Department of Medicine 1, University Hospital Erlangen, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research, Erlangen, Germany Max Eder Research Group supported by the German Cancer Aid, University Hospital Erlangen, Erlangen, Germany.
Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Erlangen, Germany.
Gut. 2016 Jul;65(7):1139-50. doi: 10.1136/gutjnl-2014-308227. Epub 2015 Apr 2.
IBDs have an increased risk for development of colorectal cancer (CRC). Here, we aimed at the characterisation of the functional role of Th17-associated transcription factors in sporadic and colitis-associated colon cancer in vivo.
We used mice deficient or transgenic for the activating protein 1 family member basic leucine zipper transcription factor ATF-like (Batf) to evaluate the role of Th17 cells during sporadic and inflammation-induced colon carcinogenesis. We also studied the expression of Batf and RORγt in patients with IBD and CRC.
Batf but not retinoic acid-related orphan receptor γt(RORγt) expression was significantly increased together with interleukin (IL) 23 expression in UC but not in Crohn's disease (CD) tissue samples. In CRC also Batf but not RORγt expression was increased and its expression correlated with the IL-23 and IL-23 receptor (IL-23R) expression. Finally, Batf but not RORγt was coexpressed with IL-17a, IL-23R and IL-6 within CRC-infiltrating CD4(+) T cells. Functional studies in mice revealed that Batf-dependent T cells are crucial regulators of sporadic and inflammation-induced CRC. Colitis-associated Batf(-/-) tumours lacked IL-17a(+)IL-23R(+)IL-6(+)CD4(+) T cells, hence displaying characteristics reminiscent of human CRC-infiltrating CD4(+) T cells. Strikingly, Batf(-/-) tumours contained low IL-23 but high IL-17a expression levels. Tumour formation and intratumoral IL-23 expression could be restored by administration of Hyper-IL-6 consisting of IL-6 and soluble IL-6 receptor.
Batf-dependent IL-23R(+)IL-6(+)CD4(+) Th17 cells critically control IL-23 driven colitis-associated tumour formation and the progression of sporadic colon tumours. Batf-dependent IL-23R(+) T cells represent a potential future therapeutic target limiting CRC progression.
IBD 患者发生结直肠癌（CRC）的风险增加。在此，我们旨在研究 Th17 相关转录因子在散发型和结肠炎相关结肠癌中的功能作用。
我们使用缺乏激活蛋白 1 家族成员碱性亮氨酸拉链转录因子 ATF 样（Batf）或转基因的小鼠来评估 Th17 细胞在散发型和炎症诱导的结肠癌发生过程中的作用。我们还研究了 Batf 和 RORγt 在 IBD 和 CRC 患者中的表达。
Batf 而非维甲酸相关孤儿受体γt（RORγt）的表达在 UC 中与白细胞介素（IL）23 表达显著增加，但在 CD 组织样本中没有增加。在 CRC 中，Batf 而非 RORγt 的表达增加，其表达与 IL-23 和 IL-23 受体（IL-23R）的表达相关。最后，Batf 而非 RORγt 与 CRC 浸润性 CD4（+）T 细胞中的 IL-17a、IL-23R 和 IL-6 共同表达。在小鼠中的功能研究表明，Batf 依赖性 T 细胞是散发型和炎症诱导的 CRC 的重要调节因子。结肠炎相关的 Batf（-/-）肿瘤缺乏 IL-17a（+）IL-23R（+）IL-6（+）CD4（+）T 细胞，因此表现出类似于人类 CRC 浸润性 CD4（+）T 细胞的特征。引人注目的是，Batf（-/-）肿瘤中 IL-23 的表达较低，但 IL-17a 的表达水平较高。肿瘤形成和肿瘤内 IL-23 表达可以通过给予由 IL-6 和可溶性 IL-6 受体组成的 Hyper-IL-6 来恢复。
Batf 依赖性 IL-23R（+）IL-6（+）CD4（+）Th17 细胞可显著控制 IL-23 驱动的结肠炎相关肿瘤形成和散发型结肠肿瘤的进展。Batf 依赖性 IL-23R（+）T 细胞代表了限制 CRC 进展的潜在未来治疗靶点。
