Bjerrum Jacob T, Nielsen Ole H, Riis Lene B, Pittet Valerie, Mueller Christoph, Rogler Gerhard, Olsen Jørgen
*Department of Cellular and Molecular Medicine, the Panum Institute, University of Copenhagen, Copenhagen, Denmark; †Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark; ‡Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark; §Health Care Evaluation Unit, Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; ‖Division of Experimental Pathology, Institute of Pathology, Division of Immunopathology, University of Bern, Bern, Switzerland; and ¶Division of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland.
Inflamm Bowel Dis. 2014 Dec;20(12):2340-52. doi: 10.1097/MIB.0000000000000235.
It is unknown why patients with extensive ulcerative colitis (UC) have a higher risk of colorectal cancer compared with patients with left-sided UC. This study characterizes the inflammatory processes in left-sided UC, pancolitis, and UC-associated dysplasia at the transcriptional level to identify potential biomarkers and transcripts of importance for the carcinogenic behavior of chronic inflammation.
The Affymetrix GeneChip Human Genome U133 Plus 2.0 was applied on colonic biopsies from UC patients with left-sided UC, pancolitis, dysplasia, and controls. Reverse transcription polymerase chain reaction and immunohistochemistry were performed for validating selected transcripts in the initial cohort and in 2 independent cohorts of patients with UC. Microarray data were analyzed by principal component analysis, and reverse transcription polymerase chain reaction and immunohistochemistry data by the Wilcoxon's rank-sum test.
The principal component analysis results revealed separate clusters for left-sided UC, pancolitis, dysplasia, and controls. Close clustering of dysplastic and pancolitic samples indicated similarities in gene expression. Indeed, 101 and 656 parallel upregulated and downregulated transcripts, respectively, were identified in specimens from dysplasia and pancolitis. Validation of selected transcripts hereof identified insulin receptor alpha (INSRA) and MAP kinase interacting serine/threonine kinase 2 (MKNK2) with an enhanced expression in dysplasia compared with left-sided UC and controls, whereas laminin γ2 (LAMC2) was found with a lower expression in dysplasia compared with the remaining 3 groups.
This study demonstrates pancolitis and left-sided UC as distinct inflammatory processes at the transcriptional level, and identifies INSRA, MKNK2, and LAMC2 as potential critical transcripts in the inflammation-driven preneoplastic process of UC.
与左侧溃疡性结肠炎（UC）患者相比，广泛性溃疡性结肠炎患者患结直肠癌的风险更高，原因尚不清楚。本研究在转录水平上对左侧UC、全结肠炎和UC相关发育异常中的炎症过程进行了表征，以确定潜在的生物标志物以及对慢性炎症致癌行为具有重要意义的转录本。
将Affymetrix GeneChip人类基因组U133 Plus 2.0应用于左侧UC、全结肠炎、发育异常的UC患者及对照的结肠活检组织。进行逆转录聚合酶链反应和免疫组织化学以验证初始队列以及另外2个独立UC患者队列中的选定转录本。通过主成分分析对微阵列数据进行分析，通过Wilcoxon秩和检验对逆转录聚合酶链反应和免疫组织化学数据进行分析。
主成分分析结果显示左侧UC、全结肠炎、发育异常和对照各自形成聚类。发育异常和全结肠炎样本的紧密聚类表明基因表达存在相似性。确实，在发育异常和全结肠炎的标本中分别鉴定出101个平行上调和656个平行下调的转录本。对其中选定转录本的验证发现，与左侧UC和对照相比，胰岛素受体α（INSRA）和丝裂原活化蛋白激酶相互作用的丝氨酸/苏氨酸激酶2（MKNK2）在发育异常中表达增强，而与其他3组相比，层粘连蛋白γ2（LAMC2）在发育异常中的表达较低。
本研究证明全结肠炎和左侧UC在转录水平上是不同的炎症过程，并将INSRA、MKNK2和LAMC2鉴定为UC炎症驱动的肿瘤前过程中的潜在关键转录本。
