贵的内镜分析。这项研究首次表明，需要超越炎症的角度来理解 IBD 或 CRC，并且有价值的治疗方法可以针对结肠中改变的增殖和代谢状态进行重置。此类治疗方法的应用可能真正使患者缓解疾病。
